A 16-year-old boy presents with a 6-month history of auditory hallucinations, paranoid delusions, and social withdrawal. On examination, he has a long narrow face, malar flatness, and hypernasal speech. Cardiac evaluation reveals tetralogy of Fallot. FISH analysis of his karyotype shows the pattern marked **A** in the diagram — a single fluorescent signal at the 22q11.2 locus on one chromosome 22, with two signals on the other chromosome 22. Which of the following best explains the psychiatric phenotype in this patient?

Explanation

## Why option 1 is correct The single FISH signal at **A** represents hemizygous loss of the 22q11.2 region — the pathognomonic finding in velocardiofacial syndrome (VCFS/Shprintzen syndrome). This ~3 Mb deletion encompasses the COMT gene, which encodes catechol-O-methyltransferase, a key enzyme in dopamine catabolism. Hemizygosity of COMT leads to altered prefrontal dopamine signaling, a major mechanism linking 22q11.2 deletion to the high incidence of schizophrenia and schizoaffective disorder (up to 25–30% by adulthood). The combination of conotruncal cardiac disease (tetralogy of Fallot), characteristic facies, hypernasal speech (velopharyngeal insufficiency), and new-onset psychosis in a teenager is the classic presentation of 22q11.2 deletion syndrome. The FISH pattern — one signal on the deleted chromosome, two on the normal — is diagnostic. [Kaplan and Sadock 11e Ch 30; Robbins 10e Ch 5] ## Why each distractor is wrong - **Option 2 (Trisomy 21)**: Trisomy 21 would show three FISH signals at chromosome 21, not a single signal at 22q11.2. While Down syndrome can be associated with behavioral and psychiatric features, it does not present with the cardiac, facial, and speech phenotype of VCFS, nor does it produce the specific dopaminergic pathology linked to COMT hemizygosity. - **Option 3 (Balanced translocation)**: A balanced translocation preserves gene dosage and would not produce the hemizygous loss pattern seen at **A** (single signal). Balanced rearrangements typically do not cause the psychiatric phenotype or the CATCH-22 features seen in this patient. - **Option 4 (Mosaic aneuploidy)**: Mosaic aneuploidy would produce a mixed pattern of cells with different signal numbers on FISH, not the consistent single signal at **A**. Moreover, mosaic 22q11.2 loss is extremely rare and would not account for the systemic cardiac and immunologic features of VCFS. **High-Yield:** 22q11.2 deletion (VCFS/Shprintzen) is the second most common genetic risk factor for schizophrenia after family history; COMT hemizygosity is the leading mechanistic hypothesis; FISH showing one signal = deletion. [Kaplan and Sadock 11e Ch 30; Robbins 10e Ch 5]