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Abstract：
Waardenburg syndrome (WS) is characterized by hearing loss and pigmentary abnormalities of the eyes, hair, and skin. The condition is genetically heterogeneous, and is classified into four clinical types differentiated by the presence of dystopia canthorum in type 1 and its absence in type 2. Additionally, limb musculoskeletal abnormalities and Hirschsprung disease differentiate types 3 and 4, respectively. Genes PAX3, MITF, SOX10, KITLG, EDNRB, and EDN3 are already known to be associated with WS. In WS, a certain degree of molecularly undetected patients remains, especially in type 2. This study aims to pinpoint causative variants using different NGS approaches in a cohort of 26 Brazilian probands with possible/probable diagnosis of WS1 (8) or WS2 (18). DNA from the patients was first analyzed by exome sequencing. Seven of these families were submitted to trio analysis. For inconclusive cases, we applied a targeted NGS panel targeting WS/neurocristopathies genes. Causative variants were detected in 20 of the 26 probands analyzed, these being five in PAX3, eight in MITF, two in SOX10, four in EDNRB, and one in ACTG1 (type 2 Baraitser-Winter syndrome, BWS2). In conclusion, in our cohort of patients, the detection rate of the causative variant was 77%, confirming the superior detection power of NGS in genetically heterogeneous diseases.
摘要：
Waardenburg综合征（WS）的特征是听力损失和眼睛色素异常，头发,和皮肤。这种情况是遗传异质性的，并分为四种临床类型，其区别在于1型中存在反天视角囊，2型中不存在反天视角囊。此外,肢体肌肉骨骼异常和先天性巨结肠病分别区分为3型和4型。基因PAX3,MITF,SOX10KITLG,EDNRB,和EDN3已知与WS相关联。在WS中,有一定程度的未被分子检测到的病人，尤其是2型。这项研究旨在使用不同的NGS方法在26名巴西先证者的队列中确定致病变异，这些人可能/可能诊断为WS1（8）或WS2（18）。首先通过外显子组测序分析来自患者的DNA。这些家庭中的七个被提交给三人分析。对于不确定的案件，我们应用了针对WS/神经病理学基因的靶向NGS小组。在分析的26位先证中的20位检测到了因果关系变异，这些是PAX3中的五个，MITF中的八个，两个在SOX10中，四个在EDNRB中，ACTG1（2型Baraitser-Winter综合征，BWS2)。总之,在我们的患者队列中，致病变异体的检出率为77%，证实了NGS在遗传异质性疾病中的优越检测能力。
