Phenotypic spectrum of dual diagnoses in developmental disorders.

IF 8.1 1区 生物学 Q1 GENETICS & HEREDITY American journal of human genetics Pub Date : 2024-11-07 Epub Date: 2024-09-30 DOI:10.1016/j.ajhg.2024.08.025
Alys M Ridsdale, Anna Dickerson, V Kartik Chundru, Helen V Firth, Caroline F Wright
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Abstract

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.

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发育障碍双重诊断的表型谱。
随着越来越多的患者接受全基因组测序,被诊断出患有多种单基因疾病的人数也在增加。我们试图通过人工编辑和计算方法来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2表型(DDG2P)数据库中1,417个基因的所有可能配对的1,003,236个语义相似性得分。接下来,我们针对 "解密发育障碍 "研究中具有两种分子诊断结果的 62 位病例,计算了病例表型与这两种疾病相关的 DDG2P 表型之间的语义相似性得分,并将结果与人工将病例表型归因于无基因、一种基因或两种基因的结果进行了比较。我们发现,在所有 DDG2P 基因中以及在双重诊断的探查者中,双重诊断的表型相似度范围从表型不同到混合再到无差别。两个 DDG2P 基因之间的成对语义相似性得分可以很好地预测探查者的表型混合程度。涉及与协同表型相关的基因的双重诊断可能会导致更极端的表现,而涉及拮抗表型的双重诊断尽管可能有较轻的非典型表现,但其配对语义相似性得分却会虚假地偏高。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。从概念上认识这种表型谱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。
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来源期刊
CiteScore
14.70
自引率
4.10%
发文量
185
审稿时长
1 months
期刊介绍: The American Journal of Human Genetics (AJHG) is a monthly journal published by Cell Press, chosen by The American Society of Human Genetics (ASHG) as its premier publication starting from January 2008. AJHG represents Cell Press's first society-owned journal, and both ASHG and Cell Press anticipate significant synergies between AJHG content and that of other Cell Press titles.
期刊最新文献
Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs. Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants. Large-scale application of ClinGen-InSiGHT APC-specific ACMG/AMP variant classification criteria leads to substantial reduction in VUS. Phenotypic spectrum of dual diagnoses in developmental disorders. Cross-ancestry analysis of brain QTLs enhances interpretation of schizophrenia genome-wide association studies.
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