Biallelic KIF24 Variants Are Responsible for a Spectrum of Skeletal Disorders Ranging From Lethal Skeletal Ciliopathy to Severe Acromesomelic Dysplasia

Abstract

Skeletal 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.

TOPORS as a novel causal gene for Joubert syndrome

“…Interestingly, this haplotype is common in individuals of European and Latin American ancestry but is much less common in individuals of African and East Asian ancestry. Two OMIM genes map within this haplotype: UBAP1 , a component of the endosomal sorting machinery associated with autosomal dominant spastic paraplegia, and KIF24 , encoding a kinesin motor protein that plays a role in ciliary disassembly associated with ciliopathy‐spectrum skeletal dysplasia (Farazi Fard et al, 2019; Reilly et al, 2022). SNP markers in this haplotype have been associated with an eQTL of KIF24 in brain (cerebellum, frontal cortex), GI tract (sigmoid colon, esophagus, gastroesophageal junction), skeletal muscle, and testes (https://www.gtexportal.org/home/gene/KIF24).…”

Regulation of ciliary homeostasis by intraflagellar transport-independent kinesins

“…These include kidney disorders resultant from KIF26B mutations [ 87 ], and KIF19A depletion leading to female infertility [ 22 ]. Complementing these insights, recent discoveries have delineated biallelic variants of KIF24 as pathogenic factors in skeletal ciliopathies, encompassing variants such as acromesomelic skeletal dysplasia and spondylometaphyseal dysplasia [ 88 ]. Furthermore, genetic variants in KIF1B , KIF21B , and KIF5A have been associated with increased vulnerability to multiple sclerosis [ 89 – 91 ].…”

Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling

“…Pathogenic variants in KIF-related genes, also known as "kinesinopathies" [15], have been associated with variable human phenotypes, including neurodevelopmental disorders and skeletal dysplasias [16][17][18][19][20][21][22]. Itay et al reported heterozygous missense variants in KIF5B in individuals that were clinically diagnosed with kyphomelic dysplasia and presented with short stature, osteoporosis, fractures, bone deformities, and variable developmental delay [23].…”