[Genotype and phenotype analysis of a family with Waardenburg syndrome type Ⅰcaused by a novel mutation in PAX3 gene].

Objective:To identify gene mutation and analysis the association between clinical characterizes and the mutations in a family of Waardenburg syndrome （WS） type I in Yunnan, China. Methods:With informed consent, the proband with WS phenotype and his family members were given medical history collection, physical examination and audiological evaluation. Peripheral blood was obtained, genomic DNA was extracted, and deafness related genes were detected by high-throughput sequencing. Sanger sequencing was used to verify the mutation sites of proband and his family members. Results:C. 602C>G mutation in exon 5 of PAX3 gene was identified, which is nonsense mutation and may cause a truncated protein. The mutation cause 201 amino acid of the protein changed from serine to stop codon. According to the American College of Medical Genetics and Genomics （ACMG）, it is considered as Pathogenicity（PVS1+PM2+PP3）. This mutation has not been included in the database also not been reported in the literature. Conclusion:Combined with the results of clinical diagnosis and gene diagnosis, this mutation was considered as the cause of the disease. This study enriched mutation spectrum of PAX3 gene.目的：通过对云南地区Ⅰ型Waardenburg综合征（WS）一家系的突变基因致病性进行鉴定分析，探讨可能的分子生物学致病原因。 方法：经知情同意，对具有WS表型的先证者及其家属进行病史采集、体格检查、听力学评估。获取外周血，提取基因组DNA，高通量测序方法对耳聋相关基因进行检测，对先证者及其家属进行突变位点的Sanger测序验证分析。 结果：先证者高通量测序发现PAX3基因第5外显子c.602C>G突变，该突变为无义突变。导致编码蛋白质第201位氨基酸由丝氨酸变为终止密码子，氨基酸提前终止翻译，蛋白质截短。经Sanger测序验证先证者父亲携带相同位点的突变，弟弟该位点未突变。根据美国医学遗传学与基因组学学会遗传变异分类标准与指南（ACMG），判定为致病性（PVS1+PM2+PP3）。保守性分析提示多个物种氨基酸序列一致，具有高度保守性。 结论：结合临床诊断及基因诊断结果，初步认定该突变为患儿致病原因。本研究丰富了PAX3基因的突变图谱，为临床分子诊断及遗传咨询提供了一定参考。.