Novel Biallelic Variants in KIF21A Cause a Novel Phenotype of Fetal Akinesia with Neurodevelopmental Defects

Background: Fetal akinesia (FA) is a complex disease entity, sharing arthrogryposis as a common feature.

Methods: Using whole-exome-sequencing, we identified eight mutations that are loss of function mutations predicted to cause premature stop codon or essential splice site mutations that would lead to aberrant KIF21A isoforms.

Results: We report five unrelated individuals with bi-allelic variants in the kinesin family member 21A gene (KIF21A), a member of the kinesin-4 family that is functional in axon growth and guidance by transporting cargo anterograde to the synapses. We showed that the affected individuals with those variants had severe phenotypes with neurodevelopmental disorder, structural brain abnormalities, arthrogryposis of multiple joints, muscular hypotonia, and hypokinesia. Furthermore, all these phenotypes strongly correlate with the recently published porcine phenotype that also has bi-allelic truncating variants, with a few of patients showing features of a neuropathy.

Discussion: In contrast with our findings, previous reports have indicated that the known phenotypic effect of KIF21A caused by the heterozygous variants that lead to missense mutations or deletions and are significantly clustered in the motor domain or coiled-coil region of KIF21A, which in turn causes an isolated ophthalmologic phenotype with congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Conclusively, we describe a novel disease in the FA spectrum with a primary neurogenic defect due to biallelic variants in the KIF21A.

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Publikationsverlauf

Artikel online veröffentlicht:
28. Oktober 2021