Huntington’s disease and Fragile X syndrome are caused by trinucleotide repeat expansions, making options (A) and (C) correct. β-thalassemia and cystic fibrosis result from other mutation types, such as point mutations or deletions.​

Option Analysis

Huntington’s Disease (A):
This autosomal dominant disorder arises from CAG trinucleotide repeat expansion (>36 repeats) in the HTT gene on chromosome 4, leading to a toxic polyglutamine tract in the huntingtin protein, causing neurodegeneration. Larger expansions correlate with earlier onset and severity due to repeat instability during transmission.​

β-Thalassemia (B):
This results from point mutations, deletions, or splicing defects in the HBB gene on chromosome 11, reducing β-globin chain production and causing anemia; no trinucleotide repeat expansions are involved.​

Fragile X Syndrome (C):
The most common inherited intellectual disability, caused by CGG trinucleotide repeat expansion (>200 repeats) in the FMR1 gene’s 5′ UTR, leading to gene silencing, loss of FMRP protein, and symptoms like macroorchidism.​

Cystic Fibrosis (D):
An autosomal recessive disorder from mutations (e.g., ΔF508 deletion) in the CFTR gene on chromosome 7, impairing chloride transport; over 2,000 mutations identified, but none are trinucleotide repeat expansions.​

Correct Answer

(A) and (C).​

Trinucleotide repeat expansions represent a unique class of genetic mutations where short DNA sequences (three nucleotides) abnormally lengthen, disrupting gene function and causing disorders like Huntington’s disease and Fragile X syndrome. These expansions often show anticipation, worsening across generations due to meiotic instability. For CSIR NET Life Sciences aspirants, understanding this mechanism distinguishes them from point mutations in conditions like β-thalassemia.​

Mechanism of Expansions

Expansions occur via DNA slippage during replication or repair, forming hairpin loops in repeats like CAG or CGG, leading to extra copies (> threshold, e.g., 36 CAG in HTT). Paternal transmission often drives larger expansions in Huntington’s, while maternal does so in Fragile X.​

• CAG/CTG repeats (polyglutamine diseases): Huntington’s (HTT gene).​

• CGG/CCG repeats (non-coding): Fragile X (FMR1 gene).​

• Threshold instability accelerates in somatic cells, worsening symptoms.​

Affected Disorders

Huntington’s disease features chorea, cognitive decline from CAG>36 repeats, onset 30-50 years. Fragile X causes intellectual disability via CGG>200, silencing FMR1. Over 40 such disorders exist, mostly neurological.​

Diagnosis and Implications

Genetic testing measures repeat length via PCR; premutations (55-200 CGG) risk expansion. No cure exists; management is symptomatic. Research targets base editing to shrink repeats. For exams, note: only A and C fit the criterion.​