AI Article Synopsis

  • KIAA1109 variants are linked to Alkuraya-Kucinskas syndrome, which causes issues like cerebral underdevelopment, clubfeet, and arthrogryposis, with severity depending on the type of genetic change.
  • Severe cases often stem from biallelic truncating variants leading to miscarriage or early death, while milder forms may result from biallelic missense variants causing developmental delays.
  • A family study revealed a specific splice donor mutation in KIAA1109, resulting in partial mRNA skipping, which may explain the milder phenotypes seen in some patients.

Article Abstract

Disease-associated variants in KIAA1109 associate with autosomal recessive Alkuraya-Kucinskas syndrome, which is typified by cerebral parenchymal underdevelopment, clubfeet, and arthrogryposis. Biallelic truncating variants occur with severe disease resulting in miscarriage or early neonatal death, whereas biallelic missense variants can occur with a milder phenotype of global developmental delay and intracranial malformation. This suggests that hypomorphic alleles in KIAA1109 give rise to a milder phenotype than do amorphic alleles. We describe a consanguineous family with pseudodominant segregation of a homozygous noncanonical splice donor variant (NM_015312.2:c.[13438+3A>G];[13438+3A>G]) in mother and daughter. In peripheral blood, sequencing of cDNA detected skipping of exon 76 (NM_015312.3:c.13281_13438del) and, by qRT-PCR quantification, occurred in 82-95% of peripheral blood KIAA1109 mRNA. Although the deletion of exon 76 is predicted to encode p.(Trp4428Serfs*4), 46-83% of KIAA1109 mRNA in peripheral blood evaded nonsense mediated mRNA decay as measured by qRT-PCR. These observations expand understanding of the genotype-phenotype association in KIAA1109-related disease and suggest hypotheses for milder presentations of Alkuraya-Kucinskas syndrome.

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Source
http://dx.doi.org/10.1016/j.ejmg.2022.104427DOI Listing

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