Prenatal diagnosis and reproductive genetics — formative SAQs

SAQ 1 — Pathogenic microarray finding after an increased-risk screen (20 marks, ~15 minutes)

A 39-year-old woman at 16 weeks gestation had a cell-free DNA screen that returned a high probability of trisomy 21. She underwent amniocentesis. The result is not a simple trisomy 21 — the chromosomal microarray reveals a pathogenic 22q11.2 deletion (approximately 2.5 Mb), consistent with 22q11.2 deletion (DiGeorge) syndrome. The fetal anatomy scan shows a conotruncal cardiac defect. She asks whether the baby will be "normal" and what happens next. ^{[1] [6]}

Questions

1. Explain why chromosomal microarray was the appropriate first-tier test and what it detected that karyotype would have missed. (4 marks) ^[1]
2. Distinguish between a pathogenic finding, a variant of uncertain significance and a likely benign finding, and explain why this distinction drives counselling. (4 marks) ^[6]
3. Describe the phenotype of 22q11.2 deletion syndrome and outline the neonatal issues the team must anticipate. (5 marks) ^{[1] [11]}
4. Outline the multidisciplinary pathway from this result to delivery, including who should be involved and what neonatal preparations are needed. (4 marks) ^[6]
5. Counsel the recurrence risk for this couple and discuss whether preimplantation genetic testing is relevant for future pregnancies. (3 marks) ^[8]

Model answer anchors

1. Microarray detects submicroscopic copy-number variants (deletions and duplications) down to approximately 50–200 kilobases — far below karyotype's optical resolution. The Wapner trial showed microarray identifies clinically significant CNVs in approximately 6% of structurally abnormal fetuses with normal karyotype. The 22q11.2 deletion is a submicroscopic CNV that a conventional karyotype would not have resolved. ^[1]
2. Pathogenic: sufficient evidence to assert the variant causes disease. Likely pathogenic: strong but not conclusive. VUS: evidence is conflicting or insufficient — the meaning is genuinely unknown, and the variant must not be over-called as pathogenic or dismissed as benign. Likely benign / benign: evidence does not support disease causation. The distinction drives prognosis, reproductive decisions and neonatal planning. ^[6]
3. 22q11.2 deletion syndrome: conotruncal cardiac defects (tetralogy of Fallot, interrupted aortic arch, truncus arteriosus), palatal dysfunction (cleft palate, velopharyngeal insufficiency), immune deficiency (thymic hypoplasia), hypocalcaemia (parathyroid hypoplasia), characteristic facies, developmental delay and learning difficulty, and psychiatric illness in adolescence and adulthood. Neonatal priorities: cardiac evaluation, calcium monitoring, immune assessment, feeding assessment. ^{[1] [11]}
4. Multidisciplinary team: clinical genetics (phenotype correlation, counselling), maternal-fetal medicine (ongoing pregnancy surveillance, delivery planning), paediatric cardiology and cardiac surgery (conotruncal defect), neonatology (neonatal transition, calcium and immune surveillance), and parent support. Deliver at a centre with neonatal cardiac capability. Prepare the neonatal team for hypocalcaemia and immune work-up. ^[6]
5. Most 22q11.2 deletions are de novo, giving an empirical recurrence risk of approximately 1% for future pregnancies (due to possible parental germline mosaicism). If a parent carries the deletion, recurrence risk is 50%. PGT-M or prenatal diagnosis (CVS or amniocentesis with targeted testing for the deletion) is available for future pregnancies. ^[8]