一个Smith-Lemli-Opitz综合征家系的临床特征和基因变异分析

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

目的对1个Smith-Lemli-Opitz综合征家系两例患儿进行临床表型和基因变异分析,探讨基因型与临床表型的相关性。方法收集家系成员的临床资料和家族史,采用全外显子组测序分析患儿致病基因,确定可疑变异位点后对家系成员行Sanger测序验证。结果该家系先证者及其妹妹临床均表现为喂养困难,面容异常,癫痫,智力和语言发育障碍等;第3胎生后表现为喂养困难、体重不增,重度营养不良,于6月龄不明原因死亡,未行基因检测。第4胎,男,体健。测序结果显示先证者及其妹妹均携带DHCR7基因(NM_001360.2)c.127G>T(p.Val43Phe)和c.820_825del(p.Asn274_Val275del)复合杂合变异,第4胎未检测到上述变异。这两个变异均未在文献及疾病相关数据库中报道,也未在正常人群数据库(1000G和gnomAD数据库)中收录。其中c.820_825del变异位于DHCR7蛋白的甾醇敏感区域,导致DHCR7蛋白第274位的天冬酰胺和275位的缬氨酸缺失,使蛋白长度变短,可能影响蛋白空间构象的稳定性,从而造成酶活性下降。c.127G>T变异位于蛋白的第一个跨膜区域,推测其会对蛋白的跨膜运输产生影响,且多种软件预测该变异有害。保守性分析结果提示上述3个氨基酸均处于蛋白的高度保守区域。结合本家系患儿的临床表型、家族史及基因检测结果,推测两例患儿均为DHCR7基因变异导致的Smith-Lemli-Opitz综合征。结论本家系丰富了Smith-Lemli-Opitz综合征的表型与基因型的数据,明确了患儿的遗传学病因,为该家系的遗传咨询提供了依据。

Objective To analyze the clinical features and genetic variants of two patients from a pedigree affected with Smith-Lemli-Opitz syndrome and explore their genotype-phenotype correlation.Methods Clinical data and family history of the pedigree were collected.Whole exome sequencing was carried out to identify the potential variants.Suspected variants were verified by Sanger sequencing of the family members.Results The proband and her sister both presented with feeding difficulty,facial dysmorphism,seizures,and mental and speech retardation.The third child of this family presented with feeding difficulty,poor weight gain and severe malnutrition after birth.He had died of unknown cause at 6 months without genetic testing.The fourth child was a healthy boy.Genetic testing showed that both the proband and her sister have carried c.127G>T(p.Val43Phe)and c.820_825del(p.Asn274_Val275del)compound heterozygous variants of the DHCR7 gene(NM_001360.2),but the fourth child carried neither of the variants.The two variants were unreported in the literature and disease-related databases,and were not included in the 1000G and gnomAD databases.The c.820_825del variant may affect the sterol-sensitive region of the DHCR7 protein,which can lead to deletion of two amino acids at positions 247 and 275,causing truncation of the DHCR7 protein.It is speculated that this may affect the stability of protein’s spatial conformation,thereby decrease the activity of the enzyme.The c.127G>T variant may affect the first transmembrane region of the protein,which is involved in the transmembrane transport of proteins.Multiple software predicted it to be harmful.Conservation analysis suggested that the three amino acids all locate in a highly conserved region of the protein.In consideration of the clinical phenotype,family history and result of genetic testing,we speculated that both patients had Smith-Lemli-Opitz syndrome due to variants of the DHCR7 gene.Conclusion This pedigree has enriched the phenotypic and genotypic data of Smith-Lemli-Opitz syndrome,which clarified the genetic etiology of the patients and provided a basis for genetic counseling of this pedigree.