一例罕见Guion-Almeida型下颌骨颜面发育障碍胎儿的遗传学分析

Genetic analysis of a rare fetus with mandibulofacial dysostosis Guion-Almeida type

目的对1例超声检查表现为小下颌畸形伴双耳低位、小耳畸形、羊水过多、胃无回声的胎儿进行临床和遗传学分析,以明确其遗传学病因。方法应用全外显子组测序(whole exome sequencing,WES)技术对1例常规染色体核型分析和染色体微阵列分析(chromosome microarray analysis,CMA)未见异常的超声结构异常胎儿行基因变异检测,针对可疑变异进行先证者及其父母Sanger测序验证和生物信息学预测。结果WES检测发现胎儿EFTUD2基因第23外显子存在一个无义变异c.2302C>T(p.Q768X),其父母未检测到该变异。该变异为未报道过的新变异,导致其编码的EFTUD2蛋白在768位氨基酸处翻译提前终止。经生物信息学预测,768位氨基酸在不同物种中高度保守,Q768X变异体改变了EFTUD2蛋白空间结构,可能影响蛋白的功能。结论应用WES技术明确EFTUD2基因c.2302C>T变异是引起胎儿Guion-Almeida型下颌骨颜面发育障碍的遗传学病因。该变异丰富了EFTUD2基因的变异谱,为家系的遗传咨询和产前诊断提供依据。

Objective To delineate the clinical and genetic features of a fetus with micrognathia,low-set ears,microtia,polyhydramnios and anechoic stomach by ultrasonography.Methods Whole exome sequencing(WES)was carried out to detect genetic variant in the fetus,for which routine chromosomal karyotyping and chromosomal microarray analysis(CMA)yielded no positive finding.Candidate variants were verified by Sanger sequencing and bioinformatic analysis.Results WES revealed that the fetus has carried a de novo nonsense c.2302C>T(p.Q768X)variant in exon 23 of the EFTUD2 gene,which was detected in neither parent.The variant was unreported previously and may lead to premature termination of the translation of EFTUD2 protein at the 768th amino acid.Bioinformatic analysis predicted the amino acid to be highly conserved and may alter the structure and function of the EFTUD2 protein.Conclusion The c.2302C>T variant of the EFTUD2 gene probably underlay the mandibulofacial dysostosis Guion-Almeida type in the fetus.Discovery of the novel variant has enriched variant spectrum of the EFTUD2 gene and provided a basis for genetic counseling and prenatal diagnosis for the family.