TY - JOUR
T1 - Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis
AU - Boschann, Felix
AU - Cogulu, Muhsin
AU - Pehlivan, Davut
AU - Balachandran, Saranya
AU - Vallecillo-Garcia, Pedro
AU - Grochowski, Christopher M.
AU - Hansmeier, Nils R.
AU - Coban Akdemir, Zeynep H.
AU - Prada-Medina, Cesar A.
AU - Aykut, Ayca
AU - Fischer-Zirnsak, Björn
AU - Badura, Simon
AU - Durmaz, Burak
AU - Ozkinay, Ferda
AU - Hägerling, René
AU - Posey, Jennifer E.
AU - Stricker, Sigmar
AU - Gillessen-Kaesbach, Gabriele
AU - Spielmann, Malte
AU - Horn, Denise
AU - Brockmann, Knut
AU - Lupski, James R.
AU - Kornak, Uwe
AU - Schmidt, Julia
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85136750056&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2022.07.012
DO - 10.1016/j.gim.2022.07.012
M3 - Journal articles
C2 - 35962790
AN - SCOPUS:85136750056
SN - 1098-3600
VL - 24
SP - 2187
EP - 2193
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 10
ER -