As more patients receive genome-wide sequencing, the number of individuals diagnosed with multiple monogenic conditions is increasing. We sought to investigate the relative phenotypic contribution of dual diagnoses using both manual curation and computational approaches. First, we computed 1,003,236 semantic similarity scores for all possible pairs of 1,417 genes in the Developmental Disorder Gene2Phenotype (DDG2P) database using Human Phenotype Ontology terms. Next, for 62 probands with two molecular diagnoses in the Deciphering Developmental Disorders study, we computed semantic similarity scores between the probands’ phenotypes and DDG2P phenotypes associated with the two disorders and compared the results with manual attribution of proband phenotypes to none, one, or both of the genes. We found a spectrum of phenotypic similarity for dual diagnoses, both across all DDG2P genes and within dual diagnosed probands, from phenotypically distinct through blended to indistinguishable conditions. Pairwise semantic similarity scores between two DDG2P genes were a good predictor of the extent of phenotypic blending observed in probands. Dual diagnoses involving genes linked with synergistic phenotypes can result in more extreme presentations while those involving antagonistic phenotypes have spuriously high pairwise semantic similarity scores despite a potentially milder atypical presentation. We suggest that the phenotypic contribution of two molecular diagnoses may contain discrete, synergistic, or antagonistic elements. Conceptual recognition of this phenotypic spectrum is important for making a final clinico-molecular diagnosis and providing accurate genetic counseling.

中文翻译：

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发育障碍中双重诊断的表型谱


随着越来越多的患者接受全基因组测序，被诊断患有多种单基因疾病的个体数量正在增加。我们试图使用手动管理和计算方法研究双重诊断的相对表型贡献。首先，我们使用人类表型本体术语计算了发育障碍基因 2Phenotype （DDG2P） 数据库中所有可能的 1,417 个基因对的 1,003,236 个语义相似性分数。接下来，对于破译发育障碍研究中具有两种分子诊断的 62 名先证者，我们计算了先证者表型与两种疾病相关的 DDG2P 表型之间的语义相似性评分，并将结果与先证者表型手动归因于无、一个或两个基因进行了比较。我们发现了双重诊断的表型相似性范围，无论是在所有 DDG2P 基因中还是在双重诊断的先证者中，从表型不同到混合到难以区分的情况。两个 DDG2P 基因之间的成对语义相似性评分是先证者中观察到的表型混合程度的良好预测指标。涉及与协同表型相关的基因的双重诊断可能导致更极端的表现，而涉及拮抗表型的双重诊断尽管非典型表现可能较轻，但成对语义相似性评分却高得离谱。我们认为两种分子诊断的表型贡献可能包含离散、协同或拮抗元素。对这种表型谱的概念识别对于做出最终的临床分子诊断和提供准确的遗传咨询非常重要。