ArticleGenetics in medicine : official journal of the American College of Medical Genetics2018
Phenotypic expansion illuminates multilocus pathogenic variation.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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90 citing papers in PubMed, 150 citations in OpenAlex.
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- Ending diagnostic odyssey by reanalysis of whole exome sequencing data: reclassification of suspected Fanconi anemia cases to dyskeratosis congenita and Diamond-Blackfan anemia.Orphanet journal of rare diseases · 2025Article
- Genome Sequencing Uncovers Additional Findings in Phelan-McDermid Syndrome.American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics · 2025Article
- Improving automated deep phenotyping through large language models using retrieval-augmented generation.Genome medicine · 2025Article
- Contribution of rare coding variants to microcephaly in individuals with neurodevelopmental disorders.Genome medicine · 2025Article
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- Prevalence of Individuals With Multiple Diagnosed Genetic Diseases in the Undiagnosed Diseases Network.American journal of medical genetics. Part A · 2025Article
- Homozygous variants in WDR83OS lead to a neurodevelopmental disorder with hypercholanemia.American journal of human genetics · 2024Article
- Pontocerebellar Hypoplasia Type 9: A New Case with a Novel Mutation and Review of Literature.Journal of pediatric genetics · 2024Article
- Multilocus pathogenic variants contribute to intrafamilial clinical heterogeneity: a retrospective study of sibling pairs with neurodevelopmental disorders.BMC medical genomics · 2024Article
- Biallelic variation in the choline and ethanolamine transportermedRxiv : the preprint server for health sciences · 2024Article
- An adult with cystathionine beta-synthase deficiency, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, and deafness: A case report.Genetics and molecular biology · 2024Article
- The impact of the Turkish population variome on the genomic architecture of rare disease traits.Genetics in medicine open · 2024Article
30 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 7 institutions in 3 countries.
Funding
Abstract
purposeMultilocus 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.
methodsAnalyses 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.
resultsMultilocus 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.
conclusionOur 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.
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