Genetics and Disease

Genetics and Disease Indian Medical PG Question 1: Gene not involved in SCID:

• A. BTK (Correct Answer)
• B. ZAP70
• C. IL2RG
• D. JAK3

Genetics and Disease Explanation: ***BTK*** - **Bruton's tyrosine kinase (BTK)** is associated with **X-linked agammaglobulinemia (XLA)**, a primary immunodeficiency characterized by the absence of mature B cells and significantly reduced antibody production. While it causes severe immune deficiency, it is not a direct cause of **SCID**. - XLA results in recurrent bacterial infections due to an inability to produce antibodies, rather than the severe combined T and B cell dysfunction seen in SCID. *ZAP70* - **ZAP70** deficiency is a cause of **SCID**. It leads to impaired T-cell receptor signaling, resulting in profound functional T-cell lymphopenia. - Patients with ZAP70 deficiency have normal numbers of CD4 T cells but very low or absent CD8 T cells, and their T cells are functionally impaired, leading to severe immunodeficiency. *IL2RG* - The **IL2RG** gene encodes the common gamma chain (γc), a crucial component of several **interleukin receptors (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21)**. [1] - Mutations in IL2RG cause **X-linked SCID (X-SCID)**, the most common form of SCID, leading to a block in T-cell and NK-cell development due to defective cytokine signaling. [1] *JAK3* - **Janus kinase 3 (JAK3)** is a tyrosine kinase that associates with the **common gamma chain (γc)** and is essential for cytokine signaling downstream of the γc-containing receptors. [1] - **JAK3 deficiency** results in an **autosomal recessive form of SCID**, clinically indistinguishable from X-SCID, with impaired T-cell and NK-cell development due to defective cytokine signaling. [1] **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Diseases of the Immune System, pp. 247-248.

Genetics and Disease Indian Medical PG Question 2: Best method for the detection of mutations with low allele frequency is:

• A. FISH
• B. Droplet digital PCR (Correct Answer)
• C. Sanger sequencing
• D. Nested PCR

Genetics and Disease Explanation: ***Droplet digital PCR*** - **Droplet digital PCR (ddPCR)** offers superior sensitivity for detecting **low allele frequency mutations** by partitioning the sample into thousands of individual reactions. - This compartmentalization allows for the direct quantification of target DNA molecules without relying on a standard curve, making it highly accurate for rare mutation detection. *FISH* - **Fluorescence in situ hybridization (FISH)** primarily detects **chromosomal abnormalities** like translocations, deletions, or amplifications, rather than single-nucleotide variants or small indels with low allele frequencies [2]. - It visualizes genetic changes at a **cytogenetic level** on an intracellular basis, not typically for quantifying rare DNA mutations in a heterogeneous sample. *Sanger sequencing* - **Sanger sequencing** is the gold standard for **sequencing individual DNA fragments** but has a detection limit of around 15-20% for allele frequency, making it unsuitable for very low allele frequency mutations [1]. - It struggles to reliably detect minor alleles when they are present in a small proportion of the total DNA pool. *Nested PCR* - **Nested PCR** increases the sensitivity and specificity of amplification by using two sets of primers in a sequential manner but does not inherently provide the **quantification capability** or the same level of **low allele frequency detection** as ddPCR processes. - While sensitive for detecting target sequences, it is not designed for precise quantification of rare mutations in a background of wild-type sequences. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, p. 185. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 185-186.

Genetics and Disease Indian Medical PG Question 3: Genetic disorder predisposing patients to develop Berry aneurysm includes all EXCEPT:

• A. Marfan’s syndrome
• B. Adult polycystic kidney
• C. Neurofibromatosis Type II (Correct Answer)
• D. Fibromuscular dysplasia

Genetics and Disease Explanation: ***Neurofibrofomatosis Type II*** - This condition is primarily associated with **central nervous system tumors** like **vestibular schwannomas** and **meningiomas**, not Berry aneurysms [2]. - While it affects the nervous system, its vascular manifestations are typically different from those predisposing to aneurysms. *Marfan’s syndrome* - Patients with Marfan's syndrome have **fragile connective tissue** due to a defect in **fibrillin-1**, which can weaken arterial walls. - This weakness increases the risk of **aortic aneurysms** and dissections, and can also predispose to intracranial aneurysms like Berry aneurysms. *Adult polycystic kidney* - This **autosomal dominant** disorder is characterized by the formation of **cysts in the kidneys**, but also has systemic manifestations [1]. - There is a well-established association between **autosomal dominant polycystic kidney disease (ADPKD)** and an increased incidence of **Berry aneurysms**. *Fibromuscular dysplasia* - This condition involves **abnormal cellular development** in the **arterial walls**, leading to areas of narrowing and enlargement. - It commonly affects the **renal arteries** and **carotid arteries**, and is also a known risk factor for the development of **intracranial aneurysms**, including Berry aneurysms.

Genetics and Disease Indian Medical PG Question 4: What is meant by the melting of double-stranded DNA?

• A. Splitting of double strands into single strands (Correct Answer)
• B. Splitting of DNA into fragments
• C. Formation of triple helix
• D. Separation of double-stranded bases

Genetics and Disease Explanation: ***Splitting of double strands into single strands*** * **DNA melting**, also known as **DNA denaturation**, refers to the process where the two complementary strands of a **double-stranded DNA** molecule separate to form two individual single strands. * This process involves the breaking of the **hydrogen bonds** between the paired bases (**A-T and G-C**) due to increased temperature or changes in pH. * The temperature at which 50% of the DNA is denatured is called the **melting temperature (Tm)**, which depends on GC content (higher GC = higher Tm due to three hydrogen bonds vs. two in AT pairs). *Splitting of DNA into fragments* * The splitting of DNA into fragments is referred to as **DNA fragmentation**, which typically occurs due to processes like **restriction enzyme digestion**, mechanical shearing, or programmed cell death (apoptosis). * This process involves the breaking of the **phosphodiester bonds** within the DNA backbone, not just the hydrogen bonds between strands. *Formation of triple helix* * The formation of a **triple helix** (triplex DNA) is a less common DNA structure where a third oligonucleotide strand binds into the major groove of a **B-form DNA duplex**. * This process is distinct from DNA melting, which involves the *separation* of existing double strands rather than the *addition* of a third strand. *Separation of double-stranded bases* * The term "double-stranded bases" is imprecise terminology; bases are paired (e.g., A with T, G with C) within the double helix structure. * While the separation of base pairs does occur during melting, the more accurate description is the **separation of the entire double helix into two single strands**, not just the individual bases.

Genetics and Disease Indian Medical PG Question 5: Mutations are due to changes in:

• A. DNA nucleotide sequence (Correct Answer)
• B. RNA nucleotide sequence
• C. Amino acid sequence of ribonuclease
• D. Cell membrane

Genetics and Disease Explanation: ***DNA nucleotide sequence*** - **Mutations** are defined as changes in the **genetic material**, which is primarily composed of **DNA**. - These changes in the **nucleotide sequence** of DNA can alter the genetic code, leading to changes in **protein structure and function**. *RNA nucleotide sequence* - While RNA can have its nucleotide sequence altered, these changes are generally not considered true **mutations** in the heritable sense for most organisms. - RNA is typically a temporary molecule, and changes to its sequence are usually not passed down to subsequent generations. *Amino acid sequence of ribonuclease* - An altered **amino acid sequence** in a protein like ribonuclease is a consequence of a **mutation in the DNA**, not the mutation itself. - **Ribonucleases** are enzymes that catalyze the degradation of RNA, and their structure is determined by the **DNA sequence**. *Cell membrane* - The cell membrane is a **lipid bilayer** with embedded proteins that regulates cellular transport and communication. - While its components can be affected by genetic mutations, alterations in the cell membrane itself do not constitute the primary definition of a **mutation**.

Genetics and Disease Indian Medical PG Question 6: X-linked disease leading to intellectual disability is -

• A. Tuberous sclerosis
• B. Phenylketonuria
• C. Myotonic dystrophy
• D. Fragile-X syndrome (Correct Answer)
• E. Down syndrome

Genetics and Disease Explanation: ***Fragile-X syndrome*** - This is the most common inherited cause of **intellectual disability** and is inherited in an **X-linked dominant pattern**. - It is caused by an expansion of a **CGG trinucleotide repeat** in the *FMR1* gene on the X chromosome. *Down syndrome* - This is a **chromosomal disorder** (trisomy 21), not X-linked. - It is the most common **genetic cause** of intellectual disability overall, resulting from an extra copy of chromosome 21. *Tuberous sclerosis* - This is an **autosomal dominant** disorder, not X-linked. - It involves the growth of **benign tumors** in various organs, including the brain, skin, kidneys, and heart. *Phenylketonuria* - This is an **autosomal recessive** metabolic disorder, not X-linked. - It results from a deficiency of the enzyme **phenylalanine hydroxylase**, leading to a buildup of phenylalanine. *Myotonic dystrophy* - This is an **autosomal dominant** disorder, not X-linked. - It is characterized by progressive **muscle wasting** and **myotonia** (delayed muscle relaxation).

Genetics and Disease Indian Medical PG Question 7: A mother brings her daughter with short stature, webbed neck, and other physical features. What is the most likely finding on ultrasound?

• A. Hepatomegaly with altered echotexture
• B. Echo showing tricuspid stenosis
• C. Streak ovaries with small uterus (Correct Answer)
• D. Single kidney

Genetics and Disease Explanation: ***Streak ovaries with small uterus*** - The constellation of **short stature** and **webbed neck** is highly suggestive of **Turner syndrome (45,X0)**. - A characteristic feature of Turner syndrome is **gonadal dysgenesis**, which manifests as **streak ovaries** and a **small uterus** due to the absence of normal ovarian development. *Hepatomegaly with altered echotexture* - This finding is more indicative of **liver disease** or metabolic disorders, which are not primary features of Turner syndrome. - While Turner syndrome can be associated with various health issues, **hepatomegaly** is not a common or defining ultrasonographic finding. *Echo showing tricuspid stenosis* - **Cardiac abnormalities** are common in Turner syndrome, but the most frequent ones are **bicuspid aortic valve** and **coarctation of the aorta**, not typically **tricuspid stenosis**. - **Tricuspid stenosis** is a rare congenital heart defect and not specifically associated with Turner syndrome. *Single kidney* - **Renal anomalies**, such as a **horseshoe kidney** or **renal agenesis**, can occur in Turner syndrome. - However, the description of **single kidney** is less specific than **streak ovaries** in identifying the most likely finding given the presented clinical features of short stature and webbed neck.

Genetics and Disease Indian Medical PG Question 8: Which of the following is not a major criterion for diagnosing Marfan syndrome?

• A. Dilatation of the ascending aorta
• B. Dural ectasia
• C. Ectopia lentis
• D. Striae over the buttocks (Correct Answer)

Genetics and Disease Explanation: Striae over the buttocks - While striae (stretch marks) can be common in individuals with Marfan syndrome due to connective tissue fragility, they are considered a minor criterion rather than a major one based on the Ghent nosology. - Major criteria are defined by their higher diagnostic specificity and clinical significance in identifying Marfan syndrome. Ectopia lentis - Ectopia lentis (dislocation of the ocular lens) is a major diagnostic criterion for Marfan syndrome and is highly specific to the condition. - It results from the weakness of the suspensory ligaments of the lens due to fibrillin-1 deficiency. Dilatation of the ascending aorta - Aortic root dilatation and aortic dissection are critical cardiovascular manifestations and major diagnostic criteria for Marfan syndrome [1]. - These reflect the systemic connective tissue defect affecting the integrity of the aortic wall and are associated with significant morbidity and mortality [1]. Dural ectasia - Dural ectasia, which is the widening of the dural sac due to weakening of connective tissue, is a major criterion for the diagnosis of Marfan syndrome when observed on imaging studies. - It often occurs in the lumbosacral region and can cause neurological symptoms.

Genetics and Disease Indian Medical PG Question 9: Subtelomeric rearrangement of genes is frequently associated with intellectual disability. All of the following techniques can be used to diagnose them except:

• A. MALDI (Correct Answer)
• B. FISH
• C. MAPH
• D. cGH array

Genetics and Disease Explanation: ***MALDI*** - **Matrix-assisted laser desorption/ionization (MALDI)** is a soft ionization technique used in mass spectrometry for analyzing biomolecules like proteins and peptides. - It is not suitable for detecting large-scale chromosomal rearrangements such as **subtelomeric deletions or duplications**. *FISH* - **Fluorescence in situ hybridization (FISH)** uses fluorescent DNA probes that bind to specific target regions on chromosomes, allowing for the detection of deletions or duplications [1]. - **Subtelomeric FISH** specifically targets the ends of chromosomes and is a common method for identifying subtelomeric rearrangements [1]. *MAPH* - **Multiplex amplifiable probe hybridization (MAPH)** is a technique used for detecting copy number variations (CNVs), including deletions and duplications, in specific genomic regions. - It can be applied to **subtelomeric regions** by designing probes specific to those areas, making it useful for diagnosing subtelomeric rearrangements. *CGH array* - **Comparative genomic hybridization array (CGH array)** is a high-resolution method that compares the patient's DNA to a control DNA to detect unbalanced chromosomal abnormalities across the entire genome [1]. - It is highly effective in identifying **copy number changes**, including subtelomeric deletions and duplications, associated with intellectual disability [1], [2]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 186-187. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, p. 187.

Genetics and Disease Indian Medical PG Question 10: Which of the following is a single gene autosomal recessive disease?

• A. Wilson's disease (Correct Answer)
• B. Tuberous sclerosis
• C. Huntington's disease
• D. Schizophrenia

Genetics and Disease Explanation: ***Wilson's disease*** - This is an **autosomal recessive disorder** [1] characterized by excessive **copper accumulation** in the liver, brain, and other organs due to a mutation in the ATP7B gene. - Manifestations include **hepatic dysfunction**, neurological symptoms, and characteristic **Kayser-Fleischer rings** in the eyes [1]. *Tuberous sclerosis* - This is an **autosomal dominant disorder** caused by mutations in the TSC1 or TSC2 genes, leading to the formation of benign tumors in multiple organs. - Clinical features include **epilepsy**, intellectual disability, facial angiofibromas, and renal angiomyolipomas. *Huntington's disease* - This is an **autosomal dominant neurodegenerative disorder** caused by a CAG trinucleotide repeat expansion in the HTT gene. - It presents with **progressive chorea**, psychiatric symptoms, and cognitive decline, typically in mid-adulthood. *Schizophrenia* - This is a **complex psychiatric disorder** with a multifactorial etiology, involving a combination of genetic predisposition and environmental factors. - It is not a single gene disorder but rather involves many genes contributing to risk, indicating a **polygenic inheritance pattern**.

Genetics and Disease Flashcard 1 of 8

Question: What type of Hereditary angioedema will have normal or high C1 inhibitor levels?_____

Answer: Type II

Genetics and Disease Flashcard 2 of 8

Question: _____ cardiomyopathy / polyneuropathies are characterized by deposition of mutated transthyretin (TTR) protein in the heart and nerves

Answer: Familial amyloid

Genetics and Disease Flashcard 3 of 8

Question: _____ cardiomyopathy is associated with the trinucleotide repeat expansion disease Friedreich ataxia

Answer: Hypertrophic

Genetics and Disease Flashcard 4 of 8

Question: Male breast cancer is associated with _____ mutation and Klinefelter syndrome

Answer: BRCA2

Genetics and Disease Flashcard 5 of 8

Question: What HLA subtypes are associated with celiac disease? _____ and DQ8

Answer: DQ2

Genetics and Disease Flashcard 6 of 8

Question: _____ disease may be treated with oral zinc or chelating agents (e.g. penicillamine, trientine)

Answer: Wilson

Genetics and Disease Flashcard 7 of 8

Question: In the treatment of Cystic Fibrosis, the combination drug _____ is indicated for patients who have two copies of the F508del mutation in the CFTR gene

Answer: lumacaftor/ivacaftor

Genetics and Disease Flashcard 8 of 8

Question: Patients with Refsum disease have _____ skin and shortening of the 4th toe

Answer: scaly