Biallelic KIF24 Variants Are Responsible for a Spectrum of Skeletal Disorders Ranging from Lethal Skeletal Ciliopathy to Severe Acromesomelic Dysplasia
More than 700 different forms of skeletal dysplasias have been described, each with characteristic clinical and radiographic features. The underlying genetic and molecular pathology is known for several forms. Correct diagnosis is important for genetic counseling, treatment decisions, follow-up and for predicting long-term outcome. With advances in molecular genetics, it has become evident that variable phenotypes can be caused by mutations in one gene, depending on the mutation type and location within the gene.
In this study, the researchers investigated the genetic cause of skeletal dysplasia in three unrelated families by genome, exome and ciliome panel sequencing. The affected patients had variable phenotypes, including lethal skeletal ciliopathy, severe acromesomelic dysplasia and spondylometaphyseal dysplasia. In all affected individuals, biallelic missense variants were identified in KIF24, a gene encoding a microtubule-dependent motor protein that acts as a negative regulator of ciliogenesis.
In the two families with lethal ciliopathy and acromesomelic dysplasia, the homozygous missense variants (c.1457A>G; p.(Ile486Val) and c.1565A>G; p.(Asn522Ser) were located in the functionally important motor domain, likely accounting for the severe phenotype in both families. In contrast, compound heterozygous variants (c.1697C>T; p.(Ser566Phe)/c.1811C>T; p.(Thr604Met)), located in a potential regulatory region outside the motor domain, resulted in the less severe phenotype of the patient with spondylometaphyseal dysplasia. The study also showed that ciliogenesis and cytogenesis were impaired in fibroblasts of a fetus affected by the lethal ciliopathy.
To summarize, this study describes new forms of skeletal dysplasia associated with KIF24, a gene that was previously not linked to any disorder. The findings also highlight the importance of the role of primary cilia in skeletal development and expand the genetic heterogeneity and phenotypic spectrum of rare bone disorders.
Biallelic KIF24 Variants Are Responsible for a Spectrum of Skeletal Disorders Ranging from Lethal Skeletal Ciliopathy to Severe Acromesomelic Dysplasia. Reilly ML, Ain NU, Muurinen M, Tata A, Huber C, Simon M, Ishaq T, Shaw N, Rusanen S, Pekkinen M, Högler W, Knapen MFCM, van den Born M, Saunier S, Naz S, Cormier-Daire V, Benmerah A, Makitie O, J Bone Miner Res. 2022 Sep;37(9):1642-1652.