Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis

Pontocerebellar hypoplasia (PCH) is a heterogeneous neurodegenerative disorder with a prenatal onset. Using whole-exome sequencing, we identified variants in the gene Coenzyme A (CoA) synthase (COASY) gene, an enzyme essential in CoA synthesis, in four individuals from two families with PCH, prenata...

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Bibliographic Details
Published in:European journal of human genetics : EJHG 2018-12, Vol.26 (12), p.1752-1758
Main Authors: van Dijk, Tessa, Ferdinandusse, Sacha, Ruiter, Jos P N, Alders, Mariëlle, Mathijssen, Inge B, Parboosingh, Jillian S, Innes, A Micheil, Meijers-Heijboer, Hanne, Poll-The, Bwee Tien, Bernier, Francois P, Wanders, Ronald J A, Lamont, Ryan E, Baas, Frank
Format: Article
Language:English
Subjects:
Aborted Fetus - abnormalities
Arthrogryposis
Arthrogryposis - genetics
Arthrogryposis - pathology
Cells, Cultured
Cerebellar Diseases - genetics
Cerebellar Diseases - pathology
Coenzyme A
Humans
Hypoplasia
Infant, Newborn
Loss of Function Mutation
Male
Microcephaly
Microcephaly - genetics
Microcephaly - pathology
Microencephaly
Neurodegeneration
Neurodegenerative diseases
Nonsense mutation
Phenotypes
Ribonucleic acid
RNA
Stop codon
Syndrome
Transferases - genetics
Transferases - metabolism
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Summary:Pontocerebellar hypoplasia (PCH) is a heterogeneous neurodegenerative disorder with a prenatal onset. Using whole-exome sequencing, we identified variants in the gene Coenzyme A (CoA) synthase (COASY) gene, an enzyme essential in CoA synthesis, in four individuals from two families with PCH, prenatal onset microcephaly, and arthrogryposis. In family 1, compound heterozygous variants were identified in COASY: c.[1549_1550delAG]; [1486-3 C>G]. In family 2, all three affected siblings were homozygous for the c.1486-3 C>G variant. In both families, the variants segregated with the phenotype. RNA analysis showed that the c.1486-3 C>G variant leads to skipping of exon 7 with partial retention of intron 7, disturbing the reading frame and resulting in a premature stop codon (p.(Ala496Ilefs*20)). No CoA synthase protein was detected in patient cells by immunoblot analysis and CoA synthase activity was virtually absent. Partial CoA synthase defects were previously described as a cause of COASY Protein-Associated Neurodegeneration (CoPAN), a type of Neurodegeneration and Brain Iron Accumulation (NBIA). Here we demonstrate that near complete loss of function variants in COASY are associated with lethal PCH and arthrogryposis.
ISSN:1018-4813
1476-5438
DOI:10.1038/s41431-018-0233-0