Clinical Context

• Two consecutive pregnancies with cerebellar hypoplasia on anomaly scan
• Products of conception (POC) from 2nd pregnancy: WES confirmed Pontocerebellar Hypoplasia Type 12 (PCH12)
• PCH12 is caused by biallelic (autosomal recessive) mutations in the COASY gene (chromosome 17q21.2), which encodes Coenzyme A synthase
• The COASY c.1486-3C>G variant is a well-recognized founder mutation in South Asian (Indian) populations, present with an allele frequency of ~0.62% in Asian Indian databases (Mishra et al., 2022, PMID 35499143)
• Both parents are confirmed obligate heterozygous carriers - recurrence risk is 25% in every pregnancy

Next Steps in Preconception Management

1. Confirm Parental Carrier Status (if not already done)

• Targeted Sanger sequencing or WES in both parents to document the exact pathogenic variant(s) (homozygous vs. compound heterozygous in the proband)
• This is mandatory before PGT-M probe design

2. Preimplantation Genetic Testing for Monogenic Disease (PGT-M) - PRIMARY RECOMMENDATION

• The couple undergoes IVF/ICSI to create embryos
• Embryos undergo trophectoderm biopsy at blastocyst stage (day 5-6)
• Each embryo is tested for the known COASY pathogenic variant(s)
• Only unaffected embryos (homozygous normal or heterozygous carriers) are selected for transfer
• Unaffected = 75% of embryos; carrier = 50%; affected = 25%
• PGT-M avoids the need for repeated terminations of affected pregnancies
• ASRM (2023) guidelines support PGT-M for severe, lethal autosomal recessive conditions as a clear indication

3. Genetic Counseling (Mandatory Component)

• Detailed discussion of:
  • 25% recurrence risk per pregnancy
  • Natural history of PCH12 (perinatal lethal, no effective treatment)
  • Options: PGT-M, prenatal diagnosis, gamete donation, adoption
  • Emotional and psychological support for recurrent perinatal loss

4. Alternative: Prenatal Diagnosis (if IVF/PGT-M not feasible)

• Chorionic villus sampling (CVS) at 11-13 weeks for targeted mutation testing (known COASY variant)
• CVS is preferred over amniocentesis because it gives an earlier result, allowing decision-making before ultrasound features appear
• A published Indian case report (Bansal et al., 2024) specifically documented early CVS-based diagnosis in a subsequent pregnancy of a PCH12-affected family, enabling earlier intervention

5. Gamete Donation (If Both Options Declined)

• If PGT-M and prenatal diagnosis are not acceptable, egg or sperm donation (from a non-carrier donor) eliminates the 25% recurrence risk entirely

Summary Algorithm

Confirm exact COASY variant in both parents
         ↓
Is IVF/PGT-M feasible and acceptable?
  YES → PGT-M (primary recommendation)
   NO → CVS at 11-13 weeks for prenatal diagnosis
         ↓
      Affected? → Discuss termination (couple's decision)
   Alternatively → Gamete donation or adoption

Key Points for Indian Context

• The COASY c.1486-3C>G variant is likely a common Indian founder mutation - targeted single-variant testing is sufficient (no need for full exome in prenatal/PGT setting once the index variant is known)
• PCH12 is perinatally lethal with no curative treatment - this strongly justifies PGT-M
• PGT-M avoids recurrent pregnancy loss and repeated terminations, which carry both physical and psychological burden