Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Noor Genetics Laboratory, Ahvaz, Iran.
J Gene Med. 2019 Aug;21(8):e3103. doi: 10.1002/jgm.3103. Epub 2019 Jul 11.
Short-stature (SS) is multifactorial pathologic condition that originates from either genetic or environmental factors. The diagnosis is based on family history, clinical findings, radiological examination and genetic analysis. A variety of genes have been reported for SS, among which FGFR-3 was the main gene in achondroplasia and hypochondroplasia. In other forms of SS, the gene involved varies from one patient to another. Whole exome sequencing (WES) and comparative genomic hybridization (CGH) have recently introduced a growing body of genes annually. The present study performed a WES analysis on an Iranian family suffering from an inherited form of SS aiming to diagnose the causative gene. The father and all of his four sons were diagnosed as SS.
The blood samples were collected from the proband and his available family members. Genomic DNA was extracted using salting-out method. The DNA of the proband was analyzed using WES and confirmed through polymerase chain reaction (PCR)-sequencing. The WES-extracted variant was evaluated in silico using software aiming to determine whether this nucleotide change is pathogenic. The presence of the variant was traced in other affected family members using PCR-sequencing.
Following segregation analysis, variant c.896 G>A of the COMP gene was found in all of the affected individuals in a heterozygous form. This variant resulted in substitution of glycine 299 with arginine and was previously predicted as pathogenic in the Human Gene Mutation Database dataset, although it represents the first report in Iran.
The findings of the present study suggest consideration of the c.896 G>A variant of the COMP gene with respect to the genetic counseling of inherited skeletal dysplasia in Iran.
身材矮小（SS）是一种多因素的病理状况，起源于遗传或环境因素。诊断基于家族史、临床发现、影像学检查和基因分析。已经报道了多种与 SS 相关的基因，其中 FGFR-3 是软骨发育不全和软骨发育不良的主要基因。在其他形式的 SS 中，涉及的基因因患者而异。全外显子组测序（WES）和比较基因组杂交（CGH）近年来每年都会发现越来越多的基因。本研究对一个患有遗传性 SS 的伊朗家庭进行了 WES 分析，旨在诊断致病基因。父亲和他的四个儿子都被诊断为 SS。
从先证者和他的可用家庭成员中采集血液样本。使用盐析法提取基因组 DNA。使用 WES 分析先证者的 DNA，并通过聚合酶链反应（PCR）-测序进行验证。使用软件对 WES 提取的变体进行计算机分析，以确定该核苷酸变化是否具有致病性。使用 PCR-测序在其他受影响的家庭成员中追踪该变体的存在。
在进行分离分析后，发现 COMP 基因的 c.896G>A 变体在所有受影响的个体中均以杂合形式存在。该变体导致甘氨酸 299 被精氨酸取代，并且先前在人类基因突变数据库数据集中被预测为致病性，尽管这是在伊朗的首次报道。
本研究的结果表明，在伊朗遗传骨骼发育不良的遗传咨询中，应考虑 COMP 基因的 c.896G>A 变体。
