Al-Gazali skeletal dysplasia constitutes the lethal end of ADAMTSL2-related disorders
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(Published version)
Date
2023
Authors
Batkovskyte, D.
McKenzie, F.
Taylan, F.
Simsek-Kiper, P.O.
Nikkel, S.M.
Ohashi, H.
Miyahara, H.
Eriksson, G.
Ha, T.
Utine, G.E.
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Journal article
Citation
Journal of Bone and Mineral Research, 2023; 38(5):692-706
Statement of Responsibility
Dominyka Batkovskyte, Fiona McKenzie, Fulya Taylan, Pelin Ozlem Simsek-Kiper, Sarah M Nikkel, Hirofumi Ohashi, Roger E Stevenson, Thuong Ha, Denise P Cavalcanti, Hiroyuki Miyahara, Steven A Skinner, Miguel A Aguirre, Zühal Akçören, Gulen Eda Utine, Tillie Chiu, Kenji Shimizu, Anna Hammarsjö, Koray Boduroglu, Hannah W Moore, Raymond J Louie, Peer Arts, Allie N Merrihew, Milena Babic, Matilda R Jackson, Nikos Papadogiannakis, Anna Lindstrand, Ann Nordgren, Christopher P Barnett, Hamish S Scott, Andrei S Chagin, Gen Nishimura, and Giedre Grigelioniene
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Abstract
Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356) is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located.
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Published May 2023
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© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Received in original form November 25, 2022; revised form March 1, 2023; accepted March 4, 2023. Address correspondence to: Giedre Grigelioniene, MD, PhD, Department of Molecular Medicine and Surgery, Karolinska Institutet, Visionsgatan 4, 17164 Solna, Stockholm, Sweden. E-mail: giedre.grigelioniene@ki.se Additional Supporting Information may be found in the online version of this article.