Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Genet Med. 2018 Dec;20(12):1528-1537. doi: 10.1038/gim.2018.33. Epub 2018 Apr 26.
Multilocus variation-pathogenic variants in two or more disease genes-can potentially explain the underlying genetic basis for apparent phenotypic expansion in cases for which the observed clinical features extend beyond those reported in association with a "known" disease gene.
Analyses focused on 106 patients, 19 for whom apparent phenotypic expansion was previously attributed to variation at known disease genes. We performed a retrospective computational reanalysis of whole-exome sequencing data using stringent Variant Call File filtering criteria to determine whether molecular diagnoses involving additional disease loci might explain the observed expanded phenotypes.
Multilocus variation was identified in 31.6% (6/19) of families with phenotypic expansion and 2.3% (2/87) without phenotypic expansion. Intrafamilial clinical variability within two families was explained by multilocus variation identified in the more severely affected sibling.
Our findings underscore the role of multiple rare variants at different loci in the etiology of genetically and clinically heterogeneous cohorts. Intrafamilial phenotypic and genotypic variability allowed a dissection of genotype-phenotype relationships in two families. Our data emphasize the critical role of the clinician in diagnostic genomic analyses and demonstrate that apparent phenotypic expansion may represent blended phenotypes resulting from pathogenic variation at more than one locus.
两个或更多疾病基因中的多位点变异-致病变体-可能解释了明显表型扩展的潜在遗传基础，在这些情况下，观察到的临床特征超出了与“已知”疾病基因相关的报告。
分析集中在 106 名患者身上，其中 19 名患者的明显表型扩展以前归因于已知疾病基因的变异。我们使用严格的变异调用文件过滤标准对全外显子组测序数据进行了回顾性计算重新分析，以确定是否涉及其他疾病部位的分子诊断可能解释观察到的扩展表型。
在表型扩展的 19 个家庭中的 31.6%（6/19）和没有表型扩展的 87 个家庭中的 2.3%（2/87）中发现了多位点变异。两个家庭中同胞间的家族内临床变异性由受影响更严重的兄弟姐妹中发现的多位点变异解释。
我们的发现强调了不同部位多个罕见变异在遗传和临床异质队列病因中的作用。两个家庭中的家族内表型和基因型变异性允许对两种基因型-表型关系进行剖析。我们的数据强调了临床医生在诊断基因组分析中的关键作用，并表明明显的表型扩展可能代表来自一个以上位点的致病变异导致的混合表型。
