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The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience.

ABSTRACT: PURPOSE:Using exome sequence data from 159 families participating in the National Institutes of Health Undiagnosed Diseases Program, we evaluated the number and inheritance mode of reportable incidental sequence variants. METHODS:Following the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings from next-generation sequencing, we extracted variants in 56 genes from the exome sequence data of 543 subjects and determined the reportable incidental findings for each participant. We also defined variant status as inherited or de novo for those with available parental sequence data. RESULTS:We identified 14 independent reportable variants in 159 (8.8%) families. For nine families with parental sequence data in our cohort, a parent transmitted the variant to one or more children (nine minor children and four adult children). The remaining five variants occurred in adults for whom parental sequences were unavailable. CONCLUSION:Our results are consistent with the expectation that a small percentage of exomes will result in identification of an incidental finding under the American College of Medical Genetics and Genomics recommendations. Additionally, our analysis of family sequence data highlights that genome and exome sequencing of families has unavoidable implications for immediate family members and therefore requires appropriate counseling for the family.

SUBMITTER: Lawrence L

PROVIDER: S-EPMC4190001 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience.

Lawrence Lauren L Sincan Murat M Markello Thomas T Adams David R DR Gill Fred F Godfrey Rena R Golas Gretchen G Groden Catherine C Landis Dennis D Nehrebecky Michele M Park Grace G Soldatos Ariane A Tifft Cynthia C Toro Camilo C Wahl Colleen C Wolfe Lynne L Gahl William A WA Boerkoel Cornelius F CF

Genetics in medicine : official journal of the American College of Medical Genetics 20140501 10

<h4>Purpose</h4>Using exome sequence data from 159 families participating in the National Institutes of Health Undiagnosed Diseases Program, we evaluated the number and inheritance mode of reportable incidental sequence variants.<h4>Methods</h4>Following the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings from next-generation sequencing, we extracted variants in 56 genes from the exome sequence data of 543 subjects and determined the reporta ...[more]

PMID: 24784157

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Project description:One of the IRDiRC goals for 2017?2027 is to achieve definitive diagnosis for rare undiagnosed diseases within one year, as delay in diagnosis remains one of the pending issues in the rare diseases field. The Spanish Undiagnosed Rare Diseases Program (SpainUDP) was created in response to this challenging scenario to cover patients' needs and after seeing the success of the Undiagnosed Diseases Program (UDP) in the USA. SpainUDP offers a multidisciplinary approach to those patients who have long sought a diagnosis without any success. During the first phase of the protocol, undiagnosed cases are sent to SpainUDP by individual patients or families, patient organizations or hospitals. After careful analysis of phenotype, data from sequencing experiments (WES) is processed with a standard pipeline and detailed standardized phenotypic information (mapped to the Human Phenotype Ontology, HPO) is connected to genetic data. In addition, the participation of SpainUDP in international initiatives such as the European projects RD-Connect and Solve RD, the Undiagnosed Diseases Network International (UDNI), and the MatchMaker Exchange (MME) platform, allows the establishment of a global data sharing strategy across multiple projects submitting data to these international initiatives. From the official beginning of the program (at the end of 2015) until early 2018, 147 cases were accepted in SpainUDP. During this time, 37 cases (25%) dropped out the program due to several reasons. The remaining 110 cases are distributed as follows: phenotypic and genotypic (WES) characterization was finished in 30 cases, of which 20 (67%) were diagnosed; 21 cases are pending on variants' validation by Sanger sequencing; in 25 cases, WES is ongoing and 34 cases are being studied for deep phenotypic characterization. In conclusion, SpainUDP aims to achieve a diagnosis following two recommendations of the IRDiRC: the patients' diagnosis in as short a time as possible and the promotion of data sharing (especially genomic) at the international level.

Dataset Information

The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience.

Publications

The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience.

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