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

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.

Kidins220/ARMS transgenic lines could be instrumental in the understanding of the molecular mechanisms leading to spastic paraplegia and obesity

“…This is a very interesting finding, as similar heterozygous mutations have been recently reported to cause spastic paraplegia, intellectual disability, nystagmus and obesity ('SINO' syndrome) in three unrelated children [2]. Moreover, when in homozygosis, loss-of-function KIDINS220 variants cause extremely severe neurodevelopmental defects that are embryonically lethal [3]. Thus, evidence is accumulating in support of the notion that this protein plays a fundamental role during nervous system development as well as in the maintenance of neuronal homeostasis during adolescence and adulthood.…”

“…Knockout embryos present extensive apoptosis in the central and peripheral nervous systems, coupled to hydrocephalus as well as to defects of cardiovascular development [8,9]. Importantly, some of the phenotypes characterizing the Kidins220 knockout embryos resemble the defects observed in the human embryos carrying homozygous Kidins220 loss-of-function mutations [3]. Moreover, the immune system-specific deletion of Kidins220 leads to severe alterations of B cell development and activation [10].…”

Heterozygous KIDINS220 mutation leads to spastic paraplegia and obesity in an Asian girl

“…Three patients have been previously reported to be affected by KIDINS220 mutation [1] and four fetuses were reported to be lethal due to homozygous mutations of KIDINS220 derived from the same consanguineous parents [2]. The major findings of heterozygous mutants were milder than those of homozygous mutants, including spastic paraplegia, intellectual disability, nystagmus and obesity, termed SINO by the authors [1].…”

Atypical, milder presentation in a child with CC2D2A and KIDINS220 variants

“…Heterozygous truncating variants in KIDINS220 have been associated with spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO -OMIM 617296) (Josifova et al, 2016;Yang et al, 2018). Pathogenic homozygous variants seem to be associated with a more severe phenotype with limb contractures and hydrocephalus (Mero et al, 2017).…”