Fetal Expression of Pontocerebellar Hypoplasia Linked to Pathogenic COASY Variants

Pontocerebellar hypoplasia (PCH) comprises a group of rare, perinatal-onset neurodegenerative genetic disorders characterized by reduced cerebellar and brainstem volume. Among the 17 recognized subtypes listed in the OMIM database, PCH12 is notable for its severe presentation. This subtype results from biallelic pathogenic variants in the COASY gene, leading to loss of function and impair coenzyme A (CoA) biosynthesis.

We report 2 fetal cases from a consanguineous Pakistani couple, referred to a fetal medicine center for PCH associated with a homozygous COASY c.1486-3C>G pathogenic variant. The couple's first pregnancy was uneventful. However, the second and third pregnancies revealed severe cerebellar hypoplasia and additional brain anomalies on ultrasound and fetal MRI. Both pregnancies were terminated following prenatal findings, and post-fetopathological molecular testing confirmed the COASY variant.

These cases highlight the severe fetal phenotype of PCH12, characterized by cerebellar and brainstem hypoplasia, microcephaly, and neurodegeneration. The recurrence of this lethal condition in a consanguineous family underscores the importance of molecular diagnosis for early detection and genetic counseling. Preimplantation genetic testing for future pregnancies and cascade testing of extended family members are essential in such populations. Our antenatal report emphasizes the need for a multidisciplinary approach to the diagnosis and management of PCH12.