小头畸形-骨发育不良-原基性侏儒症Ⅱ型家系的临床及遗传学分析

Clinical and genetic analysis of a pedigree with Microcephalic osteodysplastic primordial dwarfism typeⅡ

目的小头畸形-骨发育不良-原基性侏儒症Ⅱ型(MOPDⅡ)罕见病家系的中心粒周蛋白基因(PCNT)新发变异的鉴定,以及流产胚胎的PCNT基因突变筛查。方法对两名MOPDⅡ疑似患儿及其父母进行全外显子测序(WES)的家系分析,并通过一代测序和实时荧光相对定量PCR验证。同时,对流产组织进行全外显子测序分析以筛查PCNT基因的突变情况。结果通过全外显子测序发现先证者及其弟弟的PCNT基因外显子34存在c.7469_7472del杂合突变,以及17~21号外显子杂合缺失。经过父母的验证,c.7469_7472del缺失遗传自父亲,17~21号外显子缺失遗传自母亲。对30例流产组织进行筛查,发现有4例突变,其中有3例为杂合突变且均为新的突变位点,1例为复合杂合突变。结论在先证者及家系中发现了一个新的插入缺失突变(InDel)变异和一个新的拷贝数变异(CNV),复合杂合突变是导致MOPDⅡ发生的主要原因。对流产组织的检测,进一步揭示了PCNT基因突变在流产患儿中的携带率。

Objective Identification of novel variants of PCNT gene in MOPDⅡ families and screening of PCNT mutations in aborted embryos. Methods Whole exome sequencing(WES) was performed on two suspected MOPDⅡ children and their parents, and verified by sanger sequencing and qPCR. At the same time, WES analysis was performed on the aborted tissue for mutations screen in the PCNT gene. Results WES revealed that the proband and his younger brother had the c.7469_7472del heterozygous mutation in exon 34 of the PCNT gene inherited from the mother, and the c.7469_7472del heterozygous deletion in exons 17~21 inherited from the father. Screening of 30 aborted tissues revealed that 4 samples carried mutations, of which 3 samples were heterozygous mutations and all were new mutation sites, and 1 sample was compound heterozygous mutation. Conclusion A novel InDel variant and a novel CNV variant were found in the family, and compound heterozygous mutation was the main cause of MOPDⅡ. The detection of aborted tissue further revealed the carrying rate of PCNT gene mutation in aborted tissue.