Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis

Felix Boschann, Muhsin Cogulu, Davut Pehlivan, Saranya Balachandran, Pedro Vallecillo-Garcia, Christopher M. Grochowski, Nils R. Hansmeier, Zeynep H. Coban Akdemir, Cesar A. Prada-Medina, Ayca Aykut, Björn Fischer-Zirnsak, Simon Badura, Burak Durmaz, Ferda Ozkinay, René Hägerling, Jennifer E. Posey, Sigmar Stricker, Gabriele Gillessen-Kaesbach, Malte Spielmann, Denise HornKnut Brockmann, James R. Lupski, Uwe Kornak*, Julia Schmidt

*Korrespondierende/r Autor/-in für diese Arbeit

Abstract

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.

OriginalspracheEnglisch
ZeitschriftGenetics in Medicine
Jahrgang24
Ausgabenummer10
Seiten (von - bis)2187-2193
Seitenumfang7
ISSN1098-3600
DOIs
PublikationsstatusVeröffentlicht - 10.2022

Strategische Forschungsbereiche und Zentren

  • Querschnittsbereich: Medizinische Genetik

DFG-Fachsystematik

  • 205-03 Humangenetik

Zitieren