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 12
KeywordsChild, Preschool, Exome, Female, Genetic Association Studies, Genetic Diseases, Inborn, Genetic Variation, Genotype, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Male, Mutation, Pathology, Molecular, Pedigree, Phenotype, Whole Exome Sequencing

PURPOSE: Multilocus 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.

METHODS: Analyses 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.

RESULTS: Multilocus 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.

CONCLUSION: Our 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.

Alternate JournalGenet Med
PubMed ID29790871
PubMed Central IDPMC6450542
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States

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