Correction: Corrigendum: ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing

Green, Robert C; Berg, Jonathan S.; Grody, Wayne W.; Kalia, Sarah S.; Korf, Bruce R.; Martin, Christa Lese; McGuire, Amy L.; Nussbaum, Robert L.; O’Daniel, Julianne; Ormond, Kelly E.; Rehm, Heidi L.; Watson, Michael S.; Williams, Marc S.; Biesecker, Leslie G.

doi:10.1038/gim.2017.18

Cited by 27 publications

(19 citation statements)

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“…These causative mutations in nonrenal disease genes were reported back to the referring physician according to the American College of Medical Genetics guidelines. [60][61][62] Spectrum of Mutations in Known CAKUT Genes It is known that, in consanguineous pedigrees, the likelihood of detecting a homozygous causative mutation in a recessive gene rather than compound heterozygous mutations rises with the degree of relatedness or homozygosity across the genome. 63 We, therefore, plotted homozygosity in descending order for families in which we identified a likely causative mutation or a candidate mutation in a CAKUT gene or a CAKUT phenocopy gene (Figure 3).…”

Section: Detecting Monogenic Causes For Non-cakut Diseases In Familiementioning

confidence: 99%

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

Ven

Connaughton

Ityel

et al. 2018

JASN

154

149

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Section: Detecting Monogenic Causes For Non-cakut Diseases In Familiementioning

confidence: 99%

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

Ven

Connaughton

Ityel

et al. 2018

JASN

154

149

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“…The majority of accredited laboratories follow the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants and use specific standard terminology (such as ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’ and ‘benign’) to describe variants identified in genes that cause Mendelian disorders ( 53 ). At present, the general recommendation is to report variants classified as ‘pathogenic’, ‘likely pathogenic’ and of ‘uncertain significance’ in gene(s) related to the patient phenotype, while variants detected by clinical exome and genome sequencing in unrelated genes will be reported as secondary findings ( 54 , 55 ). With generation of more robust genomic data in this field, these guidelines will evolve as the relationship between the genotype and the phenotype becomes increasingly coherent.…”

Section: General Approach To the Genetic Diagnosis Of Dsdmentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’

Audí

Ahmed

Krone

et al. 2018

European Journal of Endocrinology

129

118

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The differential diagnosis of differences or disorders of sex development (DSD) belongs to the most complex fields in medicine. It requires a multidisciplinary team conducting a synoptic and complementary approach consisting of thorough clinical, hormonal and genetic workups. This position paper of EU COST (European Cooperation in Science and Technology) Action BM1303 ‘DSDnet’ was written by leading experts in the field and focuses on current best practice in genetic diagnosis in DSD patients. Ascertainment of the karyotpye defines one of the three major diagnostic DSD subclasses and is therefore the mandatory initial step. Subsequently, further analyses comprise molecular studies of monogenic DSD causes or analysis of copy number variations (CNV) or both. Panels of candidate genes provide rapid and reliable results. Whole exome and genome sequencing (WES and WGS) represent valuable methodological developments that are currently in the transition from basic science to clinical routine service in the field of DSD. However, in addition to covering known DSD candidate genes, WES and WGS help to identify novel genetic causes for DSD. Diagnostic interpretation must be performed with utmost caution and needs careful scientific validation in each DSD case.

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“…The indication for WES testing and the interpretation of incidental variants is evolving. Current American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation and reporting of WES results mandate the reporting of incidentally identified variants in genes associated with heritable channelopathies and cardiomyopathies, perpetuating a significant burden of false positives (Green et al, 2017). Given the remarkable similarity between WES and control variants, it is likely that a WES variant found incidentally reflects rare population variation.…”

Section: Discussionmentioning

confidence: 99%

Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy‐associated genes among children undergoing exome sequencing reflect healthy population variation

Headrick

Rosenfeld

Yang

et al. 2019

Molec Gen & Gen Med

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Background With expanding use of clinical whole exome sequencing (WES), genetic variants of uncertain significance are increasingly identified. As pathologic mutations in genes associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) carry a risk of sudden death, determining the diagnostic relevance of incidentally identified variants associated with these genes is critical. Methods WES variants from a large, predominantly pediatric cohort (N = 7,066 probands) were obtained for nine ARVC‐associated genes (Baylor Miraca). For comparison, a control cohort was derived from the gnomAD database and an ARVC case cohort (N = 1,379 probands) was established from ARVC cases in the literature. Topologic mapping was performed and signal‐to‐noise analysis was conducted normalizing WES, or case variants, against control variant frequencies. Retrospective chart review was performed of WES cases evaluated clinically (Texas Children's Hospital). Results Incidentally identified variants occurred in 14% of WES referrals and localized to genes which were rare among ARVC cases yet similar to controls. Amino acid‐level signal‐to‐noise analysis of cases demonstrated “pathologic hotspots” localizing to critical domains of PKP2 and DSG2 while WES variants did not. PKP2 ARM7 and ARM8 domains and DSG2 N‐terminal cadherin‐repeat domains demonstrated high pathogenicity while normalized WES variant frequency was low. Review of clinical data available on WES referrals demonstrated none with evidence of ARVC among variant‐positive individuals. Conclusions Incidentally identified variants are common among pediatric WES testing with gene frequencies similar to “background” variants. Incidentally identified variants are unlikely to be pathologic.

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Correction: Corrigendum: ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing

Cited by 27 publications

References 0 publications

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’

Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy‐associated genes among children undergoing exome sequencing reflect healthy population variation

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