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]

SAQ 2 — Consanguineous couple at one-in-four risk (20 marks, ~15 minutes)

A couple are first cousins. Their first child died at 18 months of age from an undiagnosed neurodegenerative disorder with developmental regression, hypotonia and seizures. No molecular diagnosis was achieved. The mother is now at 8 weeks gestation and asks what can be done to find out whether this baby will be affected. She lives in a rural town three hours from the nearest genetics centre. [7] [11]

Questions

1. Estimate the empirical recurrence risk for this couple and explain the biological basis for consanguinity-related autosomal recessive risk. (4 marks) [7]
2. Outline the diagnostic strategy to identify the causative gene from the deceased child, including the role of autozygosity mapping and exome sequencing. (5 marks) [11]
3. Explain the reproductive options available once (and if) a gene is identified — PGT-M versus prenatal diagnosis — and the factors that guide the choice. (5 marks) [8]
4. Design a capability-matched rural follow-up and safety-net plan for this pregnancy while the molecular work-up is in progress. (3 marks) [6]
5. Discuss why non-directive counselling is essential and what the paediatrician's role is if the family declines all testing. (3 marks) [7]

Model answer anchors

1. First-cousin couples carry an approximately 2–3% excess risk above the population baseline for major congenital anomalies and autosomal recessive conditions combined. Because both parents share common ancestors, they are more likely to carry the same rare recessive allele inherited from a shared ancestor (autozygosity). The prior child's neurodegenerative phenotype in a consanguineous union strongly suggests an autosomal recessive condition, giving an empirical recurrence risk of approximately 1 in 4 per pregnancy. [7]
2. If DNA from the affected child is available (or from both parents), autozygosity mapping identifies regions of homozygosity shared by descent that may contain the causative gene. Whole-exome or genome sequencing of the child (trio if possible) identifies candidate pathogenic variants within those autozygous intervals. If the child's DNA is unavailable, exome sequencing of both parents with autozygosity mapping is less powerful but may still yield a diagnosis. Confirmation of the gene opens targeted testing for this pregnancy. [11]
3. If the gene is identified before this pregnancy progresses beyond the diagnostic window, targeted prenatal diagnosis by CVS (from 11 weeks) or amniocentesis (from 15 weeks) can determine whether the fetus is affected. PGT-M is an alternative for future pregnancies: IVF, embryo biopsy, testing for the familial variant, and transfer of unaffected embryos — but it requires a confirmed familial mutation, and PGT-M does not guarantee a live birth. The choice depends on the gestation, the family's values, IVF access, cost, and the feasibility of prenatal diagnosis timing. Many programmes recommend prenatal confirmation of PGT-M results. [8]
4. Named owner (a specific clinician at the regional genetics centre), a booked appointment within the diagnostic window, telehealth genetics consultation to reduce travel, interpreter if needed, clear documentation of residual risk, and a safety-net plan for neonatal surveillance (metabolic screening, developmental monitoring) in case no molecular diagnosis is achieved before birth. [6]
5. Non-directive counselling presents information, options and outcomes without steering the family toward a particular decision. The family may decline testing for cultural, religious, values-based or access reasons. The paediatrician's role is to document the residual risk, maintain the medical-home relationship, ensure neonatal surveillance (newborn screening for metabolic conditions, developmental monitoring), and keep the door open without coercion. [7]