A 6-year-old boy with progressive cerebellar ataxia, oculomotor apraxia, and oculocutaneous telangiectasias is evaluated for suspected Ataxia-Telangiectasia. Cytogenetic analysis of his lymphocytes reveals the karyotypic abnormality marked **B** in the diagram. Which of the following best explains the mechanism underlying this characteristic chromosomal finding?

Question

Accepted Answer

A. Loss of ATM kinase activity impairing p53-mediated apoptosis and V(D)J recombination, leading to unrepaired double-strand breaks in TCR and IGH loci. ## Why option 1 is correct

The karyotypic abnormality marked **B** — translocations and inversions involving chromosomes 7 (TCR loci) and 14 (TCR and IGH loci) — is the hallmark cytogenetic finding in Ataxia-Telangiectasia. This occurs because biallelic ATM gene mutations at 11q22-23 cause loss of the ATM serine/threonine kinase, which is central to the DNA-damage response. Without functional ATM, cells cannot properly activate p53, CHK2, BRCA1, and H2AX following double-strand breaks. During V(D)J recombination in lymphocytes, the RAG1/RAG2 endonuclease intentionally creates double-strand breaks at TCR and IGH loci. Normally, ATM detects these breaks and coordinates their repair. In AT, defective ATM signaling allows these breaks to persist and misrepair, resulting in characteristic translocations t(7;14), inv(7), and inv(14) found in 5–15% of lymphocytes. This mechanism is pathognomonic for AT and directly reflects the underlying genetic defect (Nelson 21e Ch. 631; Rothblum-Oviatt Orphanet 2016).

## Why each distractor is wrong

- **Option 2**: The Philadelphia chromosome t(9;22) is the hallmark of chronic myeloid leukemia and results from BCR-ABL fusion, not ATM dysfunction. This is labeled **C** in the diagram and is not associated with Ataxia-Telangiectasia.
- **Option 3**: Trisomy 13 (Patau syndrome) results from meiotic nondisjunction and is labeled **D** in the diagram. It is not related to AT and does not cause the 7;14 translocations characteristic of this disorder.
- **Option 4**: Lynch syndrome is caused by mismatch repair deficiency (MLH1, MSH2, MSH6, PMS2) and presents with colorectal cancer predisposition, not the neurological and immunological features of AT. The cytogenetic pattern is entirely different.

**High-Yield:** AT = ATM gene loss → defective double-strand break repair → characteristic 7;14 translocations in lymphocytes + ataxia + telangiectasia + elevated AFP + radiosensitivity.

[cite: Nelson 21e Ch. 631; Rothblum-Oviatt Orphanet 2016]

Answer

B. Trisomy of chromosome 13 due to nondisjunction during meiosis II

Answer

C. Constitutive activation of BCR-ABL fusion protein causing Philadelphia chromosome formation

Answer

D. Deficiency of mismatch repair proteins MLH1 and MSH2 causing Lynch syndrome-associated translocations

Explanation

Why option 1 is correct

Why each distractor is wrong

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