Name: LRP5

MIM number: 603506

Chromosomal location: 11q13.2.

Normal function: LRP5 is expressed by osteoblasts during osteogenesis and helps to transduce Wnt signaling, so as to properly regulate increase of bone-mass.

Mutations: Mutant LRP5 causes issues with bone-mass accrual during growth, resulting in individuals with osteoporosis-like symptoms despite not being of an elderly age.

Beneficial Variants: A gly171-to-val mutation in LRP5 causes an autosomal dominant variant called G171V that can result in bone-mass hypertrophy, resulting in increased bone-mass and thickness. Reducing fracture-risk.

Modification: In principle, LRP5 can be gene edited, since scientists have knocked out LRP5 genes in healthy mice. So if the gene can be targeted and deactivated, I think that means it should be possible to repair it with CRISPR?

Ethical Implications: You could eliminate this genetic disease in those afflicted, bringing them back up to baseline. Or you could actively modify the gene to naturally increase bone density in baseline individuals to enhance them. There is a possibility of reducing osteoporosis risk in old-age, enhancing quality of life.

Unintended Consequences: Being too heavy to swim? 

Definition of Improvement: I define this as an increase in any "stat" that would be "natural" from birth. E.g. if someone is born with cystic fibrosis then genetically modifying them to not have cystic fibrosis is considered an improvement. 

Kate Chiuh

Dioquino Jazlene Pearl Uminga

Disease: Colorectal Cancer

Gene: BUB1

MIM number: 114500

Gene name: BUB1 mitotic checkpoint serine/threonine kinase

Chromosomal location: 2q13

Normal function of the gene: Establishes a mitotic spindle checkpoint and chromosome congression; Helps preserve chromosomal stability

Mutations associated with the disease: Defects in BUB1 checkpoint allows premature mitotic exit, which causes aneuploidy

As it is a mutation, it can be solved with gene editing techniques.

Ethical implications: The editing of the gene could affect other genes on the locus. It can lead to unintended consequences, such as the suppression of certain genotypes or the cause of other diseases. It can also lead to more tumour formation and thus cause more cancers.

Editing suggestion: Using exon-knockout to remove the mutated areas of the BUB1 gene to study the gene without those areas of the exon and check if there is an upregulation without the mutated areas present. After the exon is removed, there can be a check done to see if there are similarities to other species and if those exons could be transferred to the BUB1 gene using mouse models. This could also help to check if the BUB1 gene is still able to restore partial function.

Beta thalassemia

2. Identify at least one gene associated with the condition.

A mutation in the beta-globin gene (HBB; 141900) on chromosome 11p15

3. Record the MIM number, gene name, and chromosomal location.

   
   

   
   

   Step3 Analyze the Gene

   
   

   1. What is the normal function of the gene?

   Transport oxygen

   
   

   2. What mutations are associated with disease?

   Sickle cell disease (e.g., HbS variant)
   Beta-thalassemia (reduced or absent beta-globin production)
   Other hemoglobinopathies

   
   

   3. Are there known beneficial variants?

   The HbS variant results from a single-point mutation in the HBB gene (Glu6Val). People who are heterozygous have sickle cell trait, not the disease which improves survival in malaria borne areas

   Beta thalassemia minor (one mutant allele) also helps increase survival of malaria.

   
   

   4. Could gene editing (e.g., CRISPR) be used to correct or enhance this gene?

   Yes gene editing may be used to correct/enhance this gene by correcting the point mutation in HBB using CRISPR-Cas9

   Another method may be to use CRISPR-Cas9 to disable the BCL11A gene, which allows the fetal haemoglobin HbF to continue to be produced and not switched over to Hba. 

   
   

   Step 4: Ethical Reflection

   
   

   1. What are the ethical implications of editing this gene?

   The problem with editing any gene is always the germline editing and if it is ethical since embryos will not be able to give consent, may potentially have unintended mutations after birth which may affect their quality of life and lead to other problems like socio-economic problems where this technology may only be available for the wealthy.

   
   

   2. Could this lead to unintended consequences?

   Yes it may create more socio-economic divide in the society on who could use this technology

   It could also cause unintended mutations for the lifeform.

   
   

   3. How do we define “improvement” in this context?

   When the quality of life has drastically been made better for the individual/lifeform.

   Lesser of the harmful gene in the population

   
   

Gene associated is GYG1

MIM number: 603942

Gene name: glycogenin 1

Chromosomal location: 3q24

The normal function of the gene is to initiate glycogen synthesis through autoglycosylation whereby a glucose subunit attaches to glycogenin, acting as a primer for glycogen synthesis. 

What mutations are associated with disease?

The mutation of guanine to cytosine transversion (c.143+3G-C) in intron 2 of GYG1 gene resulted in aberrant splicing and causes frameshift (Asp3GlufsTer4). 

A heterozygous mutation, c.970C-T transition in exon 8 which results in arg324 to ter substitution and splice site mutation. 

A heterozygous mutation, c.304G-C transversion in exon 4 which results in asp102 to his substitution. A c.749G-A transition in exon 6 resulting in trp250 to ter substitution.

A homozygous 1 bp deletion in exon 5 of the gene which resulted in frameshift and premature termination.

Are there known beneficial variants?

There are no beneficial variants of GYG1. 

Could gene editing (e.g., CRISPR) be used to correct or enhance this gene?

Yes. Base editing which could remove or modify the splice site could help to restore the correct mRNA splicing. For example, it could correct the mutation of guanine to cytosine transversion (c.143+3G-C) in intron 2 of the gene. 

Gene replacement could also be made by introducing the normal GYG1 gene using adeno-associated virus (AAV) if gene editing is not possible. 

What are the ethical implications of editing this gene?

If germline gene editing is done, it will alter heritable genes which is not ethical to do so. There may be long-term effects or consequences and future generations may not have consent for any gene editing. 

Enhancement gene editing may lead to unfairness since it may increase muscle strength. It will be more ethically controversial. 

Could this lead to unintended consequences?

Athletes may take use of this enhancement which may result in unfairness in competitions if their muscle strength is greater than normal.

How do we define “improvement” in this context?

When polyglucosan accumulation is reduced, slowing down the progression of disease. 

When people are able to walk independently which will improve their quality of life.

done by: Guan Hui Thong

MIM number: 300278

Chromosomal location: Xp11.4

Normal function: Encodes for nyctalopin which is a component required for the synaptic function of retina during low light situations.

Mutations associated with disease: A 24 base pair deletion results in the loss of 8 amino acids from the N-terminal cysteine cluster of nyctalopin, resulting in the disease.

Beneficial variants: Currently no known beneficial variants.

Possibility of correction: Gene editing techniques should be able to correct the defective gene through base pair insertions into germ cells during embryonic development, and reduces the heritability of the disease.

Ethical reflection: We can define the improvement as the absence of burden from the existing disease in this context. While this simple gene edition could drastically improve the lives of an individual and subsequent generations, the idea of editing one's DNA which will then affect the subsequent generations, can definitely push the line of what is acceptable in society. If this line were to be blurred, the limits of gene editing seems endless yet frightening, to the point humans may not even be considered as just one species, but rather a collection instead.

gene name: CHRM3

chromosomal location: 1q43

• What is the normal function of the gene?

codes for a protein which functions as a GPCR to acetylcholine for smooth muscle contraction, and when stimulated, causes secretion of glandular tissue. in the urinary tract, it is important for the bladder muscle contraction.

• What mutations are associated with disease?

homozygous mutation leading to loss-of-function

• Are there known beneficial variants?

it is not well-established, but psuedo prune belly syndrome (PPBS) may result in a better prognosis for renal function.

• Could gene editing (e.g., CRISPR) be used to correct or enhance this gene?

Possibly yes, by editing the mutation to the correct one

• What are the ethical implications of editing this gene?

it could affect other genes because it is expressed in multiple organ systems. e.g. vision problems, chronic diarrhoea

• Could this lead to unintended consequences?

yes

• How do we define “improvement” in this context?

since prune belly syndrome has a spectrum of varying effects, improvement has to be patient-centric, addressing their individual effects appropriately.

Gene name: D4Z4

Chromosomal location: 4q35

MIM Number: 158900

What is the normal function of the gene? - The D4Z4 region of Chromosome 4 consists of 11 to more than 100 repeat segments. Normally, the entire D4Z4 region is hypermethylated, meaning that the genes are silenced (turned off).

What mutations are associated with disease? - The disease occurs when the D4Z4 region is abnormally shortened (contracted), containing between 1 and 10 repeats instead of the usual 11 to 100 repeats. As a result, the D4Z4 region becomes hypomethylated. Hypermethylation of the D4Z4 region normally keeps a gene called DUX4 silenced in most adult cells and tissues. The DUX4 gene is located in the segment of the D4Z4 region closest to the end of chromosome 4. In people with facioscapulohumeral muscular dystrophy, hypomethylation of the D4Z4 region prevents the DUX4 gene from being silenced in cells and tissues where it is usually turned off. Although little is known about the function of the DUX4 gene when it is active, researchers believe that it influences the activity of other genes, particularly in muscle cells. It is unknown how abnormal activity of the DUX4 gene damages or destroys these cells, leading to progressive muscle weakness and atrophy.

Are there known beneficial variants? - No.

Could gene editing (e.g., CRISPR) be used to correct or enhance this gene? - Yes, CRISPR can be used to knock-in more repeat sequences in the D4Z4 region, in order to silence the DUX4 gene and hence prevent FSHD1.

Ethical Reflections:

What are the ethical implications of editing this gene? - There are little to no negative ethical implications, because editing of the gene is done to restore the gene back to its natural (normal) state.

Could this lead to unintended consequences? - Maybe, the function of DUX4 gene is still largely unknown.

How do we define “improvement” in this context? - Restoration of the gene back to its natural state which removes the disease from the afflicted individual. They will now have healthy muscles that allow them to have a better quality of life.

Gene Name: Collagen Type V Alpha-1 (COL5A1)

Chromosomal Location: 9q34.3

What is the normal function of the gene?

The gene codes for type V collagen, which plays a fundamentally role in fibrillogenesis, potentially by forming the core within fibril threads.

What mutations are associated with disease?

Heterozygous mutations can cause diseases such as Ehlers-Danlos syndrome I and multifocal fibromuscular dysplasia.

Are there known beneficial variants?

Certain variants of the gene have been associated to better athletic performance due to an inherited increased resistance against soft tissue injury.

Could gene editing be used to correct or enhance this gene?

In theory, CRISPR could be used to repair a defective COL5A1 gene. However, the gene is expressed in manmy tissues throughout the body, and thus delivery of CRISPR repaired copies of the gene is a challenge. Castle Creek Bioscience and Mayo Clinic are currently running clinical trials to administer healthy COL5A1. CRISPR technology has been shown to restore the function of the similar COL1A1 gene (the mutation of which causes osteogenesis imperfecta), and thus similar techniques may be used on the COL5A1 gene.

What are the ethical implications of editing this gene?

COL5A1 and other collagen genes are expressed all throughout the body in connective tissues. Thus, tampering with genes that express collagen could lead to heritable effects on mobility. Furthermore, the widespread expression of the gene complicates gene therapy treatments, which translates to higher costs. Accessibility, therefore, becomes another issue. Would it be ethical for only the richest to have access to life-saving gene editing therapies?

Could this lead to unintended consequences?

Yes. As mentioned previously, COL5A1 and other collagen genes are widely expressed and play major roles in connective tissue function. Slight edits could have large implications in mobility,

How do we define "improvement" in this context?

Improvement in this case would be defined as better quality of life for the affected patients in the form of decreased chronic pain and better mobility.

Malabanan Alden Bryle Malones

Gene name: LDHD

Chromosomal location: 16q23.1

Normal function of gene: interact specifically with the LIM domain protein CRP3

Mutations associated with the disease: homozygosity for 2 different missense mutations, T463M (607490.0001) and W374C (607490.0002)

Known beneficial variants: NIL

Could gene editing be used to correct/enhance this gene?

• Introduction of human wildtype LDHD in ldhd-knockout zebrafish with elevated D-lactate excretion could rescue the phenotype, whereas LDHD with either of the missense variants could not

What are the ethical implications of editing this gene?

• Risk of off-target effects: Gene editing tools (like CRISPR-Cas9) can accidentally modify other genes, possibly worsening gout and affecting kidney function, triggering new metabolic disorders.

• Unknown interactions: Correcting D-lactic aciduria might change purine metabolism pathways, potentially worsening uric acid buildup.

Could this lead to unintended consequences?

• Yes, as mentioned above.

How do we define "improvement" in this context?

• Sharing all risks, uncertainties and monitoring results openly

By Yap Rui Ting (U2340603J)

MIM Number: 607876

Gene associated: STARD7

Chromosomal location: 2q11

Normal function: STARD7 belongs to the STARD2 subfamily of steroidogenic acute regulatory protein-related lipid transfer (START) domain proteins. These proteins transfer phospholipids among intracellular membranes, specifically, facilitating phosphatidylcholine (PC) transfer to mitochondria.

Mutations associated: a heterozygous 5-bp repeat expansion, (ATTTC)n, in intron 1 of the STARD7 gene. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat, which the authors noted is a similar molecular finding in other forms of FAME (Corbett et al. (2019)).

Any known beneficial variants: None

Gene editing: CRISPR-Cas9 could be used to remove/delete the additional repeat expansions in intron 1 of the STARD7 gene.

Ethical implications and unintended consequences: As it is an autosomal dominant disease, it may raise concerns of the gene editing causing other birth defects or potentially affecting heritable traits. Additionally, the most efficient way of preventing the disease in future generations is germline editing, which is still under debate due to ethical and social concerns over the risk/benefit factor.

Improvement: Further research in the effects/risks and benefits of germline editing, and refinement of CRISPR-Cas9 precision.

• By: Li Jiaxing

Gene name: LCT gene

MIM number: 603202

Chromosomal location: 2q21.3

Normal function:

LCT gene encodes for lactase-phlorin hydrolase (LPH), which mainly catalyse the hydrolysis of lactose (a sugar found in milk) into glucose and galactose

Mutations associated:

Congenital lactase deficiency is associated with mutations in the coding regions of lactase-phlorin hydrolase (LPH). A common example is the Fin mutation, whereby patients are homozygous for a stop codon at Tyrosine 1390 (Y1390X), resulting in nonsense mutation forming a truncated protein. This mutation can also be found in a compound heterozygote pattern of inheritance with either R1587H or V565fsX567. Other mutations, such as S1666fsX1722 and S218fsX224, resulted in a frameshift mutation and a premature stop codon or an amino acid substitution mutation (Q268H and G1363S). Two more mutations were also identified, one resulting in an amino acid substitution S688P and another in a stop codon E1612X.

Known beneficial variant:

None in LCT coding region. Even though lactase persistance which is beneficial can occur with variants in MCM6 gene, this is not relevant to LCT gene.

Gene editing:

Yes, gene editing like CRISPR can help to correct pathogenic variants in LCT in intestinal stem cells, ensuring the small intestine has sufficient LPH to hydrolyse lactose.

Ethical implications:

Pro: Beneficial because gene editing can prevent life-threatening complications of the infant and increase its survival chances

Con: Controversial because of potential for misuse and safety concerns regarding the embryos

Unintended consequences:

Gene editing of LCT may cause disruptions in the production of other enzymes in the small intestine, resulting in other health issues arising

Improvement:

Defined as restoration of normal infant lactase activity to digest lactose, allowing for normal breastfeeding and consumption of formula milk

Tan Jia Wen (U2340428K)

Gene name: PTEN-INDUCED KINASE 1; PINK1

Gene MIM number: 608309

Chromosomal location: 1p36.12

What is the normal function of the gene?

PINK1 is associated with the mitochondria and it may phosphorylate mitochondrial proteins in response to cellular stress, protecting against mitochondrial dysfunction. It is an essential pro-survival factor of mitochondria in the face of pathologic oxidative stress, as well as a downstream modulator of the anti-oxidative stress functions of the family of FOX transcription factors. It is also important for the activation of mitophagy to remove damaged mitochondria. 

 What mutations are associated with disease?

The  G309D PINK1 mutant is a 11185G-A transition in exon 4 of the PINK1 gene, resulting in a gly309-to-asp substitution at a highly conserved position in the putative kinase domain of the PINK1 protein. The inheritance of this mutation is autosomal recessive and it causes decreased mitochondrial membrane potential under stress conditions.

Another mutation is the R246X mutation where there is a 736C-T transition in exon 3 of the PINK1 gene, resulting in an arg246-to-ter substitution. The mutation was predicted to result in a truncated protein lacking 336 amino acids, including a highly conserved protein kinase domain.

Are there known beneficial variants?

No

Could gene editing (e.g., CRISPR) be used to correct or enhance this gene?

Yes. CRISPR-Cas9 could be used to edit the gene such that the mutation is reverted back to the normal sequence. As the mutations usually are only point mutations, only one nucleotide would have to be corrected, making the correction back to the original using CRISPR-Cas9 to be easier. Furthermore, the mutations are usually autosomal recessive, so only one copy of the gene would have to be edited back to normal for the disease to potentially be prevented.

What are the ethical implications of editing this gene?

As different families or individuals across the globe have different disease causing mutations associated with the PINK1 gene, genome sequencing and genotyping of the individuals or families must be done. Specific CRISPR-Cas9 treatments must be developed. This would increase the cost of the gene editing which could increase inaccessibility for people of lower income status. This might thus increase inequality in access to treatment.

Could this lead to unintended consequences?

It is possible that even after gene editing and the person becomes heterozygous for the mutation, the person might still develop the disease as the PINK1 gene interacts with other mutated genes that can cause the disease.

How do we define “improvement” in this context?

Improvement would be the ability to prevent more people from having Parkinson disease and thus seeing a decrease in the number of parkinson disease and early onset parkinson disease overall.

Kelly Loh Cheng Mun

Done by: Alicia Twan Ying Xuan

Gene Name: LCT

Location: 2q21.3

What is the normal function of the gene?

• LCT encodes for lactase which breaks down lactose into galactose and glucose which are then absorbed in the small intestine

What mutations are associated with the disease?

• Lactose intolerance is not a disease

• There are no mutations related to this. This occurs naturally where there is a decrease in LCT expression after weaning due to a decrease in affinity of transcription factor to MCM6 enhancer

Are there known beneficial variants?

• Lactose persistence is the beneficial variant

• Where the regulatory region MCM6 located upstream of LCT contains a mutation. This causes persistent strong affinity of transcription factors to enhancer region of MCM6, allowing high expression of LCT

• This allows high expression of LCT, lactase present to digest and break down lactose. Hence adults are able to consume dairy products such as milk to attain nutrients such as calcium which serves as a benefit for survival. For instance, decrease the probability of having osteoporosis at an old age.

Could gene editing (eg CRISPR) be used to correct or enhance this gene?

• Yes. By targeting the MCM6 regulatory region to introduce a lactase persistence allele

What are the ethical implications of editing this gene?

• Since lactose intolerance isn't life threatening, it would be seen as a waste of resource to invest in

• Only advantages in places where there is heavy dairy consumption

Could this lead to unintended consequences

• CRISPR could potentially cause mutations in other regions of DNA and might even result in cancer

• The regulation of lactase expression is not fully understood, editing the regulatory region MCM6 might disrupt other pathways

How do we define "improvement" in this context?

• Able to digest milk more efficiently

• Only seem like an improvement for those in places where dairy products are consumed frequently

• Less symptoms such as diarrhoea and bloating

• If we were to consider lactase persistence as an "improvement", this would indicate that the ancestral state of lactose intolerance is "defective"

Done by Chong Ming Hui Kylie

MIM number:

Phenotype MIM: 114480

Gene/Locus MIM: 600185

Gene name: BRCA2

Chromosomal location: 13q13.1

Gene Analysis

• What is the normal function of the gene?

BRCA2 acts as a tumour suppressor gene which produces the BRCA2 protein, whose function is involved in DNA repair.

• What mutations are associated with disease?

BRCA2 is one of the main genes associated with breast cancer, it can increase a person’s lifetime risk of breast and even other cancers.

• Are there known beneficial variants?

BRCA2 mutations are rare in the general population and many variants are of unknown significance and there are very few clearly identified beneficial variants of BRCA2.

• Could gene editing (e.g., CRISPR) be used to correct or enhance this gene?

Yes, CRISPR is able to correct the mutated BRCA2 gene by cutting out the mutation and using a healthy BRCA2 sequence as a template to repair the mutation via HDR (homology directed repair)

Ethical Reflection

• What are the ethical implications of editing this gene?

CRISPR editing for the BRCA2 gene has only occurred ex vivo, and currently it is not yet safe for in vivo use. However, if technology becomes reliable, fixing the BRCA2 mutations could prevent many deaths and suffering from breast cancer, which is one of the most prevalent types of cancer in the world.

• Could this lead to unintended consequences?

Usage of CRISPR editing may cause off-target effects and introduce new diseases or risks.

• How do we define “improvement” in this context?

Improvement would be defined as the correction of the BRCA2 mutation which reduces breast cancer occurrence and associated death in the society, increasing life expectancy.

Nadia Firdaus (U2340911E)

MIM: 613004

Chromosomal location: 4p16.3

What mutations are associated with disease? 

Huntington’s disease is an autosomal dominant progressive neurodegenerative disorder caused by a heterozygous expanded CAG repeat in the huntingtin (HTT) gene. This results in an abnormal expansion of a glutamine stretch in the N-terminal of the protein. In healthy individuals, the trinucleotide sequence is repeated 9 to 36 times, with an average median of between 17 and 20 repeats. In those with HD, the repeat number is ≥ 37. The severity of the disease and age of onset is correlated with the number of CAG repeats. The disease is characterised by progressive chorea, rigidity, and dementia. The average age of onset is placed at 40 years. 

What is the normal function of the gene? 

The huntingtin protein (HTT) is ubiquitous at both tissue and subcellular levels, and found in several mammal species. Its expression is higher in the nervous system than other tissues. Expression of HTT begins in embryonic development and persists into adulthood. 

The functions of HTT have mainly been determined through studying its interactions with various other proteins (~350 proteins have been found to interact with wild-type HTT). It has so far been identified to play a role in transcription, RNA splicing, endocytosis, trafficking, and cellular homeostasis. Other interactions, although not fully understood yet, implicate HTT in several cellular pathways, including those related to cellular dynamics (cytoskeleton, endocytosis, trafficking, and adhesion), metabolism, protein turnover, and gene expression (transcription and RNA processing). Due to this, it has been postulated that HTT is a molecular scaffold or “hub” that facilitates several key cellular functions. 

Definitive functions of wild-type HTT on a molecular level include vesicle-trafficking, coordination of cell division, regulation of ciliogenesis, mediation of endocytosis, and regulation of transcription. 

Are there known beneficial variants? 

Research suggests that longer CAG tracts below the pathogenic threshold increase neurogenic potential and alter transcription networks responsible for neuronal function. 

Could gene editing be used to correct or enhance this gene?

Yes, it is likely that using CRISPR-Cas9 or another gene editing technology to reduce the number of CAG repeats in the genes of affected individuals would allow for expression of wild-type HTT and prevent onset of the disease. Furthermore, it is possible that it could be advantageous to insert further repeats below the pathogenic threshold in healthy individuals to increase neural functioning and intelligence.

What are the ethical implications of editing this gene? 

Huntington disease has a frequency of 5 to 10 per 100,000 persons in the Caucasian population. Given its nature as an autosomal dominant trait, an affected individual will always pass the trait down to their children. By editing the gene, the propagation of the disease could be prevented, and the affected individuals would be able to live longer, healthier, and happier lives. However, it must be considered that editing the gene would be incredibly difficult as it is ubiquitous in all tissues, therefore any editing would likely have to occur in embryonic development, which makes the treatment by gene editing preventative rather than a cure for anyone already suffering from the condition. There is also the question of who would be able to afford (both financially and otherwise) going through such a rigorous and intensive process. 

Could this lead to unintended consequences? 

An unintended consequence could be the desire for healthy individuals to edit the genes to insert further CAG repeats below the pathogenic threshold to enhance their or their children’s intelligence. It could move into the territory of “designer babies” and the beginnings of normalising eugenicist ideas. 

How do we define “improvement” in this context?

Huntington’s is a horrible disease that causes much pain to those affected and their loved ones, not only physically, but emotionally as well. Affected individuals are unlikely to want to have children due to the guarantee of passing down the disease, and the relatively early onset means that many years of their life is lost to disease. By editing the gene to prevent the onset, affected individuals will not manifest painful symptoms and would be able to live long, happy, fulfilling lives. 

Daniella Homan (U2440809L)   

gene associsiated: somatic changes in several genes, including OPCML, PIK3CA , AKT1 , CTNNB1, RRAS2 , CDH1 , ERBB2 , and PARK2 .

MIM number:167000

chromosomal location: 3q26.32

normal function: encodes the catalytic subunit p110α of the phosphoinositide 3‑kinase (PI3K) enzyme which plays a critical part of the PI3K/AKT signaling pathway by regulating xell growth and proliferation, survival ,anti-apoptosis and metabolism

mutation related:

E545K (glutamate → lysine at codon 545)

somatic E545K mutation gain-of-function mutation leading to hyperactivation of the PI3K/AKT signaling pathway, promoting uncontrolled proliferation.

known beneficiary variant: no known beneficial variants described

could gene editing be used to correct or enhance this gene:

yes, by correcting pathogenic mutations like E545K. for instance: converting lysine back to glutamate in somatic tumor cells

ethical implications of editing this gene:

• Could this lead to unintended consequences?

  Targeting a cancer-causing mutation can possibly treat life threatening disease but editing somatic tumor cells can lead to unintended consequences like potentially causing genomic instability, worsening the situation

How do we define “improvement” in this context?

if improvement is defined as we aiming to cure the cancer, it can be hard.However if the improvement is aiming to reduce tumor burden, or prolong survival, we might be able to do so. When people are less likely affected by cancers, this can suggest that there is indeed an improvement.

LEE LE YAO WEEK 1 OVARIAN CANCER

Gene name: PAX8

MIM number: 218700

Chromosomal location: 2q14.1

Normal function: In the thyroid, the PAX8 gene is essential for the formation of thyroxine-producing follicular cells. It encodes for PAX8, a transcription factor involved in thyroid development. 

Mutations associated: Heterozygous mutation in the PAX8 gene causes amino acid substitutions in the PAX8 protein thereby reducing its capability for DNA-binding. This results in abnormal thyroid development, also known as thyroid dysgenesis. In these cases, the thyroid gland can be absent (agenesis), ectopically located, and/or severely reduced in size (hypoplasia). Congenital hypothyroidism can cause severe neurologic, mental, and motor damage.

Known beneficial variants: There is a benign polymorphic variant that involves a mutation in the C-terminal portion of PAX8, which is outside the paired domain. However, there are no known beneficial variants that affect the paired domain, which is responsible for DNA binding of PAX8. 

Use of CRISPR to correct or enhance this gene: CRISPR could potentially be used to correct pathogenic PAX8 mutations, such as ARG108TER or CYS57TYR, by replacing the defective nucleotide with the wildtype sequence using homology-directed repair. While enhancement of PAX8 expression is theoretically possible through CRISPR activation, this approach is highly experimental and carries risks.

Ethical implications of editing this gene: This includes concerns about germline modifications affecting future generations, issues of consent, and the potential for unequal access to such treatments. 

Unintended consequences: Yes, they could arise from off-target edits, developmental effects on the thyroid or kidneys, and variable interactions with other genes, potentially producing unexpected phenotypes.

How do we define “improvement” in this context?: The restoration of normal thyroid development and hormone production, leading to increased survival, growth, and reproductive fitness, rather than enhancement beyond normal function.

AME BOONWIWAT (U2240912L)

MIM No.: 300377

Chromosomal location: Xp21.2-p21.1

Normal function: Confers instructions for synthesizing the dystrophin protein (involved in skeletal muscular movement and in cardiac muscles)

Mutations: Deletion (mainly), duplication and point mutations of the DMD gene

Known beneficial variants: NIL

Gene editing: Gene editing systems, such as CRISPR-Cas9, could be capable of treating or preventing these mutations. Current therapeutic treatments involve "skipping" the mutated sequence in the exon to restore accurate dystrophin synthesis. CRISPR-Cas9 could aid in this exon-skipping and provide non-mutated reading frames for accurate downstream dystrophin synthesis.

Ethical implications & unintended consequences: Editing the DMD gene could cause harmful and irreversible long-term effects, as off-target mutations and unintended protein syntheses changes may pose as potential side effects. Additionally, gene editing could be inherited by future generations, along with their harmful side effects.

"Improvement": Although these side effects pose as a risk to patients receiving this treatment, DMD patients are at risk of suffering poor quality of life (QOL) and possibly even a shortened life span, with many suffering from myocardial dystrophy as their lives progress. Gene editing may provide a glimmer of hope in "improving" these patients' QOL.

-            APOE  (Apolipoprotein E)

-            A major function of apoE is to mediate the binding of lipoproteins or lipid complexes in the plasma or interstitial fluids to specific cell-surface receptors. 

-            APOE has several alleles.

-            APOE ε3, the most common allele, is believed to have a neutral effect on the disease.

What mutations are associated with disease?

-            APOE ε4 increases risk for Alzheimer’s and is found to be associated with an earlier age of disease onset in certain populations.

Are there known beneficial variants?

-            APOE ε2 may provide some protection against the disease. If Alzheimer’s occurs in a person with this allele, it usually develops later in life.

Could gene editing (e.g., CRISPR) be used to correct or enhance this gene?

• CRISPER editing could be used to reduce the expression of APOE ε4

• Use of base editing could be used to convert APOE ε4 to APOE ε3 or APOE ε2

Step 4: Ethical Reflection

What are the ethical implications of editing this gene?

-            Editing would raise questions of equality as the technology is costly and potentially only available to the wealthy.

Could this lead to unintended consequences?

-            APOE ε2 is linked to a higher risk of cerebral amyloid angiopathy and type III hyperlipoproteinemia despite offering protective effects against Alzheimer's Disease.

How do we define “improvement” in this context?

-            Increased Darwinian fitness

-            Increase cognitive and physical abilities

-            Longer lifespan

References:

1.       https://pmc.ncbi.nlm.nih.gov/articles/PMC4253862/

2.       https://www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/alzheimers-disease-genetics-fact-sheet

Gene name: NOD2 (NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 2)

Chromosomal location: 16q12.1

Normal function of the gene:

The NOD2 gene encodes a protein that is expressed in immune cells such as macrophages and dendritic cells.

Its primary function is to detect muramyl dipeptide (MDP) of the invading bacteria's cell walls.

Once recognition occurs, NOD2 activates inflammatory signaling pathways such as NFKB, initiating appropriate immune responses to combat invading bacteria.

It also plays a crucial role in maintaining the stability of the intestinal mucosal barrier and in promoting tolerance to the gut microbiota.

Mutations associated with the disease:

The main ones are single nucleotide polymorphism that result in a loss of function. The three major risk SNPs are R702W, G908R, and 1007fs (Croucher et al., 2003).

Normally, NOD2 functions to properly recognize bacteria and regulate immune responses. Mutations impair this function, preventing the body from effectively detecting and responding to gut bacteria. This dysfunction leads to immune dysregulation—either excessive inflammation against harmless gut microbes or an inability to clear harmful bacteria. The end result is chronic, destructive intestinal inflammation.

Known beneficial variants:

N/A

Gene editing for correction/enhancement:

Technically challenging and ethically complex.

Crohn’s disease is polygenic, activation of NOD2 gene alone requires multiple other genes such as RIPK2, PI3K, and ATG5 etc, editing just NOD2 may not be enough to prevent or cure the condition. In addition, NOD2 has complex roles in the immune system, simply “fixing” it could disrupt immune balance, potentially leading to other issues such as increased susceptibility to infections or autoimmune diseases.

Ethical Implications:

The ethical implications of editing the NOD2 gene are complex. Since NOD2 variants increase susceptibility rather than directly causing disease, the necessity of such an intervention is difficult to justify—many carriers of risk alleles never develop Crohn’s disease. Moreover, because environmental factors such as diet, stress, and the gut microbiome play a critical role, it may be more reasonable to prioritize lifestyle and environmental interventions over pursuing high-risk genetic editing. Finally, questions of resource allocation arise: given the technical difficulty and enormous cost of gene editing, is it fair to dedicate significant resources to such approaches for Crohn’s disease, when those same resources could be directed toward broader improvements in public health and healthcare access?

Unintended: consequences:

Editing such gene can possibly lead to immune system imbalance. Force to enhance such immune-related gene might increase susceptibility to autoimmune diseases such as rheumatoid arthritis or lupus.

Improvement definition:

It is difficult to define "improvement" in such context. If everyone’s NOD2 gene were “edited” into a so-called “optimal version,” it could significantly reduce the diversity of the human immune system, making us more vulnerable to future emerging infectious diseases.

If, however, the edition succeeded and would give only benefits to the edited individuals, major societal consequences may arise.

References:

Croucher, P. J. P., Mascheretti, S., Hampe, J., Huse, K., Frenzel, H., Stoll, M., Lu, T., Nikolaus, S., Yang, S.-K., Krawczak, M., Kim, W. H., Schreiber, S. Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations. Europ. J. Hum. Genet. 11: 6-16, 2003.

Cooney, R., Baker, J., Brain, O., Danis, B., Pichulik, T., Allan, P., Ferguson, D. J. P., Campbell, B. J., Jewell, D., Simmons, A. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Med. 16: 90-97, 2010.

Gene MIM Number: 607252

Gene name: APOL2

Chromosomal location: 22q12.3

The normal function of the gene:

APOL2 gene is a member of the apolipoprotein L genes and expresses Apoloprotein L2 (APOL), which plays a central role in cholesterol transport. Cholesterol content is important in modulating gene transcription and signal transduction in developing brains as well as adult brains. In addition, APOL2 was found to be involved in endothelial function and may contribute to lipid regulatory pathways.

What mutations are associated with disease:

For APOL2, mainly single polynucleotide polymorphisms were found to cause an increase in upregulation of the gene. However, the disease itself is complex, and the associated genes are not very well researched, so the specifics are unclear. Other genes that were found to be associated with schizophrenia may have deletions, such as in the NTN4R gene.

Are there known beneficial variants:

No

Could gene editing (e.g., CRISPR) be used to correct or enhance this gene:

Theoretically possible via CRISPR-cas9 to target the SNP. However, practically it isn't very, since schizophrenia is a highly polygenic disease caused by a large number genes and a huge number of common variants, and just targeting APOL2 alone isn't likely going to make a significant impact.

What are the ethical implications of editing this gene?

Schizophrenia is affected by multiple genes as well as the environment, so the risk that comes with editing this gene may not be worth it especially if it's after birth, since we would have to specifically target cells in the brain, and crossing the blood-brain barrier is a huge challenge. Germline editing is illegal as well, with issues such lack of consent and unknown long-term effects. The knowledge of the disease and the genes involved is too low to obtain a justifiable level of success.

Could this lead to unintended consequences?

The role of APOL2 itself is not well researched, so editing the gene may cause unknown side effects, and CRISPR may cause off-target edits. Plus, neurons and cells in the brain don't regenerate, so any damage done when gene-editing would be permanent.

How do we define “improvement” in this context?

When the number of people and their children who develop the disorder decreases, or when most development of the disorder becomes on the lower end of the spectrum which makes it more manageable

Tan Liang Xuan

Gene name: BCKDHA

Chromosomal location: 19q13.2

What is the normal function of the gene?

BCKDHA encodes for the E1-alpha subunit of the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex. The BCKD enzyme complex is responsible for the oxidative decarboxylation of branched-chain amino acids (BCAAs).

Mutations in the BCKDHA gene result in the inability to effectively break down BCAAs such as leucine, isoleucine and valine (which are found in proteins), causing a buildup of amino acids in the body, leading to symptoms of the MSUD.

What mutations are associated with the disease?

Mutations associated with the disease are point mutations- particularly missense mutations. In the Old Order Mennonite population, where the disease occurs frequently, The BCKDHA gene has a mutation where the amino acid Tyrosine is replaced by Asparagine at position 438 (Tyr438Asn or Y438N).

Are there known beneficial variants?

No beneficial variants are currently known.

Could gene editing (eg. CRISPR) be used to correct or enhance this gene?

Yes, in theory, gene editing, particularly prime editing would be able to precisely swap the Asn amino acid with the Tyr without the need for a double stranded break, and correct the single point mutation in the gene.

Reflections:

What are the ethical implications of editing this gene?

Editing this gene would prevent severe neurological impairment, improve the quality of life and eliminate the need for lifelong dietary restrictions for individuals with the disease. However, as classic MSUD is typically observed in the first week of life, it raises ethical concerns about gene editing treatments in newborns, such as consent, the risks of editing at an early age and also the potential misuse of gene editing beyond therapy.

Could this lead to unintended consequences?

Yes. Off-target edits may lead to new diseases due to the disruption of other essential genes.

How do we define "improvement" in this context?

In this case, improvement would mean correcting the mutation to prevent toxic buildup, allowing an improved quality of life for individuals with the disease to allow them a chance into adulthood without lifelong dietary restrictions.

Aghnia Taib (U2340156J)

Identify  at least one gene associated with the condition.

The Niemann-Pick disease (Type C1) is often associated with NPC1 and NPC2 genes, more commonly with the former. 

 Record the MIM number, gene name, and chromosomal location.

NPC1 gene

MIM number: 257220

Chromosomal location: 18q11.2

NPC2 gene

MIM number: 257220

Chromosomal location: 14q24.3

Step 3: Analyze the Gene

What is the normal function of the gene?

Both NPC1 and NPC2 genes play a role in egressing lipids (primarily cholesterol) from late endosomes or lysosomes. Identical biochemical patterns suggest a coordinated mechanisms between the two. 

1. The NPC1 gene encodes a large transmembrane glycoprotein, primarily located in late endosomes.

2. The NPC2 gene plays a more prominent role in the cellular post-lysosomal/ late endosomal transport of cholesterol, glycolipids and others. 

   
   

 What mutations are associated with disease?

The Niemann-Pick type C is caused by mutations in either the NPC1 (type C1) or NPC2 genes (type C2).

 Are there known beneficial variants?

There are no documented beneficial variants of the NPC1 or NPC2 gene.

 Could gene editing (e.g., CRISPR) be used to correct or enhance this gene?

Yes, potentially.  Base editing in mice has proven to correct an NPC mutation and slow down neurodegenerative symptoms, using cytosine/ adenine base editors. Another approach would be to replace the gene with AAV-NPC1, which has also yielded promising results in studies with mice where they exhibit improved survival, motor function and neuropathology. Similarly, AAV-NPC2 employed in mice to replace the NPC2 gene has shown improved motor function that combat the symptoms of Niemann-Pick disease. Though the studies presented are largely in the stages of testing with mice, they hold promising potential for further in-vivo tests in gene therapy with humans. 

Step 4: Ethical Reflection
What are the ethical implications of editing this gene?

Editing this gene may be considered more ethically acceptable than other genes as it involves somatic editing rather than germline editing. Somatic editing is more well-received by CRISPR bioethics, which encourage clinical uses of somatic editing over germline editing. 

However, given that the disease (autosomal recessive) is often pediatric, early editing (especially pre-symptomatically) can pose ethical risks. More research is needed to determine when precautionary gene-editing is effective. 

 Could this lead to unintended consequences?

Yes. Since Niemann-Pick disease involves neurodegenerative symptoms, it poses high risk of irreversibly gaining unknown side-effects primarily in the brain, liver and spleen. Hence, more rigorous trials, research and ethical scrutiny are required. 

 How do we define “improvement” in this context?

“Improvement” can be interpreted as mainly symptom stabilisation at this stage – the neurological symptoms developed from Niemann-Pick disease affects multiple areas that include motor function and seizure control. Hence, symptom management through the approaches mentioned above can be considered an improvement in addressing the disease.

Further on, stressing on the potential of NPC gene editing, “improvement” may evolve into entirely restoring the function of the protein coded by NPC1 or NPC2 genes, that is lipid egress. Successful corrections via gene editing and gene therapy would lead to successful interventions, therefore improving the state of patients afflicted with the disease.

Gene name: HEXA

Chromosomal location: 15q23

What is the normal function of this gene?

The HEXA gene codes for the alpha subunit of β-hexosaminidase A, a lysosomal enzyme needed to break down GM2 gangliosides. Since gangliosides are important in the nervous system for processes like signal transduction and cell–cell recognition, loss of enzyme function causes GM2 to build up in neurons, leading to swelling and neural degeneration.

This disease presents itself with common symptoms such as developmental delay in the skull, loss of motor function, seizures, vision/hearing loss.

What are the mutations associated with the disease?

In Tay-Sachs, many different mutations can occur in HEXA. The most common one, especially in Ashkenazi Jews, is a 4-bp TATC insertion in exon 11, which creates a frameshift mutation and premature stop codon, producing a nonfunctional enzyme. Because the disorder is autosomal recessive, it can occur either when both alleles carry the same mutation (homozygous) or when each allele has a different one (compound heterozygous).

Are there known beneficial variants?
There aren’t really “beneficial” variants of HEXA mutations, but some mutations leave behind partial enzyme activity. These usually lead to juvenile or adult-onset forms, which progress more slowly compared to the severe infantile type.

CRISPR:

CRISPR can be a potential tool used to correct HEXA by providing a guide template to remove the insertion of TATC and restore the normal reading frame. This will allow cells to produce a functional alpha subunit of the Beta-hexosaminidase A.

CRISPR can potentially be conducted in vivo through vectors and inserted through cerebrospinal fluid to target the neurons, or be introduced into the hematopoietic cells in the bone marrow ex vivo before transplanting back into the patient.

Ethical Reflection:

CRISPR editing can also be applied to embryonic cells, which is considered germline editing because any correction would be inherited by descendants. This raises concerns about designer babies and, by extension, equity and access, given the high cost of such treatments.

Even with somatic CRISPR in infants, questions of autonomy and consent arise, since the patients cannot make decisions for themselves.

Could this lead to unintended consequences?

For sure! CRISPR is not perfect and there is always a risk of off-target mutations (especially since TATC is a short sequence, likely to be found in other parts of our DNA) or mosaicism where only some cells are edited, and others are not. In these cases, once CRISPR is introduced, the gene edit is permanent. 

How do we define “improvement” in this context?

In this context, “improvement” refers to any intervention that restores or preserves normal function, reduces disease severity, or extends quality of life for patients with Tay-Sachs. It could mean:

1. Restoring β-hexosaminidase A activity to prevent GM2 accumulation in neurons.

2.  Slowing or halting disease progression, so patients can maintain motor skills and cognitive function longer.

3. Reducing symptoms like muscle weakness, seizures, and vision loss, thereby improving quality of life.

In conclusion, improvement is measured by functional outcomes, survival, and quality of life.

Tan Xing Yuan(U2440684B)

MIM: 600760

Gene name: SCNN1B

Chromosomal location: 16p12.2

Analyze the Gene

What is the normal function of the gene?

SCNN1B gene codes for the beta subunit of the epithelial sodium channel (ENaC), which aids in mediating the movement of sodium ions across cell membranes in epithelial tissues, regulating fluid homeostasis in the body. ENaC influences blood pressure regulation and airway surface liquid balance.

What mutations are associated with disease?

BESC1 is caused by heterozygous mutation in the gene encoding the beta subunit of the epithelial sodium channel (SCNN1B; 600760) on chromosome 16p12.

The transmission pattern of BESC1 in families was found to be autosomal recessive inheritance.

Are there known beneficial variants?

None. Another known variation of this mutation in found on the SCNN1G gene, which codes for gamma subunit of the epithelium sodium channel and its mutation is an underlying cause of BESC3.

Could gene editing (e.g., CRISPR) be used to correct or enhance this gene?

Unlikely. Bronchiectasis with or without elevated sweat chloride-1 has many underlying causes: genetic mutations, infections and immune disorders.

Although CRISPR and other gene editing techniques could potentially correct the mutation in SCNN1B, other factors could still affect an individual and they may still have the disease.

However, correcting the mutation could potentially reduce the severity of the disease, as correcting the gene leads to production of functional beta subunit of ENaC, which leads to proper body fluid homeostasis.

Ethical Reflection

What are the ethical implications of editing this gene?

In order for the gene editing to be effective, it must be done in-utero, which could be deemed as unethical due to its unprecedented outcomes. Furthermore, there are also ethical challenges related to safety and informed consent.

Could this lead to unintended consequences?

Yes, we do not know if new diseases can arise from the gene edit.

How do we define “improvement” in this context?

Improvement would be defined by a decrease in risk of having Bronchiectasis with or without elevated chloride-1.

Cathleen Liao

U2340357E

• Blood transfusion and organ transplantation compatibility barriers

• Blood type incompatibilities can lead to dangerous immune reactions in transfusion or organ transplantation. Universal (O-negative) donors are rare, and blood shortages are common.

Gene Involved

• ABO gene (determines presence of A and B antigens on red blood cells)

  • Type O individuals lack both A and B antigens, making their blood the safest for universal donation.

Proposed Editing Method

• CRISPR-Cas9 Gene Editing or Base Editing:

  • Edit the ABO gene in human hematopoietic stem cells (HSCs, which give rise to all blood cells) to inactivate the production of A and B antigens.

  • This can be achieved by knocking out (disrupting) exons that encode glycosyltransferase enzymes needed to synthesize these antigens, converting cells into the universal (O) type.

• Alternatively, Prime Editing or Base Editing can precisely change nucleotides responsible for antigen expression without creating double-stranded DNA breaks.

Potential Benefits

• Universal blood donation: Donor blood from edited stem cells could be transfused into any patient, regardless of blood type, greatly reducing complications and improving emergency response.

• Improved organ compatibility: The same editing in organs or tissues grown for transplantation (by editing donor stem cells before tissue engineering) could make organs “universal,” lowering the risk of rejection and simplifying donor-recipient matching.

• Expanded donor pool: More efficient use of available donations, potentially saving thousands of lives annually.

Potential Downsides and Risks

• Off-target effects: Gene editing could unintentionally modify other genes, leading to unknown health issues or cancer risk.

• Incomplete editing: If editing doesn’t fully eliminate antigen expression, small amounts of A/B antigens could still cause immune reactions.

• Long-term immune response: The immune system might recognize edited cells as foreign if subtle differences remain.

• Ethical concerns: Editing germline or stem cells for transplantation could prompt debates over genetic manipulation and equity in access to the technology.

Current Status and Feasibility

• Researchers have already demonstrated the conversion of type A or B blood cells to O-type using enzymatic treatment or gene editing in the laboratory. However, making permanent and safe edits in stem cells or directly in the body for therapeutic use is still under ongoing investigation.

Future Vision

• Next-generation blood banks might use banks of edited universal donor stem cells, creating “on demand” blood of any type or organs with unmatched compatibility.

• This technology could also be combined with additional edits—such as making cells resistant to infectious diseases—for truly transhuman improvements to blood safety and transplantation.

This approach stands at the intersection of genetics, immunology, and biotechnology. While challenges remain, the technical foundation for universal donor blood through targeted gene editing is strong and progressing.

Seth Ng Tian En, BS Y3 (U2340605B)

Potential therapies include genetic modification of mesenchymal stem cells to overexpress NGF, which may support residual neurons. CRISPR-Cas9 gene editing could be used to correct NTRK1 mutations in patient-derived induced pluripotent stem cells (iPSCs), enabling autologous transplantation. Additionally, engineered stem cells could be modified to overexpress functional TrkA receptors and directed to differentiate into sensory neurons, potentially restoring NGF responsiveness.

One ethical concern could be the high cost of treatments making it accessible only for wealthy individuals. Additionally, some individuals may not want treatment for this condition and choose to live with it.

Treatment might improve quality of life for patients who enjoy doing intense physical activities, reducing the risk of leaving severe injuries untreated.

U2340112J

• encodes a co-receptor in the Wnt signalling pathway which is critical for osteoblast activity

• maintains bone density by regulating bone formation as compared to resorption

• involved in eye developmet and glucose metabolism in some studies, showing pleiotropy, where one gene affects multiple traits

Mutations associated

• loss-of-function resulting in osteoporosis-pseudoglioma syndrome, typically leading to fragile bones and vision problems

• gain-of-function resulting in high bone mass (HBM) syndrome, where individuals have very dense bones (eg double the normal mass)

The known beneficial variants

• HBM variants reduce fracture risks and increase structural bone strength

• Observed in certain families and are used as models for drug developmet, such as sclerostin inhibitors mimic LRP5 gain-of-function effects

CRISPR potential

• could be used to introduce high-density variants in embryos or adults

• possibly prevent osteoporosis, protecting the elderly from fractures

• could even be used for enhancement for athletes or military personnel to give rise to "super-strength" phenotypes

Ethical reflections

• Preventing osteoporosis is therapeutic, whereas enhancing bone density beyond normal is an enhancement

• there are equity concerns as only the wealthy may be able to afford and access this "superhuman" bone enhancements

• could lead to broader societal inequites and unfairness in the sports world

Possible unintended consequences

• Increase risks during childbirth as very dense pelvis bones may complicate labor

• Lead to reduced flexibility as extra bone mass may reduce the range of motion, impacting agility or posture

• There are cardiovascular and metabolic costs as denser bones are metabolically expensive, and it could influence calcium metabolism or stress the heart or kidney's function

• Possible pleitropic effects as LRP5 also affects eye development and glucose homeostasis, thus editing this could produce unexpected changes

done by: Petra Chiang Yi Xian

Dopamine-Responsive Dystonia

MIM: 600225

Gene Name: GCH1

Chromosomal Location: 14q13

Step 3.

Normal function of gene is the synthesis of tetrahydrobiopterin (THB) which affects dopamine.

Mutations are autosomal dominant and autosomal recessive.

No known beneficial variants.

Gene editing might be useful to correct the gene provided there is a clearer relationship on the genotype and phenotype.

Step 4.

Ethical implications could be the safety of editing this gene as it indirectly affects neurological development and impacts neurological functioning which varies from person to person.

There could be unintended consequences, as while the mutations have an indirect effect on existing neurological conditions, they still ultimately impact a variety of neurological functioning. Its effect on THB leads to effects on the production of neurotransmitters crucial to the body.

Improvement could be made by having better clarity on how the gene impacts the phenotypical representations of neurological diseases in the body, and in turn better manage these symptoms beyond modifying the gene itself.

Sticky Note by Timothy Tan Jun Jie (U2330756J)

MIM Number: 161400

Chromosomal Location: 17q21.2

Normal Function: This gene encodes for precursor proteins that mature into 2 mature neuropeptides, Orexin A and Orexin B. They are responsible with regulation of sleep and arousal.

Mutations associated: Heterozygous Mutation on HCRT gene.

known beneficial variants?: There are no known beneficial variants, the condition is caused my an autosomal recessive alleles.

Can gene editing be used to correct this disorder?: currently, it cannot

Are there any significant ethical implications of editing this gene?:

No, editing of this gene alone will most likely not cause any ethical concerns as instead of a genomic coding error, it is just a trait that follows mendelian inheritance.

Could this lead to consequences?:

Likely, as the gene is responsible for producing precursor proteins that are important in regulation of other functions, we do not know how many different functions this will impact.

how do we define "improvement" in this context?:

Improved Individuals in this context are those that no longer suffer from very severe narcolepsy

Yee Tian Zheng Bryan (U2340864D)

gene name: ALDH2

chromosomal location:  12q24.12

• What is the normal function of the gene?

  The ALDH2 gene provides instructions for making the aldehyde dehydrogenase 2 enzyme. This enzyme is crucial for metabolising alcohol. It is responsible for breaking down acetaldehyde. Almost all Caucasians have mitochondrial ALDH2.

• What mutations are associated with disease?

  Not mutations, but the absence of the ALDH2 liver isozyme in East Asians is the main cause of the high frequency of acute alcoholic intoxication. Individuals will suffer from alcohol-flush reaction as a result of excessive acetaldehyde accumulation.

• Are there known beneficial variants?

  The existence of ALDH2 is beneficial to humans.

• Could gene editing (e.g., CRISPR) be used to correct or enhance this gene?

  Yes, this gene can be enhanced in East Asians to improve individuals' ability to oxidise acetaldehyde.

• What are the ethical implications of editing this gene?

  The enhancement of this gene may facilitate alcohol overuse. It is ethical to modify a gene to allow for safer consumption of a recreational substance still needs to be concerned.

• Could this lead to unintended consequences?

  Abuse of alcohol may negate the health benefits and lead to other more severe diseases, such as liver cirrhosis.

• How do we define “improvement” in this context?

  It can help East Asians reduce the discomfort or awkward physical conditions from drinking alcohol.

Gene name: DOLICHYL-DIPHOSPHOOLIGOSACCHARIDE-PROTEIN GLYCOSYLTRANSFERASE; DDOST

Gene MIM number: 602202

Chromosomal location: 1p36.12

Normal function of the gene:

DDOST, enhances AGE removal. AGE contributes to kidney disease due to diabetes or aging by means of mesangial cell receptors. Also a distinct receptor in that it suppresses AGE-mediated mesangial cell inflammatory injury through negative regulation of RAGE, a previously uncharacterized pathway that may protect from renal and other tissue injury due to diabetes and aging.

Mutations associated with disease

pathogenic DDOST variants are associated with congenital disorder of glycosylation type I (CDG I).

May cause developmental delay, neurological issues, coagulopathy, hypotonia etc. Not really linked to lactose intolerance

No known beneficial variants

For lactose intolerance, since lactose intolerance is due to LCT or MCM6 variants, editing DDOST cannot correct lactose intolerance. The relevant target could be enhancing LCT expression in the intestine.

Ethical implications of editing this gene:

For rare DDOST-related CDG, correcting mutations could be life-saving and align with therapeutic goals.

For non-therapeutic enhancement: Editing DDOST lacks justification and may disrupt essential protein glycosylation pathways.

For Lactose intolerance, editing gene to confer lactase persistence may raise doubts on whether its a medical necessity or simply a lifestyle choice. Is simply cutting lactose foods and drinks the better solution.

Unintended consequences:

Editing DDOST may disrupt other glycosylation pathways. Affect some protein expression.

Improvement is the ability to digest lactose lifelong, which may or may not be necessary depending on cultural diet and personal preference.

Chan Tat Hei Milo

U2240197G

Celiac's disease (allergy to gluten)

gene name:

HLA-DQA1 and HLA-DQB1

HLA-DQA1:

MIM-146880

Chr Location- 6p21.32

HLA-DQB1:

MIM- 604305

Chr Location- 6p21.32

HLA-DQA1 and HLA-DQB1 are genes that encode for the alpha and beta chains of the HLA-DQ heterodimer, respectively. This complex is part of the Major Histocompatibility Complex (MHC) Class II, located on chromosome 6. The HLA-DQ proteins are found on the surface of antigen-presenting cells (like B cells, dendritic cells, and macrophages). Their primary role is to present extracellular (foreign) peptides to CD4+ T cells, which then triggers an immune response

• What mutations are associated with disease?

Mutations or allelic variants in these genes are associated with several autoimmune and inflammatory diseases, including:

Celiac Disease: Specific alleles like DQB103:02* and DQB102:01* are strongly associated.

• Type 1 Diabetes: Certain combinations of HLA-DQA1 and HLA-DQB1 alleles increase susceptibility.

• Multiple Sclerosis (MS): Associations with specific HLA-DQB1 alleles have been observed.

• Narcolepsy with cataplexy: Linked to particular HLA-DQB1 variants.

• Are there known beneficial variants?

Yes, some HLA alleles are associated with protection against certain diseases, such as DQB1*06:02 which are protective against Type 1 Diabetes and multiple sclerosis as well as DQA1*0103 that is associated with protection against Vogt–Koyanagi–Harada disease

• Could gene editing (e.g., CRISPR) be used to correct or enhance this gene?

Yes, but apparently, it is quite difiicult.

-CRISPR can be used to correct autoimmune-associated alleles such as

-Knock out problematic HLA molecules.

-Engineer immune tolerance in diseases like T1D or celiac.

Step 4: Ethical Reflection

• What are the ethical implications of editing this gene?

  
  

Modifying HLA genes could weaken immune responses or create unknown vulnerabilities, and altering HLA profiles could complicate organ transplantation systems.

also, if editing is used for enhancement, it could contribute to social inequities or genetic stratification.

• Could this lead to unintended consequences?

most likely, considering the possibility of social inequality. In addition, Autoimmune reactions if the immune system misidentifies "self" as foreign. New susceptibilities to infection if protective variants are removed. Immune rejection issues in therapies or transplants.

Also, the epigenetic and gene–gene interactions are not fully understood — editing one gene may affect others.

• How do we define “improvement” in this context?

  
  

  Reducing disease risk (e.g., preventing autoimmune diseases).

  Possibly increasing immune surveillance or pathogen resistance — but at the cost of possible autoimmunity.

  as well as other ethical concerns.

Gene involved: DYM

Cause: Mutation or deletion of DYM gene

Function of the gene involved: The DYM gene, also known as the dymeclin gene, encodes a protein that plays a crucial role in Golgi-associated secretory pathways and is essential for endochondral bone (a bone which replaces a cartilage) formation and early brain development

Introduction: A rare, genetic primary bone dysplasia of the spondylo-epi-metaphyseal dysplasia (SEMD) group characterized by progressive short-trunked dwarfism, protruding sternum, microcephaly and intellectual disability.DMC is caused by loss-of-function mutations in the DYM gene, leading to defects in Golgi organization and vesicular trafficking.

Gene modification: Genetic modification, possibly through CRISPR-based gene editing, could correct the harmful DNA variants or introduce a functional copy of the DYM gene

Possible negative implications: Removing the gene in the process of modifying DYM gene might result in worsening the condition.

In vitro studies suggest that total loss of DYM function disrupts:

• Golgi structure and trafficking → defective cartilage and bone growth (hence severe dwarfism).

• Neurodevelopment → potentially more severe intellectual disability or even embryonic lethality if the gene is essential in early development.

  (U2440542J)
  

Caused by heterozygous mutation in the thyroid-stimulating hormone receptor gene (TSHR; 603372) on chromosome 14q31

Record the MIM number, gene name, and chromosomal location

Gene name: TSHR

MIM number: 603372

Chromosomal location: 14q31

What is the normal function of the gene?

Synthesizes receptor that binds to thyroid stimulating hormone (TSH). Binding of TSH to receptor activates a series of reactions that control development of the thyroid gland and its functions, including production of thyroid hormones which help regulate

growth, brain development, and metabolism

What mutations are associated with disease?

Gain of function mutation in TSHR gene causes hyperthyroidism (many different TSHR variants)

Are there known beneficial variants?

No

Could gene editing (e.g., CRISPR) be used to correct or enhance this gene?

Can be used to replace the mutated nucleotide with a wild type nucleotide

What are the ethical implications of editing this gene?

What are the ethical implications of editing this gene?

Concerns regarding informed consent and moral/religious perspectives

Could this lead to unintended consequences?

Yes due to concerns about off-target editing and mosaicism

How do we define “improvement” in this context?

Restoration of normal thyroid function

MIM number: 231300

Gene name: Cytochrome P4501B1 gene (CYP1B1; 601771)

Chromosomal location: 2p22

Normal Function:

• CYP1B1 is a gene that provides instructions for making the CYP1B1 protein, which is a monooxygenase enzyme.

• In the case of CYP1B1, it metabolizes a range of substrates, including drugs, steroids, and other lipids.

Mutations:

Compound heterozygous or heterozygous mutations in the CYP1B1 gene can also cause juvenile- and adult-onset primary open angle glaucoma. Mutations in CYP1B1 are strongly linked to PCG, a condition where there are developmental defects in the eye's trabecular meshwork, leading to increased intraocular pressure and potential blindness. 

There are no known beneficial variants.

Gene editing:

Gene editing can be used to correct mutations in this gene, or to lower the risk of onset of glaucoma even if we do not particularly know which mutations have an effect on causing disease phenotype. We can sequence the genome of wild-type individuals and replace or remove the mutated nucleotide sequences to make it more similar to the wild-type genome of an adult with no glaucoma.

Ethical Reflection:

Editing this gene successfully could prompt debates over who should have access to such services or technology. This gene editing technology could potentially drastically reduce the chances of glaucoma development, but if greedy corporations were to monopolise this technology and charge it at a tremendously high price for profit-seeking, it would be discriminatory as only the rich would have access to this.

This could lead to unintended consequences such as a battle over who gets access to this technology, and whether or not the people who are at risk of glaucoma or suffering from glaucoma are able to reverse engineer their impending loss of sight.

Improvement could be when the known mutated sequences are edited to follow that of a non-mutated sequence, a person's risk of suffering from glaucoma is reduced close to 0.

Izz Afiq

U2140513G

Gene name: DMPK

Chromosomal location: 19q13.32

What is the normal function of the gene?

Instructions for producing a protein known as myotonic dystrophy protein kinase is provided by the DMPK gene. This protein is crucial for brain, heart, and muscle cells. Within cells, the protein plays a role in communication and it also seems to interact with other proteins to control the synthesis and operation of key structures inside muscle cells. DMPK has been demonstrated to inhibit a portion of the muscle protein, myosin phosphatase, which is involved in both muscular contraction and relaxation.

What mutations are associated with disease?

An unstable CTG-repeat that has expanded in the 3'-untranslated region of a gene that codes for DMPK is the result of the DM1 mutation. Testicular atrophy, cataracts, cardiac arrhythmia, insulin resistance, and the inability to relax muscles correctly are all linked to the diverse clinical manifestation of DM1. It manifests as a progressive muscular dystrophy that affects distal muscles more than proximal muscles.

Are there known beneficial variants?

There are no beneficial variants known.

Could gene editing (e.g., CRISPR) be used to correct or enhance this gene?

It is possible to specifically target and alter the DNA sequence using methods like CRISPR-Cas9. Either the extended CTG repeats can be removed or the mutation can be carefully corrected by employing base editors or by adding double-strand breaks. RNA-targeting CRISPR could also block toxic RNA or release splicing factors.

What are the ethical implications of editing this gene? Could this lead to unintended consequences?

DM1 can affect up to 1 in 8000 people. Editing the DMPK gene could become a potential treatment for DM1 and thus improve the lives of many. However, like any ethical implication for gene editing, there is always the possibility of off target effects and mosaicism.

How do we define “improvement” in this context?

From a scientific and medical point of view, an improvement would be to observe a rescue of the pathological signs of the disease, such as a reduction of RNA focus accumulation on myonuclei, or a reduction of the CTG repeats in the DMPK gene.

Nicole Tan (U2340207G)

Gene name: WILMS TUMOR 1 WT1

Chromosomal location: 11p13

Normal function of gene: Tumor suppressor gene. Crucial for normal kidney and gonadal development, with its expression observed in both developing organs. WT1 also plays a negative regulatory role in myogenesis, actively suppressing the formation of skeletal muscle cells in the kidney's metanephric-mesenchymal stem cells, thereby preventing ectopic differentiation. Wildtype WT1 isoforms are known to suppress the growth of Wilms tumor cells. The gene encodes a zinc finger protein.

Mutations associated with disease:

• Wilms tumor-1 is caused by heterozygous mutations in the WT1 gene. Inactivation of WT1 is an early genetic event that can lead to nephrogenic rests, which are precursors to Wilms tumor.

• A 25-bp deletion spanning an exon-intron junction, leads to aberrant mRNA splicing and the loss of one of the four zinc finger consensus domains.

• Maternal transmission of a WT1 nonsense mutation has been observed, leading to Wilms tumor and decreased fertility in the mother, and genitourinary abnormalities in her son, highlighting intrafamilial variability and gender-specific effects.

Known beneficial variants: Wildtype is essential for proper development and tumor suppression, preventing disease.

Could gene editing be used to correct or enhance this gene?

Can correct disease-causing mutations in the WT1 gene. Since normal chromosome 11 was able to suppress tumorigenic expression in Wilms tumor cell lines, similarly, for individuals with identified germline or somatic mutations, CRISPR technology could precisely target and repair specific deletions, nonsense mutations, or point mutations, thereby restoring the gene's normal tumor suppressor function and preventing related developmental anomalies.

Can enhance the WT1 gene's tumor suppressor capabilities or optimize its developmental regulatory roles, especially those impacting reproductive health and overall viability. This would increase protection against various cancers, thus increasing longevity and reproductive span, which are direct measures of Darwinian fitness.

Ethical implications:

Enhancing function for accelerated human evolution ventures is controversial as it raises questions about what constitutes an "ideal" human genetic makeup.

Unintended consequences:

Since WT1 has diverse roles in development, from kidney and gonadal formation to suppressing ectopic myogenesis, enhancing one function might inadvertently disrupt another, leading to unforeseen developmental abnormalities or new health conditions. Over-enhancing myogenesis suppression might negatively impact other tissues or processes.

How do we define “improvement” in this context?

Factors that increase an individual's survival to reproductive age and their reproductive success.

• Increased survival: Preventing early childhood death from Wilms tumor and other associated severe health issues like severe developmental delay or adrenal insufficiency would be a clear improvement in survival.

• Enhanced reproductive capacity: Addressing the issue of decreased fertility observed with some WT1 mutations would directly enhance reproductive success. Preventing genitourinary abnormalities that could impair reproduction would also contribute.

Chang Chia Xuan

Gene name: Ferredoxin 2 (FDX2)

chromosome location: 19p13.2

MIM number: 614585.

Normal function of the gene: encodes proteins for Fe-S and Heme A synthesis, which are both involved in oxidative phosphorylation. Deficiency of this gene leads to decreased activity of mitochondrial enzymes and reduced content of Fe-S crystals which reduces iron accumulation and cell proliferation.

Mutations associated with disease:

homozygous missense mutation in FDX2 gene (c.431 C->T, p.P144L) resulting in decreased protein levels due to instability in the protein (FDX2 mRNA expression is normal). These mutations affect the ATG start codon of FDX2 which demonstrates severely reduced protein expression.

Follows autosomal recessive inheritance.

Beneficial variants:

Currently, there are no known beneficial mutants of FDX2 gene.

Gene editing:

Since the disease arises due to mutations in a nuclear gene rather than mitochondrial gene, gene editing is more accessible. For example, 'prime editing' involves a search and replace mechanism, where guide RNA brings a modified Cas9 protein to the site of the mutation. A single strand nick is made rather than double strand break, followed by reverse transcriptase which encodes the correct sequence from the guide RNA onto the DNA. This is more promising than homology directed repair (which would be prone to errors) and is feasible in non-dividing cells of CNS and muscles.

Ethical implications of gene editing:

Gene editing in-utero would prevent passing the disease-causing mutation to future generations, however they are permanent with unknown consequences not only to the unborn foetus but also to its descendants. Hence, this is much more controversial than somatic gene editing in an adult, although it may prevent the disease altogether.

Manasi Ravi

(Apologies for the late submission, I was enrolled late and tackling add-drop)