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Biallelic loss-of-function variants in NEK9 cause an autosomal recessive lethal skeletal dysplasia (MONDO:0014870) characterized by severe neonatal arthrogryposis. To date, two unrelated probands have been reported, each with compound heterozygous truncating variants in NEK9 (2 probands) (PMID:36712877). Both infants presented with multiple joint contractures leading to perinatal lethality. Trio-WES and copy number analysis confirmed segregation of one truncating allele from each unaffected parent in both families.
The variants observed include c.61G>T (p.Cys239Ter) and c.2824del (p.Met942CysfsTer21), both absent from population and clinical databases (PMID:36712877). The exclusive presence of premature termination codons supports a loss-of-function mechanism, likely via haploinsufficiency in skeletal development.
No functional studies modeling NEK9 deficiency in osteochondral or joint development have been reported, representing a gap in mechanistic validation.
Key take-home: NEK9-related lethal skeletal dysplasia is defined by autosomal recessive inheritance of biallelic truncating NEK9 variants, leading to congenital arthrogryposis and perinatal lethality, underscoring the utility of NEK9 in genetic testing for severe neonatal contracture syndromes.
Gene–Disease AssociationLimited2 probands with compound heterozygous truncating NEK9 variants, no additional segregation or replication ([PMID:36712877]) Genetic EvidenceLimitedAutosomal recessive inheritance in two unrelated probands with biallelic loss-of-function variants Functional EvidenceLimitedNo functional characterization of NEK9 in skeletal development to date |