一个婴儿恶性石骨症家系的TCIRG1基因突变分析

Analysis of TCIRG1 gene mutation in a Chinese family affected with infantile malignant osteopetrosis

目的通过对1例婴儿恶性石骨症先证者的T细胞免疫调节因子1（T cell immune regulatory factor 1,TCIRG1）基因进行突变分析，为该家系的分子诊断和遗传咨询提供依据。方法应用目标序列捕获及新一代测序技术对先证者及其父母进行基因检测。应用Sanger测序法对可能的致病突变进行验证。结果先证者出生后4个月发病，临床主要表现为进行性贫血、血小板少、肝脾肿大、方颅，影像学表现为骨骼密度广泛增高硬化。测序结果显示，先证者TCIRG1基因存在第8外显子c．796G〉T（p．E266X）和第12外显子c．1372G〉A（p．G458S）复合杂合突变；先证者父亲、祖母为c．796G〉T（p．E266X）杂合突变携带者；先证者母亲为c．1372G〉A（p．G458S）杂合突变携带者。因此，先证者的c．796G〉T突变和c．1372G〉A突变分别源自其父母。经检索PubMed、ClinVar数据库和文献均为未报道过的新突变。结论TCIRG1基因的c．796G〉T和c．1372G〉A复合杂合突变为该家系婴儿恶性石骨症先证者发病的原因。我们的结果丰富了TCIRG1基因突变谱，为家系的分子诊断和遗传咨询提供了依据。

Objective To detect potential mutation of the TCIRG1 gene in a boy with infantile malignant osteopetrosis. Methods Target sequence capture and next-generation sequencing were applied for the proband and his parents to identify the causative mutation, and Sanger sequencing was used to verify the suspected mutation. Results The proband manifested at 4 months of age with symptoms including anemia, thrombocytopenia, hepatosplenomegaly, and cephalus quadratus. X-ray revealed generalized increased bone density. A novel compound heterozygous mutation, c. 796G〉T （p. E266X） and c. 1372G〉A （p. G458S）, were identified in the boy. His father and grandmother also carried the c. 796G〉T （p. E266X） mutation, and his mother carried the c. 1372G〉A （p. G458S） mutation. Neither mutation was found in the PubMed and ClinVar databases. Conclusion The novel compound heterozygous mutation c. 796G〉T （p. E266X） and c. 1372G〉A （p. G458S） probably underlies the disease in the proband. Above results may enrich the mutation spectrum of the TCIRG1 gene and provide new evidence for the molecular basis of infantile malignant osteopetrosis.