TY - JOUR
T1 - Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis
AU - van Dijk, Tessa
AU - Ferdinandusse, Sacha
AU - Ruiter, Jos P. N.
AU - Alders, Mariëlle
AU - Mathijssen, Inge B.
AU - Parboosingh, Jillian S.
AU - Innes, A. Micheil
AU - Meijers-Heijboer, Hanne
AU - Poll-The, Bwee Tien
AU - Bernier, Francois P.
AU - Wanders, Ronald J. A.
AU - Lamont, Ryan E.
AU - Baas, Frank
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85052510671&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30089828
U2 - https://doi.org/10.1038/s41431-018-0233-0
DO - https://doi.org/10.1038/s41431-018-0233-0
M3 - Article
C2 - 30089828
SN - 1018-4813
VL - 26
SP - 1752
EP - 1758
JO - European journal of human genetics
JF - European journal of human genetics
IS - 12
ER -