Biallelic KIF24 Variants Are Responsible for a Spectrum of Skeletal Disorders Ranging From Lethal Skeletal Ciliopathy to Sev.pdf (9.11 MB)
Biallelic KIF24 variants are responsible for a spectrum of skeletal disorders ranging from lethal skeletal ciliopathy to severe acromesomelic dysplasia
journal contribution
posted on 2023-06-10, 05:20 authored by Louise Reilly, Noor U Ain, Mari Muurinen, Alice Tata, Celine Huber, Marleen Simon, Tayyaba Ishaq, Nick Shaw, Salla Rusanen, Minna Pekkinen, Wolfgang Högler, Maarten F C M Knapen, Myrthe van den Born, Sophie Saunier, Sadaf Naz, Valerie Cormier-Daire, Alexandre Benmerah, Outie MakitieSkeletal dysplasias comprise a large spectrum of mostly monogenic disorders affecting bone growth, patterning, and homeostasis, and ranging in severity from lethal to mild phenotypes. This study aimed to underpin the genetic cause of skeletal dysplasia in three unrelated families with variable skeletal manifestations. The six affected individuals from three families had severe short stature with extreme shortening of forelimbs, short long-bones, and metatarsals, and brachydactyly (family 1); mild short stature, platyspondyly, and metaphyseal irregularities (family 2); or a prenatally lethal skeletal dysplasia with kidney features suggestive of a ciliopathy (family 3). Genetic studies by whole genome, whole exome, and ciliome panel sequencing identified in all affected individuals biallelic missense variants in KIF24, which encodes a kinesin family member controlling ciliogenesis. In families 1 and 3, with the more severe phenotype, the affected subjects harbored homozygous variants (c.1457A>G; p.(Ile486Val) and c.1565A>G; p.(Asn522Ser), respectively) in the motor domain which plays a crucial role in KIF24 function. In family 2, compound heterozygous variants (c.1697C>T; p.(Ser566Phe)/c.1811C>T; p.(Thr604Met)) were found C-terminal to the motor domain, in agreement with a genotype–phenotype correlation. In vitro experiments performed on amnioblasts of one affected fetus from family 3 showed that primary cilia assembly was severely impaired, and that cytokinesis was also affected. In conclusion, our study describes novel forms of skeletal dysplasia associated with biallelic variants in KIF24. To our knowledge this is the first report implicating KIF24 variants as the cause of a skeletal dysplasia, thereby extending the genetic heterogeneity and the phenotypic spectrum of rare bone disorders and underscoring the wide range of monogenetic skeletal ciliopathies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Publication status
- Published
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- Published version
Journal
Journal of Bone and Mineral ResearchISSN
0884-0431Publisher
WileyExternal DOI
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9Volume
37Page range
1642-1652Event location
United StatesDepartment affiliated with
- Neuroscience Publications
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- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-11-03First Open Access (FOA) Date
2022-11-03First Compliant Deposit (FCD) Date
2022-11-03Usage metrics
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