Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Mol Genet Genomic Med. 2022 Sep;10(9):e2004. doi: 10.1002/mgg3.2004. Epub 2022 Jun 27.
Gnathodiaphyseal dysplasia (GDD) is an ultrarare autosomal dominant bone dysplasia characterized by cementoosseous lesions of the jawbones, bone fragility, frequent bone fractures at the young age, bowing of tubular bones, and diaphyseal sclerosis of long bones associated with generalized osteopenia. GDD is caused by point mutations in anoctamin-5 (ANO5) on chromosome 11p14.3. For the past few years, next generation sequencing (NGS) technology has facilitated the discovery of causative variants in genetically heterogeneous diseases.
In this study, exome sequencing (ES) was performed using the DNA sample of the proband. Family histories and clinical information were collected through comprehensive medical examination and genetic counseling.
ES results identified a heterozygous variant, NM_213599.3:c.1078T>C(p.Cys360Arg) in the ANO5 gene. Sanger sequencing was performed to confirm the detected pathogenic variant in DNA samples of the entire family (except deceased individuals), which segregated with the disease within the family. Finally, in silico analysis was applied to test the pathogenicity of the variant using various online software.
In summary, our investigation identified a novel pathogenic variant in the ANO5, responsible for gnathodiaphyseal dysplasia in a large Iranian family. Therefore, based on the present study, this variant can be helpful for diagnosis and effective management of GDD patients.
颌骨-骨干发育不良（GDD）是一种超罕见的常染色体显性遗传性骨发育不良，其特征为颌骨的牙骨质-骨性病损、骨脆弱、年轻时频繁发生骨折、管状骨弯曲以及长骨骨干硬化伴全身性骨质疏松。GDD 由 11p14.3 染色体上的 anoctamin-5（ANO5）点突变引起。在过去的几年中，下一代测序（NGS）技术促进了遗传异质性疾病中致病变异的发现。
本研究对先证者的 DNA 样本进行了外显子组测序（ES）。通过全面体检和遗传咨询收集家族史和临床信息。
ES 结果在 ANO5 基因中发现了一个杂合变异，NM_213599.3：c.1078T>C（p.Cys360Arg）。对整个家族（除已故个体外）的 DNA 样本进行了 Sanger 测序，以确认检测到的致病性变异与家族内的疾病共分离。最后，应用各种在线软件进行了计算机分析，以测试该变异的致病性。
总之，我们的研究在一个大型伊朗家族中发现了 ANO5 中的一个新的致病变异，该变异导致颌骨-骨干发育不良。因此，基于本研究，该变异可以有助于 GDD 患者的诊断和有效管理。
