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


CONCLUSIONS
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.
1] National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA [2] Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Lauren
L
Lawrence
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Murat
M
Sincan
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Thomas
T
Markello
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
David R
DR
Adams
Internal Medicine Consult Service, NIH Clinical Center, Bethesda, Maryland, USA.
Fred
F
Gill
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Rena
R
Godfrey
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Gretchen
G
Golas
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Catherine
C
Groden
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Dennis
D
Landis
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Michele
M
Nehrebecky
Internal Medicine Consult Service, NIH Clinical Center, Bethesda, Maryland, USA.
Grace
G
Park
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Ariane
A
Soldatos
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Cynthia
C
Tifft
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Camilo
C
Toro
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Colleen
C
Wahl
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Lynne
L
Wolfe
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
William A
WA
Gahl
National Institutes of Health (NIH) Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
Cornelius F
CF
Boerkoel
D000293:Adolescent; D000328:Adult; D002648:Child; D015331:Cohort Studies; D059472:Exome / Q000235:genetics*; D005192:Family Health; D005260:Female; D005817:Genetic Counseling; D030342:Genetic Diseases, Inborn / Q000175:diagnosis / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D033162:Incidental Findings; D008297:Male; D008661:Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics; D008875:Middle Aged; D009316:National Institutes of Health (U.S.); D017422:Sequence Analysis, DNA / Q000379:methods*; D014481:United States; D055815:Young Adult