一个Smith-Lemli-Opitz综合征家系的临床表型和遗传学分析

Clinical and genetic analysis of a Chinese pedigree affected with Smith-Lemli-Opitz syndrome

目的报道一个中国Smith-Lemli-Opitz综合征家系的临床表型和致病基因变异,并探讨儿童早期诊断的重要性。方法收集该家系成员的临床资料,抽取外周血基因组DNA,应用高通量测序进行全外显子组检测,对候选基因变异位点进行Sanger测序验证,并提取先证者及其父母外周血RNA进行反转录测序验证。结果先证者和家系中另一例患儿均表现有智力和运动障碍、小头畸形、小下颌、鼻孔前翻、双足2/3并趾。先证者还有尿道下裂、单一上切牙、血清胆固醇水平降低的表现,其中单一上切牙为该患儿特有的表型;2例患儿均为DHCR7基因父源c.278C>T(p.T93M)变异和母源c.907G>A(p.G303R)变异,二个变异是已知的致病变异,表型正常的姐姐是p.T93M变异携带者。结论DHCR7基因的复合杂合变异c.278C>T(p.T93M)和c.907G>A(p.G303R)是引起该家系患儿发病的遗传学病因,提高对本病的认识有助于其早期诊断和治疗。

Objective To explore the clinical phenotype and pathogenic variants in a Chinese pedigree affected with Smith-Lemli-Opitz syndrome.Methods Peripheral blood samples were collected from five members,including two affected ones,from the pedigree for the extraction of genomic DNA.Whole exome sequencing was carried out,and candidate variants were verified by Sanger sequencing as well as reverse transcription sequencing at the RNA level.Results The proband and another affected child from the pedigree showed mental retardation,dyskinesia,microcephaly,micrognathia,anteverted nares,and 2/3 toe syndactyly.The proband also had hypospadia,single upper incisor,and lower serum cholesterol level.Both children were found to harbor a paternally derived c.278C>T(p.T93M)variant and a maternally derived c.907G>A(p.G303R)variant of the DHCR7 gene.Both were known pathogenic mutations.Conclusion The compound heterozygous mutations of c.278C>T(p.T93M)and c.907G>A(p.G303R)of the DHCR7 gene probably underlay the disease in this pedigree.Above finding has enabled early diagnosis and treatment of Smith-Lemli-Opitz syndrome.