Key result
Biallelic recessive trait variants in ADAMTS15 were identified as the cause of a novel autosomal recessive connective tissue disorder resulting in a distal arthrogryposis syndrome.
Observational (n=5)
Biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder resulting in a distal arthrogryposis syndrome.
Answers are grounded in this paper and cite their sources.
May support targeted testing in unexplained distal arthrogryposis; leaves open functional validation and prevalence studies.
PURPOSE: We aimed to identify the underlying genetic cause for a novel form of distal arthrogryposis. METHODS: Rare variant family-based genomics, exome sequencing, and disease-specific panel sequencing were used to detect ADAMTS15 variants in affected individuals. Adamts15 expression was analyzed at the single-cell level during murine embryogenesis. Expression patterns were characterized using in situ hybridization and RNAscope. RESULTS: We identified homozygous rare variant alleles of ADAMTS15 in 5 affected individuals from 4 unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. Radiographic investigations showed physiological interphalangeal joint morphology. Additional features included knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. Analysis of mouse whole-embryo single-cell sequencing data revealed a tightly regulated Adamts15 expression in the limb mesenchyme between embryonic stages E11.5 and E15.0. A perimuscular and peritendinous expression was evident in in situ hybridization in the developing mouse limb. In accordance, RNAscope analysis detected a significant coexpression with Osr1, but not with markers for skeletal muscle or joint formation. CONCLUSION: In aggregate, our findings provide evidence that rare biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder, resulting in a distal arthrogryposis syndrome.
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Boschann et al. (2022) conducted an observational in Distal arthrogryposis (n=5). Biallelic variants in ADAMTS15 was evaluated on Genetic cause of a novel form of distal arthrogryposis. Biallelic recessive trait variants in ADAMTS15 were identified as the cause of a novel autosomal recessive connective tissue disorder resulting in a distal arthrogryposis syndrome.
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