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

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. © 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).

Novel form of rhizomelic skeletal dysplasia associated with a homozygous variant in GNPNAT1.

BACKGROUND: Studies exploring molecular mechanisms underlying congenital skeletal disorders have revealed novel regulators of skeletal homeostasis and shown protein glycosylation to play an important role. OBJECTIVE: To identify the genetic cause of rhizomelic skeletal dysplasia in a consanguineous Pakistani family. METHODS: Clinical investigations were carried out for four affected individuals in the recruited family. Whole genome sequencing (WGS) was completed using DNA from two affected and two unaffected individuals from the family. Sequencing data were processed, filtered and analysed. In silico analyses were performed to predict the effects of the candidate variant on the protein structure and function. Small interfering RNAs (siRNAs) were used to study the effect of Gnpnat1 gene knockdown in primary rat chondrocytes. RESULTS: The patients presented with short stature due to extreme shortening of the proximal segments of the limbs. Radiographs of one individual showed hip dysplasia and severe platyspondyly. WGS data analyses identified a homozygous missense variant c.226G>A; p.(Glu76Lys) in GNPNAT1, segregating with the disease. Glucosamine 6-phosphate N-acetyltransferase, encoded by the highly conserved gene GNPNAT1, is one of the enzymes required for synthesis of uridine diphosphate N-acetylglucosamine, which participates in protein glycosylation. Knockdown of Gnpnat1 by siRNAs decreased cellular proliferation and expression of chondrocyte differentiation markers collagen type 2 and alkaline phosphatase, indicating that Gnpnat1 is important for growth plate chondrocyte proliferation and differentiation. CONCLUSIONS: This study describes a novel severe skeletal dysplasia associated with a biallelic, variant in GNPNAT1. Our data suggest that GNPNAT1 is important for growth plate chondrogenesis.