Alys M Ridsdale, Anna Dickerson, V Kartik Chundru, Helen V Firth, Caroline F Wright
{"title":"Phenotypic spectrum of dual diagnoses in developmental disorders.","authors":"Alys M Ridsdale, Anna Dickerson, V Kartik Chundru, Helen V Firth, Caroline F Wright","doi":"10.1016/j.ajhg.2024.08.025","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":null,"pages":null},"PeriodicalIF":8.1000,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of human genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.ajhg.2024.08.025","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/30 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
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.
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.