Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Am J Med Genet A. 2022 Oct;188(10):2861-2868. doi: 10.1002/ajmg.a.62933. Epub 2022 Aug 11.
Spondylo-epi-metaphyseal dysplasias (SEMDs) are a clinically and genetically heterogeneous group of skeletal dysplasias characterized by short stature and abnormal modeling of the spine and long bones. A novel form of rhizomelic skeletal dysplasia, Ain-Naz type, associated with a homozygous variant in GNPNAT1 was recently identified. Herein, we report an Egyptian patient, offspring of consanguineous parents, who presented with a severe form of unclassified SEMD. Whole exome sequencing identified a novel homozygous variant in exon 3, c.77T>G, (p.Phe26Cys) in GNPNAT1, that was confirmed by Sanger sequencing and both parents were found to be heterozygous for the identified variant. Main features included severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings expanding the clinical phenotype described in the previously reported family. We conclude that variants in the GNPNAT1 gene cause an autosomal recessive form of SEMD resembling Desbuquois like dysplasia caused by PGM3, which is involved in the same pathway as GNPNAT1.
脊椎-干骺端-骨干发育不良（SEMDs）是一组临床和遗传上具有异质性的骨骼发育不良，其特征为身材矮小和脊柱及长骨的异常改建。最近发现了一种新型的瑞氏综合征型骨骼发育不良，与 GNPNAT1 中的纯合变异相关。在此，我们报告了一位埃及患者，为近亲结婚所生，表现为严重的未分类 SEMD。外显子组测序在 GNPNAT1 的外显子 3 中发现了一个新的纯合变异 c.77T>G（p.Phe26Cys），通过 Sanger 测序得到证实，且两位父母均为该变异的杂合子。主要特征包括严重的身材矮小、四肢干骺端缩短和广泛的干骺端增宽。短而宽的长骨、短指（趾）畸形、长骨骺端骨化延迟、骨龄提前和免疫缺陷是另外的发现，扩展了之前报道的家系中描述的临床表型。我们得出结论，GNPNAT1 基因的变异导致一种常染色体隐性形式的 SEMD，类似于由 PGM3 引起的 Desbuquois 样发育不良，PGM3 与 GNPNAT1 存在相同的途径。
