Department of Molecular Medicine, Birjand University of Medical Sciences, Birjand, Iran.
Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.
J Gene Med. 2020 Dec;22(12):e3265. doi: 10.1002/jgm.3265. Epub 2020 Sep 29.
Congenital muscular dystrophy (CMD) refers to hypotonia and delayed motor development that is manifested at or near the birth. Additional presentations have been observed in CMD syndromes.
Thorough clinical examinations were performed on two unrelated Iranian families with typical symptoms of CMD and uncommon features such as intellectual disability and nephrolithiasis. The genomic DNA of probands were subjected to whole exome sequencing. Following the detection of candidate variants with a bioinformatic pipeline, the familial co-segregation analysis was carried out using polymerase chain reaction-based Sanger sequencing.
We identified a missense homozygous variant in the fukutin-related protein (FKRP) gene (c.968G>A, p.Arg323His) related to CMD-dystroglycanopathy type B5 (MDDGB5) and a frameshift homozygous variant in the selenoprotein N (SELENON) gene (c.1446delC, p.Asn483Thrfs*11) associated with congenital rigid-spine muscular dystrophy 1 (RSMD1), which were completely segregated with the phenotypes in the families. These variants were not found in either the 1000 Genomes Project or the Exome Aggregation Consortium. The present study provides the first report of these homozygous sequence variants in Iran. Moreover, our study was the first observation of nephrolithiasis in FKRP-related dystroglycanopathy and intellectual disability in SELENON-related myopathies. Based on in silico studies and molecular docking, these variations induced pathogenic effects on the proteins.
Our findings extend the genetic database of Iranian patients with CMD and, in general, the phenotypical spectrum of syndromic CMD. It is recommended to consider these variants for a more accurate clinical interpretation, prenatal diagnosis and genetic counseling in families with a history of CMD, especially in those combined with cognitive impairments or renal dysfunctions.
先天性肌肉营养不良症（CMD）是指在出生时或出生附近表现出的张力减退和运动发育迟缓。在 CMD 综合征中还观察到其他表现。
对两个具有 CMD 典型症状和智力障碍和肾结石等不常见特征的伊朗无关家庭的先证者进行了彻底的临床检查。对先证者的基因组 DNA 进行了全外显子组测序。在用生物信息学管道检测到候选变体后，使用聚合酶链反应基于 Sanger 测序进行了家族共分离分析。
我们在与 CMD-肌营养不良蛋白聚糖病 B5 （MDDGB5）相关的 fukutin 相关蛋白（FKRP）基因（c.968G>A，p.Arg323His）中发现了一个纯合错义变异体，在与先天性刚性脊柱肌肉营养不良症 1 （RSMD1）相关的 selenoprotein N（SELENON）基因（c.1446delC，p.Asn483Thrfs*11）中发现了一个纯合框移变异体，这些变异体在家庭中与表型完全分离。这些变体在 1000 基因组计划或外显子聚集联盟中均未发现。本研究首次报道了这些纯合序列变体在伊朗的存在。此外，我们的研究首次观察到 FKRP 相关肌营养不良症中的肾结石和 SELENON 相关肌病中的智力障碍。基于计算机研究和分子对接，这些变异对蛋白质产生了致病影响。
我们的发现扩展了伊朗 CMD 患者的遗传数据库，总体上扩展了综合征性 CMD 的表型谱。建议在具有 CMD 病史的家族中，特别是在伴有认知障碍或肾功能障碍的家族中，考虑这些变体以进行更准确的临床解释、产前诊断和遗传咨询。
