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Homozygous KIDINS220 loss-of-function variants in fetuses with cerebral ventriculomegaly and limb contractures.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2017 Oct 01; Vol. 26 (19), pp. 3792-3796. - Publication Year :
- 2017
-
Abstract
- Heterozygous mutations in KIDINS220 were recently suggested a cause of spastic paraplegia, intellectual disability, nystagmus and obesity. All patients carried terminal nonsense de novo mutations that seemed to escape nonsense-mediated mRNA decay. The mechanism for pathogenicity is yet unexplained, as it seems that heterozygous loss-of-function variants of KIDINS220 are generally well tolerated. We present a consanguineous couple who experienced four pregnancy terminations due to repeated findings in the fetuses comprising enlarged cerebral ventricles and limb contractures. Exome sequencing in two of the aborted fetuses revealed a shared homozygous frameshift variant in exon 24 in KIDINS220. Sanger sequencing of the variant in available family members showed complete segregation with the affection status, resulting in a LOD score of 2.5 under an autozygous inheritance model. mRNA studies revealed destruction of the original splice site, resulting in an out-of-frame transcript and introduction of a premature termination codon in exon 25. Premature termination codons in this position are likely to cause activation of nonsense-mediated mRNA decay and result in complete absence of KIDINS220 protein in individuals homozygous for the variant. The phenotype of the presented fetuses overlaps with findings in functional studies of knockout Kidins220 mice embryos that are non-viable with enlarged cerebral ventricles. The human fetuses also exhibit several similarities to the milder phenotype described in patients with heterozygous KIDINS220 mutations. We hence propose that the identified homozygous loss-of-function variant in KIDINS220 causes the phenotype in the presented fetuses, and that this represents a hitherto undescribed severe autosomal recessive neurodevelopmental disorder.<br /> (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Codon, Nonsense
Contracture genetics
Exome
Exons
Female
Fetus
Frameshift Mutation
Homozygote
Humans
Hydrocephalus metabolism
Intellectual Disability genetics
Limb Deformities, Congenital genetics
Loss of Function Mutation genetics
Mutation
Nonsense Mediated mRNA Decay
Pregnancy
Hydrocephalus genetics
Membrane Proteins genetics
Membrane Proteins metabolism
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 26
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 28934391
- Full Text :
- https://doi.org/10.1093/hmg/ddx263