A novel variant combination in COASY associates with severe prenatal onset PCH12: Expanding the clinical and genetic spectrum

Coenzyme A (CoA) is an essential and ubiquitous cofactor that plays a central role in numerous fundamental biological processes, including energy metabolism, fatty acid synthesis and oxidation, amino acid catabolism, ketogenesis, cholesterol synthesis, and biosynthesis of neurotransmitters. The biosynthesis of CoA from pantothenate (vitamin B5) proceeds through a highly conserved five-step enzymatic pathway, with the final two steps catalyzed by a single bifunctional enzyme known as coenzyme A synthase (COASY). COASY possesses both phosphopantetheine adenylyltransferase (PPAT) and dephospho-CoA kinase (DPCK) enzymatic activities, making it an indispensable enzyme for cellular CoA homeostasis.

Given the fundamental importance of CoA in cellular metabolism, it is not surprising that genetic defects in COASY have been associated with severe human diseases, primarily affecting the nervous system, which is particularly vulnerable to metabolic perturbations due to its high energy demands and complex lipid metabolism. COASY-related disorders represent a fascinating and increasingly recognized spectrum of neurodegenerative conditions, ranging from severe perinatally lethal pontocerebellar hypoplasia to milder later-onset neurodegeneration with brain iron accumulation. Pontocerebellar hypoplasia type 12 (PCH12) is the most severe form of COASY-related disorder, characterized by profound microcephaly, hypoplasia of the pons and cerebellum, arthrogryposis multiplex congenita, and typically perinatal lethality. PCH12 was first described in 2018 by van Dijk and colleagues, who identified biallelic loss-of-function variants in COASY in four families with affected fetuses and newborns presenting with severe prenatal-onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis. Since that initial description, additional cases have been reported, bringing the total number of reported PCH12 cases to 14 fetuses and newborns from eight unrelated families worldwide.

All reported PCH12 cases to date have been associated with biallelic variants predicted to cause complete loss of COASY function, including nonsense variants, frameshift variants, and canonical splice site variants, consistent with the severe phenotype. In contrast, COASY protein-associated neurodegeneration (CoPAN), a subtype of neurodegeneration with brain iron accumulation (NBIA), represents the milder end of the COASY-related disorder spectrum. CoPAN typically presents in childhood or adolescence with progressive dystonia, spasticity, cognitive decline, and psychiatric manifestations, with characteristic brain MRI findings including iron accumulation in the basal ganglia. CoPAN is associated with biallelic missense variants in COASY that are predicted to cause partial loss of function, retaining some residual enzymatic activity. The distinction between PCH12 and CoPAN has traditionally been viewed as categorical, but emerging evidence, including this case report, suggests that COASY-related disorders may actually represent a continuous phenotypic spectrum determined by the degree of residual COASY enzymatic activity.

In this case report, the authors describe a patient with clinical features consistent with PCH12 who was found to carry a novel variant combination in the COASY gene identified through exome sequencing. The patient was a compound heterozygote for two COASY variants: a previously reported missense variant c.641C>T (p.Ala214Val) and a previously unreported nonsense variant c.1015C>T (p.Arg339*). The p.Ala214Val missense variant is of particular interest because it has been described previously in the literature, but only in combination with another missense variant (p.Arg499Cys) in two siblings with CoPAN, the milder phenotype. In those previously reported siblings, the combination of two missense variants, both predicted to cause partial loss of function, resulted in the CoPAN phenotype with onset in childhood and a protracted clinical course. In contrast, the patient described in this case report carries the same p.Ala214Val missense variant in trans with a truncating nonsense variant (p.Arg339*), which is predicted to cause complete loss of function of that allele. This variant combination would be expected to result in a greater overall reduction in COASY enzymatic activity compared with the combination of two missense variants, because the nonsense allele produces no functional protein, leaving only the p.Ala214Val missense allele to provide residual COASY activity. Consistent with this genotype-phenotype correlation hypothesis, this patient presented with a severe perinatal lethal phenotype resembling PCH12, rather than the milder CoPAN phenotype observed in the previously reported siblings with two missense variants.

This case provides important evidence supporting the hypothesis that COASY-related disorders represent a phenotypic continuum determined by the degree of residual enzymatic activity, and it demonstrates that the same missense variant can be associated with either the mild CoPAN phenotype or the severe PCH12 phenotype depending on the variant with which it is paired in trans. The identification of the novel p.Arg339* nonsense variant in this case further expands the known mutational spectrum of COASY-related disorders.