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Phenotypic Expansion Illuminates Multilocus Pathogenic Variation

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Phenotypic Expansion Illuminates Multilocus Pathogenic Variation HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Genet Med Manuscript Author . Author manuscript; Manuscript Author available in PMC 2019 April 05. Published in final edited form as: Genet Med. 2018 December ; 20(12): 1528–1537. doi:10.1038/gim.2018.33. Phenotypic Expansion Illuminates Multilocus Pathogenic Variation Ender Karaca, M.D.1,*,#, Jennifer E. Posey, M.D., Ph.D.1,*, Zeynep Coban Akdemir, Ph.D.1, Davut Pehlivan, M.D.1, Tamar Harel, M.D., Ph.D.2, Shalini N. Jhangiani, M.S.3, Yavuz Bayram, M.D.1,#, Xiaofei Song, B.S.1, Vahid Bahrambeigi, M.S.1,4, Ozge Ozalp Yuregir, M.D., Ph.D.5, Sevcan Bozdogan, M.D.6, Gozde Yesil, M.D.7, Sedat Isikay, M.D.8, Donna Muzny, M.S.3, Richard A. Gibbs, Ph.D.1,3, and James R. Lupski, M.D., Ph.D., D.Sc.(hon)1,3,9,10 1.Department of Molecular and Human Genetics, Baylor College of Medicine, Houston 77030, TX, USA 2.Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel 3.Human Genome Sequencing Center, Baylor College of Medicine, Houston 77030, TX, USA 4.Graduate Program in Diagnostic Genetics, School of Health Professions, University of Texas MD Anderson Cancer Center, Houston 77030, TX, USA 5.Genetic Diagnosis Center, University of Health Sciences, City Hospital, Adana 01370, Turkey 6.Department of Medical Genetics, Cukurova University Faculty of Medicine, Adana 01330, Turkey 7.Department of Medical Genetics, Bezmialem University, Istanbul 34093, Turkey 8.Department of Physiotherapy and Rehabilitation, Hasan Kalyoncu University, School of Health Sciences, Gaziantep 27410, Turkey 9.Department of Pediatrics, Baylor College of Medicine, Houston 77030, TX, USA 10.Texas Children’s Hospital, Houston 77030, TX, USA Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Corresponding Authors: Jennifer E. Posey, M.D., Ph.D., Assistant Professor, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 604B, Houston, TX 77030, (713) 798-6873 (Lab), [email protected]. James R. Lupski, M.D., Ph.D., D.Sc.(hon), Cullen Professor, Department of Molecular and Human Genetics and Professor of Pediatrics, Baylor College of Medicine, One Baylor Plaza, 604B, Houston, TX 77030, (713) 798-6530 (Office), (713) 798-3727 (Betty Fernandini), Fax: (713) 798-5073, [email protected]. *co-first authors #Current Addresses: Ender Karaca M.D. Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA, Yavuz Bayram M.D. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Please see Supplementary Materials and Methods for details of clinical cohort, analysis approach and exome coverage metrics. CONFLICT OF INTEREST Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), formerly the Baylor Miraca Genetics Laboratories (BMGL), which performs clinical exome sequencing. JRL serves on the Scientific Advisory Board of BG. JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. Other authors have no disclosures relevant to the manuscript. Karaca et al. Page 2 Abstract Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author 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 which apparent phenotypic expansion was previously attributed to variation at known disease genes. We performed a retrospective computational re-analysis 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 2 families was explained by multilocus variation identified in the more severely affected sibling. Conclusions: 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 2 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 multilocus variation; distinct/overlapping blended phenotypes; phenotypic expansion of Mendelizing disease traits; neurodevelopmental disorder; personal genomes INTRODUCTION The diagnostic path leading from clinical evaluation to genetic diagnosis is not always direct, and physicians have historically relied on hallmark patterns of history and physical examination findings, or phenotypic features, to formulate a differential diagnosis and guide clinical investigation. However, even ‘typical’ clinical presentations can be misleading, as illustrated by early reports of Fitzsimmons syndrome describing 6 individuals with a seemingly unique combination of spastic paraplegia, skeletal anomalies, dysarthria, and mild developmental delay.1–3 Whole exome sequencing (WES) ultimately demonstrated that despite the consistent set of shared phenotypic features, a single genetic locus did not explain the full phenotypic spectrum of the condition.4 Multiple segregating pathogenic alleles at single5,6 or multiple7,8 loci in a family or clan can challenge both clinical and molecular diagnosis. The occurrence of dual, or multiple, molecular diagnoses in an individual is not new, and reports dating back to the 1960s describe individuals with both hemolytic anemia due to glucose-6-phosphate dehydrogenase deficiency (OMIM #300908) and thalassemia minor, B- thalassemia, or sickle cell trait.9,10 The true frequency of multiple molecular diagnoses has only begun to emerge with the availability of genome-wide investigations such as Genet Med. Author manuscript; available in PMC 2019 April 05. Karaca et al. Page 3 chromosome microarray analysis (CMA)11 and WES; larger-scale analyses of diagnostic Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author WES in a clinical setting have revealed that 3.2 to 7.2% of unselected diagnostic WES cases have two or more molecular diagnoses contributing to their observed clinical phenotype. 8,12–17 This rate can be even higher, 12% (5/41), in selected cohorts.18 From a clinical standpoint, recognition of multiple molecular diagnoses can have important implications for both treatment and estimates of familial recurrence risk.8 Genome-wide analyses have been instrumental for identifying molecular diagnoses in the setting of both atypical presentations of well-characterized syndromes,7 as well as cases for which the set of observed phenotypic features extended beyond those previously reported in association with a particular locus, termed ‘phenotypic expansion’.19 Examples of phenotypic expansion attributed to previously-known disease loci abound, with a striking 18.2% (174/956) of discoveries reported by the NIH-funded Centers for Mendelian Genomics (CMG) representing apparent phenotypic expansion.19 Given the relative frequency of both phenotypic expansion and multiple molecular diagnoses, we explored the hypothesis that cases of apparent phenotypic expansion may sometimes represent a blended phenotype resulting from variation at more than one locus. We tested this hypothesis using extensive phenotyping and personal genome data (WES) from 106 unrelated subjects from a well-characterized neurodevelopmental cohort, including 19 families with apparent phenotypic expansion that had previously been attributed to variation at a known disease gene.20 A high prevalence of identity-by-descent enabled a focus on phenotypic and genotypic variability among siblings with shared genetic backgrounds.20 MATERIALS AND METHODS Patients Patients provided informed consent, including consent to publish photographs, under the Baylor Hopkins Center for Mendelian Genomics (BHCMG) protocol H-29697 approved by the Baylor College of Medicine (BCM) Institutional Review Board. RESULTS We investigated the hypothesis that an observed clinical phenotype, initially interpreted as phenotypic expansion associated with pathogenic variation at one known disease gene locus, may actually represent a blended phenotype due to multilocus variation. We compared the frequency of multilocus variation between cases with and without apparent phenotypic expansion, using a pre-existing, well-phenotyped cohort for which WES had previously demonstrated a high rate of molecular diagnoses (84.4%, 108/128 families).20 Of 108 families for whom a molecular diagnosis was identified, 19 families were classified
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