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Genet Med. 2018 Dec;20(12):1528-1537. doi: 10.1038/gim.2018.33. Epub 2018 Apr 26.

Phenotypic expansion illuminates multilocus pathogenic variation.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. Jennifer.Posey@bcm.edu.
3
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
4
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
5
Graduate Program in Diagnostic Genetics, School of Health Professions, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
6
Genetic Diagnosis Center, University of Health Sciences, City Hospital, Adana, Turkey.
7
Department of Medical Genetics, Cukurova University Faculty of Medicine, Adana, Turkey.
8
Department of Medical Genetics, Bezmialem University, Istanbul, Turkey.
9
Department of Physiotherapy and Rehabilitation, Hasan Kalyoncu University, School of Health Sciences, Gaziantep, Turkey.
10
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. Jennifer.Posey@bcm.edu.
11
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. Jennifer.Posey@bcm.edu.
12
Texas Children's Hospital, Houston, Texas, USA. Jennifer.Posey@bcm.edu.

Abstract

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.

KEYWORDS:

distinct/overlapping blended phenotypes; multilocus variation; neurodevelopmental disorder; personal genomes; phenotypic expansion of Mendelizing disease traits

PMID:
29790871
PMCID:
PMC6450542
DOI:
10.1038/gim.2018.33
[Indexed for MEDLINE]
Free PMC Article

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