Bi-allelic loss-of-function variants inKIF21Acause severe fetal akinesia with arthrogryposis multiplex

Abstract

BackgroundFetal akinesia (FA) results in variable clinical presentations and has been associated with more than 166 different disease loci. However, the underlying molecular cause remains unclear in many individuals. We aimed to further define the set of genes involved.MethodsWe performed in-depth clinical characterisation and exome sequencing on a cohort of 23 FA index cases sharing arthrogryposis as a common feature.ResultsWe identified likely pathogenic or pathogenic variants in 12 different established disease genes explaining the disease phenotype in 13 index cases and report 12 novel variants. In the unsolved families, a search for recessive-type variants affecting the same gene was performed; and in five affected fetuses of two unrelated families, a homozygous loss-of-function variant in the kinesin family member 21A gene (KIF21A) was found.ConclusionOur study underlines the broad locus heterogeneity of FA with well-established and atypical genotype–phenotype associations. We describe KIF21A as a new factor implicated in the pathogenesis of severe neurogenic FA sequence with arthrogryposis of multiple joints, pulmonary hypoplasia and facial dysmorphisms. This hypothesis is further corroborated by a recent report on overlapping phenotypes observed in Kif21a null piglets.

Characterization of cognitive impairment in adult polyglucosan body disease

“…Exome sequencing was performed as previously described [17]. Two novel heterozygous missense variants c.…”

Expanded Genetic Spectrum and Variable Disease Onset in AOPEP‐Associated Dystonia

“…1 Heterozygous mutations in TMEM151A, encoding transmembrane protein 151 A, a protein of undetermined function, have been very recently associated with paroxysmal kinesigenic dyskinesia (PKD) in the Chinese population. [1][2][3][4] TMEM151A is highly expressed in the brain, including the cerebral cortex and the thalamus and is highly conserved among species. To definitively confirm the association between TMEM151A and PKD, other mutations in the same gene should be identified in independent cohorts from different populations.…”

“…Benita Menden, MD, 1 * Alexander Gutschalk, MD, 2 Gilbert Wunderlich, MD, 3,4 and Tobias B. Haack, MD…”

“…1 and Supplementary Table S1). Both patients were the only ones affected in their families and a previous diagnostic trio-exome analysis 3 (for methods details see Supplementary Information and Supplementary Table S2, pedigrees Supplementary Fig. S1) had not revealed any evidence of potentially clinically relevant changes in established dystonia-associated disease genes.…”

“…After the initial report of the homozygous candidate stop variant (c.1477C>T, p.Arg493*, proband 1) in 2020, 2 we searched an in-house database containing diagnostic grade exome and genome datasets 3,4 from more than 15 000 individuals including 354 cases that were assigned the human phenotype ontology term dystonia (HP:0001332). Stringent filtering for recessive-type variants left 2 dystonia patients carrying different protein-truncating variants in compound heterozygosity with predicted pathogenic missense changes (Fig.…”