Homozygous KIDINS220 loss-of-function variants in fetuses with cerebral ventriculomegaly and limb contractures

Hum Mol Genet. 2017 Oct 1;26(19):3792-3796. doi: 10.1093/hmg/ddx263.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Codon, Nonsense
  • Contracture / genetics
  • Exome
  • Exons
  • Female
  • Fetus
  • Frameshift Mutation
  • Homozygote
  • Humans
  • Hydrocephalus / genetics*
  • Hydrocephalus / metabolism
  • Intellectual Disability / genetics
  • Limb Deformities, Congenital / genetics
  • Loss of Function Mutation / genetics
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Nonsense Mediated mRNA Decay
  • Pregnancy


  • Codon, Nonsense
  • KIDINS220 protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins