Dehghan Tezerjani Masoud, Vahidi Mehrjardi Mohammad Yahya, Hozhabri Hossein, Rahmanian Masoud
Abortion Research Centre, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Science, Yazd, Iran.
Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Front Pediatr. 2020 Jun 25;8:340. doi: 10.3389/fped.2020.00340. eCollection 2020.
Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is an autosomal recessive and skeletal disorder included wide spectrum of clinical abnormalities such as fetal growth restriction, disproportionate face, microcephaly, post-natal growth retardation, adult height under 100 cm, abnormal skin pigmentation, insulin resistance, and susceptibility to cerebrovascular and hematologic abnormalities. Due to heterogeneous feature of MOPDs diseases and common clinical features among the different subtypes, mutation analysis can be considered as fundamental in the accurate diagnosis and confirmation of the MOPD II disease. Some studies revealed that, variants of gene encoding Pericentrin protein, , were associated with MOPD II. We performed whole exome sequencing based on the next generation sequencing (Illumina platform), to perform correct diagnosis in a 17-year-old girl with an unknown disease who was referred to the Diabetes Research Center in Yazd, Iran. The clinical features of the patient were short stature, generalized brachydactyly, gradual deterioration of brain functioning, menstrual irregularity, clitoromegaly, acanthosis nigricans, diabetes mellitus, hyperinsulinemia, insulin resistance, and dyslipidemia. Accordingly, her parents were also first cousin with no background disease. After identifying the novel variant, it was confirmed in the proband and her family using bi-directional Sanger sequencing, and its pathogenicity was also checked by different online tools. Our study revealed a novel frame-shift variant in gene (c.7511delA, p.K2504Sfs27), which causes premature termination of Pericentrin protein. The result disclosed that, the proband was affected by MOPD II disease. In addition, the Sanger sequencing confirmed the novel homozygote variant in the proband and heterozygote one in her parents, and the extended family perfectly segregated among them. Online tools such as Varsome and MutationTaster also showed a high level of pathogenicity for the variant identified. A novel variant was identified in the proband and her extended family, which emphasized the importance of gene mutations analysis in the screening and accurate identification of MOPD II disease, especially in prenatal diagnosis.
II型小头畸形性骨发育不良性原始侏儒症（MOPD II）是一种常染色体隐性骨骼疾病，临床异常表现广泛，如胎儿生长受限、面部比例失调、小头畸形、出生后生长迟缓、成人身高不足100厘米、皮肤色素沉着异常、胰岛素抵抗以及易患脑血管和血液系统异常。由于MOPD疾病具有异质性特征且不同亚型之间存在共同临床特征，突变分析可被视为准确诊断和确诊MOPD II疾病的基础。一些研究表明，编码中心粒蛋白的基因变体与MOPD II相关。我们基于下一代测序（Illumina平台）进行了全外显子组测序，以对一名转诊至伊朗亚兹德糖尿病研究中心的17岁不明疾病女孩进行准确诊断。该患者的临床特征包括身材矮小、全身性短指畸形、脑功能逐渐衰退、月经不规律、阴蒂肥大、黑棘皮病、糖尿病、高胰岛素血症、胰岛素抵抗和血脂异常。因此，她的父母也是近亲，且无家族病史。在鉴定出该新变体后，通过双向Sanger测序在先证者及其家族中进行了确认，并使用不同的在线工具检查了其致病性。我们的研究在 基因中发现了一个新的移码变体（c.7511delA，p.K2504Sfs27），该变体导致中心粒蛋白提前终止。结果表明，先证者患有MOPD II疾病。此外，Sanger测序证实了先证者中的新纯合子变体及其父母中的杂合子变体，并且在大家庭中该变体完美分离。Varsome和MutationTaster等在线工具也显示所鉴定的变体具有高度致病性。在先证者及其大家庭中鉴定出了一个新变体，这强调了 基因突变分析在MOPD II疾病筛查和准确鉴定中的重要性，尤其是在产前诊断中。
