COASY – Pontocerebellar Hypoplasia Type 12

COASY (https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:29932) encodes CoA synthase, the terminal enzyme in coenzyme A biosynthesis. Biallelic COASY variants cause pontocerebellar hypoplasia type 12 (PCH12, https://monarchinitiative.org/MONDO:0032643), a perinatal‐lethal neurodegenerative disorder marked by cerebellar and cerebral atrophy.

Autosomal recessive inheritance is established through nine probands from five families with a recurrent splice-site variant c.1486-3C>G [PMID:35499143]. Two additional siblings homozygous for c.1664G>A (p.Arg555His) expand allelic heterogeneity [PMID:36495139].

Segregation analysis in multiplex sibships shows co-segregation of biallelic COASY variants with PCH12 in two families (one additional affected relative each) [PMID:36495139; PMID:35499143].

Clinically, PCH12 presents antenatally with cerebellar hypoplasia, microcephaly, intrauterine growth restriction, arthrogryposis, flexion contractures, and thoracic hypoplasia. Postnatal findings include severe hypotonia, poor suck, spasticity, seizures, optic neuropathy, agenesis of the corpus callosum, and simplified gyral pattern [PMID:35499143].

Functional studies demonstrate that c.1486-3C>G causes exon 7 skipping and premature termination; immunoblot and enzymatic assays reveal near-complete loss of COASY protein and activity, supporting a loss-of-function mechanism with concordant phenotype in patient fibroblasts [PMID:30089828].

Integration of genetic and experimental data yields a Strong clinical validity classification with robust segregation and functional concordance. Key take-home: Biallelic loss-of-function COASY variants reliably cause AR PCH12, enabling precise molecular diagnosis and genetic counseling.

References

• American journal of medical genetics. Part A • 2023 • Progressive brain atrophy and severe neurodevelopmental phenotype in siblings with biallelic COASY variants. PMID:36495139
• Journal Unknown • Year Unknown • Clinical and neuroradiological profile of nine fetuses/neonates with COASY c.1486-3C>G PMID:35499143
• European journal of human genetics : EJHG • 2018 • Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis. PMID:30089828

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