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Mutations in NCAPG2 cause a severe neurodevelopmental syndrome that expands the phenotypic spectrum of condensinopathies

ABSTRACT: The use of whole exome/genome sequencing has been a catalyst for a genotype-first approach to diagnostics. Under this paradigm, we have implemented systematic sequencing of neonates and young children with a suspected genetic disorder. Here we report two families with recessive mutations in NCAPG2 and overlapping clinical phenotypes that include severe neurodevelopmental defects; failure to thrive; ocular abnormalities; and defects in urogenital and limb morphogenesis. NCAPG2 encodes a member of the condensin II complex, necessary for the condensation of chromosomes prior to cell division. Consistent with a causal role for NCAPG2, we found abnormal chromosome condensation, augmented anaphase chromatin bridge formation and micronuclei in daughter cells of proband skin fibroblasts. To test the functional relevance of the discovered variants, we generated an ncapg2 zebrafish model. Morphants displayed clinically-relevant phenotypes, such as microcephaly and renal anomalies with concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR/Cas9 F0 mutants. Finally, we noted that the individual with a complex urogenital defect also harbored a heterozygous deletion of NPHP1, a common contributor to nephronophthisis. To test whether sensitization at the NPHP1 locus might contribute to a more severe renal phenotype, we co-suppressed nphp1 and ncapg2, which resulted in significantly more dysplastic renal tubules. Together, our data suggest that impaired function of NCAPG2 results in a severe condensinopathy and highlight the potential utility of examining candidate pathogenic lesions beyond the primary disease locus.

ORGANISM(S): Danio rerio

PROVIDER: GSE122932 | GEO | 2018/11/27

REPOSITORIES: GEO

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Mutations in NCAPG2 cause a severe neurodevelopmental syndrome that expands the phenotypic spectrum of condensinopathies

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