Phenotypic expansion illuminates multilocus pathogenic variation.

TitlePhenotypic expansion illuminates multilocus pathogenic variation.
Publication TypeJournal Article
Year of Publication2018
AuthorsKaraca, E, Posey, JE, Akdemir, ZCoban, Pehlivan, D, Harel, T, Jhangiani, SN, Bayram, Y, Song, X, Bahrambeigi, V, Yuregir, OOzalp, Bozdogan, S, Yesil, G, Isikay, S, Muzny, DM, Gibbs, RA, Lupski, JR
JournalGenet Med
Date Published2018 Apr 26

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.Genetics in Medicine advance online publication, 26 April 2018; doi:10.1038/gim.2018.33.

Alternate JournalGenet. Med.
PubMed ID29790871