Can leaky splicing and evasion of premature termination codon surveillance contribute to the phenotypic variability in Alkuraya-Kucinskas syndrome?

Hui-Lin Chin; Susan Lin; Joshua Dalmann; Bhavi Modi; Emily Alderman; Areesha Salman; Kate L Del Bel; Anna Lehman; Stuart E Turvey; Cornelius F Boerkoel

doi:10.1016/j.ejmg.2022.104427

Can leaky splicing and evasion of premature termination codon surveillance contribute to the phenotypic variability in Alkuraya-Kucinskas syndrome?

Eur J Med Genet. 2022 Mar;65(3):104427. doi: 10.1016/j.ejmg.2022.104427. Epub 2022 Jan 19.

Authors

Affiliations

¹ Department of Medical Genetics and Provincial Medical Genetics Program, University of British Columbia and Women's Hospital of British Columbia, Vancouver, BC, Canada; Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, Singapore. Electronic address: hui-lin_chin@nuhs.edu.sg.
² The Rare Disease Discovery Hub, BC Children's Hospital Research Institute, University of British Columbia and BC Children's Hospital, Vancouver, BC, Canada.
³ Department of Medical Genetics and Provincial Medical Genetics Program, University of British Columbia and Women's Hospital of British Columbia, Vancouver, BC, Canada.
⁴ Department of Medical Genetics and Provincial Medical Genetics Program, University of British Columbia and Women's Hospital of British Columbia, Vancouver, BC, Canada; The Rare Disease Discovery Hub, BC Children's Hospital Research Institute, University of British Columbia and BC Children's Hospital, Vancouver, BC, Canada.

PMID: 35063693
DOI: 10.1016/j.ejmg.2022.104427

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.

MeSH terms

Biological Variation, Population
Codon, Nonsense*
Genetic Association Studies
Humans
Pedigree
RNA Splicing*

Substances

Codon, Nonsense