CLINICAL REPORT Two unrelated pedigrees with achondrogenesis type 1b carrying a Japan-specific pathogenic variant in SLC26A2 Taisuke Sato 1,2,3 | Takashi Kojima 4 | Osamu Samura 1,2 | Satoshi Kawaguchi 4 | Akie Nakamura 5 | Masahiro Nakajima 6 | Akiko Tanuma-Takahashi 1 | Kazuhiko Nakabayashi 3 | Kenichiro Hata 3 | Shiro Ikegawa 6 | Gen Nishimura 7 | Aikou Okamoto 1 | Takahiro Yamada 4,8 1 Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan 2 Department of Clinical Genetics, The Jikei University Hospital, Tokyo, Japan 3 Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo, Japan 4 Department of Obstetrics, Hokkaido University, Sapporo, Hokkaido, Japan 5 Department of Pediatrics, Hokkaido University, Sapporo, Hokkaido, Japan 6 Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan 7 Center for Intractable Diseases, Saitama Medical University Hospital, Saitama, Japan 8 Clinical Genetics Unit, Kyoto University Hospital, Kyoto, Sakyo-ku, Japan Correspondence Osamu Samura, Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan, Department of Clinical Genetics, The Jikei University Hospital, 3-19-18, Nishi-Shinbashi, Minato-ku, Tokyo 105-8471, Japan. Email: osamusamura@gmail.com Takahiro Yamada, Clinical Genetics Unit, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku Kyoto 606-8507, Japan. Email: taka0197@kuhp.kyoto-u.ac.jp Funding information National Center for Child Health and Development, Grant/Award Number: NCCHD 26-13 Abstract We present two unrelated Japanese pedigrees with achondrogenesis type 1b (ACG1B), characterized by prenatally lethal fetal hydrops and severe micromelia. The affected members in these pedigrees carried a common homozygous missense point mutation in solute carrier family 26 member 2 (SLC26A2), a gene associated with ACG1B (NM_000112:c.1987G>A). This loss-of-function point mutation causes sub- stitution of glycine 663 with arginine in a highly conserved loop domain of SLC26A2. Interestingly, only a few cases of this mutation have been registered in Japanese genomic databases, and there are no reports of this mutation in any major genomic databases outside Japan. Furthermore, we confirmed the presence of a homozygous stretch of approximately 75 kb surrounding the pathogenic variant. Our findings sug- gest that this missense point mutation in SLC26A2, which is likely the cause of the ACG1B phenotypes in these unrelated fetuses, is distributed exclusively in Japan. KEYWORDS achondrogenesis, direct sequencing, skeletal dysplasia, solute carrier family 26 member 2, whole-exome sequencing 1 | INTRODUCTION Achondrogenesis type 1b (ACG1B; OMIM number 600972) is a lethal chondrodystrophy characterized by severe micromelia, broad tubular bones, a narrow chest, and deficient ossification of the vertebral bod- ies and skull, and is detected by fetal ultrasonography or neonatal radiography (Langer, Spranger, Greinacher, & Herdman, 1969). Severe fetal hydrops is also observed in the first trimester of pregnancy. Osamu Samura and Takahiro Yamada contributed equally to this study. Received: 18 September 2019 Revised: 5 November 2019 Accepted: 12 December 2019 DOI: 10.1002/ajmg.a.61469 Am J Med Genet. 2019;1–5. wileyonlinelibrary.com/journal/ajmga © 2019 Wiley Periodicals, Inc. 1