1. Personalized Care, Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
2. Division of Medical Genetics, Department of Pediatrics, Children’s Hospital Los Angeles, KeckSchool of Medicine, University of Southern California, Los Angeles, CA 90007, USA
3. Division of Genomic Medicine, Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, KeckSchool of Medicine, University of Southern California, Los Angeles, CA 90027, USA
Corresponding author:
miaosun@chla.usc.edu
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History+
Received
Accepted
Published Online
2025-11-10
2026-02-28
2026-04-27
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Abstract
Pontocerebellar hypoplasia type 12 (PCH12) is an ultra-rare, perinatal lethal, neurodegenerative disorder with microcephaly and arthrogryposis. Previous reports have associated PCH12 with complete loss-of-function variants in COASY identified in 14 fetuses and newborns from eight unrelated families. In contrast, COASY partial loss-of-function variants have been linked to COASY protein-associated neurodegeneration (CoPAN), a subtype of neurodegeneration with brain iron accumulation (NBIA). Emerging evidence suggests that COASY-related disorders may represent a phenotypic continuum between PCH12 and CoPAN. Using exome sequencing, we identified a previously reported missense variant (c.641C>T, p.Ala214Val) and a previously unreported rare nonsense variant (c.1015C>T, p.Arg339*) in the compound heterozygous state in the COASY gene in a patient presenting with clinical features consistent with PCH12. The p.Ala214Val variant has only been described in combination with another missense variant (p.Arg499Cys) in two siblings with CoPAN. The presence of p.Ala214Val in trans with the truncating p.Arg339* variant in this patient is associated with a severe perinatal lethal phenotype resembling PCH12. This case broadens the reported genetic and phenotypic spectrum of COASY-associated disorders and highlights the importance of continued genotype-phenotype correlation investigation.
Lindsey Walker, Linda M. Randolph, Miao Sun.
A novel variant combination in COASY associates with severe prenatal onset PCH12: expanding the clinical and genetic spectrum.
MedScience DOI:10.1007/s11684-026-1241-z
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