Profiling copy number variation and disease associations from 50,726 DiscovEHR Study exomes

Maxwell, EK; Packer, JS; Ó'Dúshláine, Colm; McCarthy, SE; Hare-Harris, Abby E.; Staples, Jeffrey; Gonzaga‐Jauregui, Claudia; Fetterolf, SN; Faucett, W. Andrew; Leader, JB; Moreno-De-Luca, Andrés; Gatta, G.D.; Scollan, Margaret E.; Persaud, Trikaldarshi; Penn, John S.; Hawes, Alicia; Bai, Xiaodong; Wolf, Sabrina; Lopez, AE; Ulloa, Ricardo H.; Sprangel, C; Chernomorsky, Rostislav; Borecki, IB; Fe, Dewey; An, Economides; Overton, JD; Kirchner, H. Lester; Mf, Murray; Ritchie,; Dj, Carey; Ledbetter, D.H.; Yancopoulos, G.D.; Shuldiner, AR; Baras, Aris; Gottesman, Omri; Habegger, Lukas; Martin, C. L.; Jg, Reid

doi:10.1101/119461

Cited by 7 publications

(6 citation statements)

References 29 publications

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“…The adult phenotype may not be well defined or may be unfamiliar to the adult physician. For example, a recent study of screening copy number variation in adults demonstrated that only one in 12 adults had been correctly diagnosed with the 22q11.2 deletion syndrome though 10 of 12 had clinical features consistent with the diagnosis (e.g., congenital heart defect, neurodevelopmental disorder) (Maxwell et al 2017). Phenotypic expression may also be subtler in adulthood, because of mosaicism or variable expressivity.…”

Section: Discussionmentioning

confidence: 99%

Xia–Gibbs syndrome in adulthood: a case report with insight into the natural history of the condition

Murdock

Jiang

Wangler

et al. 2019

Cold Spring Harb Mol Case Stud

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A 55-yr-old male with severe intellectual disability, behavioral problems, kyphoscoliosis, and dysmorphic features was referred for a genetic evaluation. Chromosomal microarray, RASopathy gene panel, mitochondrial sequencing, and fragile X testing were all negative. Subsequent whole-exome sequencing revealed a heterozygous, truncating variant in the AHDC1 gene, consistent with a diagnosis of Xia–Gibbs syndrome (XGS). Review of his clinical history showed many classic dysmorphic and clinical features of XGS, but no major health issues in adulthood other than intellectual disability. This individual is the oldest published XGS case to date, demonstrates the wide phenotypic spectrum of the disorder, and provides information on the condition's natural history. As more adults undergo genomic studies, we will continue to learn about the adult phenotypes of genetic conditions typically diagnosed in the pediatric setting.

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Section: Discussionmentioning

confidence: 99%

Xia–Gibbs syndrome in adulthood: a case report with insight into the natural history of the condition

Murdock

Jiang

Wangler

et al. 2019

Cold Spring Harb Mol Case Stud

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“…Medically actionable exomes are now uncovering pathogenic or likely pathogenic variants in approximately 4% of these individuals. 8,9 Cost-effectiveness modeling suggests that returning a panel of secondary findings for $250 has an incremental cost-effectiveness ratio of <$50,000 for a 25-year-old individual. 10 This is within range of covered services, such as dialysis (incremental cost-effectiveness ratio, $129,000) 11 or mammography between the ages of 50 and 69 years (incremental costeffectiveness ratio, $29,000).…”

Section: Elective Genomic Testingmentioning

confidence: 99%

Evaluation for Genetic Disorders in the Absence of a Clinical Indication for Testing

Ferber

Hagenkord

et al. 2019

The Journal of Molecular Diagnostics

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“…Although we cannot know the true family history of the deidentified individuals in our cohort, we have used PRIMUS 31 reconstructed pedigrees, ERSA distant-relationship estimates, and PADRE 37 to connect the pedigrees to identify the best pedigree representation of the mutation carriers of a tandem duplication in LDLR. 38 We used HumanOmniExpress array data (available for 25 out of the 37 carriers) to estimate the more distant relationships with the process described by Staples et. al.…”

Section: Pedigree Estimation Based On Distant Relationshipsmentioning

confidence: 99%

“…We attempted to perform visual validation of 23 high-confidence, 30 8). 38 The FH example is particularly interesting, given that we previously reported an FH-causing tandem duplication in LDLR [MIM: 606945]. 38 We have updated the CNV calls and found 37 carriers of the FH-causing tandem duplication among the 92K exomes, and we have reconstructed 30 out of the 37 carriers into a single extended pedigree.…”

Section: Compound Heterozygous Mutationsmentioning

confidence: 99%

“…38 The FH example is particularly interesting, given that we previously reported an FH-causing tandem duplication in LDLR [MIM: 606945]. 38 We have updated the CNV calls and found 37 carriers of the FH-causing tandem duplication among the 92K exomes, and we have reconstructed 30 out of the 37 carriers into a single extended pedigree. The carriers' shared ancestral history provides evidence that they all inherited this duplication event from a common ancestor approximately six generations back.…”

Section: Compound Heterozygous Mutationsmentioning

confidence: 99%

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Profiling and Leveraging Relatedness in a Precision Medicine Cohort of 92,455 Exomes

Staples

Maxwell

Gosalia

et al. 2018

The American Journal of Human Genetics

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Large-scale human genetics studies are ascertaining increasing proportions of populations as they continue growing in both number and scale. As a result, the amount of cryptic relatedness within these study cohorts is growing rapidly and has significant implications on downstream analyses. We demonstrate this growth empirically among the first 92,455 exomes from the DiscovEHR cohort and, via a custom simulation framework we developed called SimProgeny, show that these measures are in line with expectations given the underlying population and ascertainment approach. For example, within DiscovEHR we identified ∼66,000 close (first- and second-degree) relationships, involving 55.6% of study participants. Our simulation results project that >70% of the cohort will be involved in these close relationships, given that DiscovEHR scales to 250,000 recruited individuals. We reconstructed 12,574 pedigrees by using these relationships (including 2,192 nuclear families) and leveraged them for multiple applications. The pedigrees substantially improved the phasing accuracy of 20,947 rare, deleterious compound heterozygous mutations. Reconstructed nuclear families were critical for identifying 3,415 de novo mutations in ∼1,783 genes. Finally, we demonstrate the segregation of known and suspected disease-causing mutations, including a tandem duplication that occurs in LDLR and causes familial hypercholesterolemia, through reconstructed pedigrees. In summary, this work highlights the prevalence of cryptic relatedness expected among large healthcare population-genomic studies and demonstrates several analyses that are uniquely enabled by large amounts of cryptic relatedness.

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Profiling copy number variation and disease associations from 50,726 DiscovEHR Study exomes

Abstract: 21

Cited by 7 publications

References 29 publications

Xia–Gibbs syndrome in adulthood: a case report with insight into the natural history of the condition

Xia–Gibbs syndrome in adulthood: a case report with insight into the natural history of the condition

Evaluation for Genetic Disorders in the Absence of a Clinical Indication for Testing

Profiling and Leveraging Relatedness in a Precision Medicine Cohort of 92,455 Exomes

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