Abstract：
Despite increasing knowledge of disease-causing genes in human genetics, approximately half of the individuals affected by neurodevelopmental disorders remain genetically undiagnosed. Part of this missing heritability might be caused by genetic variants outside of protein-coding genes, which are not routinely diagnostically investigated. A recent preprint identified de novo variants in the non-coding spliceosomal snRNA gene RNU4-2 as a cause of a frequent novel syndromic neurodevelopmental disorder. Here we mined 164 whole genome sequencing (WGS) trios from individuals with neurodevelopmental or multiple congenital anomaly disorders that received diagnostic genomic investigations at our clinic. We identify a recurrent de novo RNU4-2 variant (NR_003137.2(RNU4-2):n.64_65insT) in a 5-year-old girl with severe global developmental delay, hypotonia, microcephaly, and seizures that likely explains her phenotype, given that extensive previous genetic investigations failed to identify an alternative cause. We present detailed phenotyping of the individual obtained during a 5-year follow-up. This includes photographs showing recognizable facial features for this novel disorder, which might allow prioritizing other currently unexplained affected individuals sharing similar facial features for targeted investigations of RNU4-2. This case illustrates the power of re-analysis to solve previously unexplained cases even when a diagnostic genome remains negative.
摘要：
尽管人类遗传学中对致病基因的认识越来越多，大约一半受神经发育障碍影响的个体仍未被基因诊断。这种缺失的部分遗传力可能是由蛋白质编码基因之外的遗传变异引起的，这不是常规的诊断调查。最近的预印本鉴定了非编码剪接体snRNA基因RNU4-2中的从头变体是常见的新型综合征性神经发育障碍的原因。在这里，我们从患有神经发育或多种先天性异常疾病的个体中挖掘了164个全基因组测序（WGS）三重奏，这些疾病在我们的诊所接受了诊断性基因组研究。我们在患有严重全球发育迟缓的5岁女孩中发现了一个反复的从头RNU4-2变体（NR_003137.2（RNU4-2）：n.64_65insT），低张力,小头畸形,癫痫发作可能解释了她的表型，鉴于以前广泛的遗传调查未能确定替代原因。我们提供了在5年随访期间获得的个体的详细表型。这包括显示这种新型疾病的可识别面部特征的照片，这可能允许优先考虑其他目前无法解释的受影响个体,这些个体具有相似的面部特征,以进行RNU4-2的针对性调查.这种情况说明了即使在诊断基因组保持阴性的情况下，重新分析也可以解决先前无法解释的病例。
