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Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

ABSTRACT: BACKGROUND:As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate. METHODS:Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES. RESULTS:Overall, 30% of patients who underwent CES had an identified pathogenic mutation. The most common phenotypes were developmental delay (83%), neuromuscular system abnormalities (81%), and multiple congenital anomalies (42%). In all, 67% of patients had a variant of uncertain significance (VUS) or gene of uncertain significance (GUS); 23% had no variants reported. There was a significant difference in the average number of body systems affected among these groups (pathogenic 5.89, VUS 6.0, GUS 6.12, and no variant 4.6; P?

SUBMITTER: Ziats MN

PROVIDER: S-EPMC7082194 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

Ziats Mark N MN Ahmad Ayesha A Bernat John A JA Fisher Rachel R Glassford Megan M Hannibal Mark C MC Jacher Joseph E JE Weiser Natasha N Keegan Catherine E CE Lee Kristen N KN Marzulla Tessa B TB O'Connor Bridget C BC Quinonez Shane C SC Seemann Lauren L Turner Lauren L Bielas Stephanie S Harris Nicholas L NL Ogle Jacob D JD Innis Jeffrey W JW Martin Donna M DM

Pediatric research 20191016 4

<h4>Background</h4>As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate.<h4>Methods</h4>Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES.<h4>Res ...[more]

PMID: 31618753

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Project description:Next-generation sequencing is increasingly used for clinical evaluation of patients presenting with thrombotic microangiopathies because it allows for simultaneous interrogation of multiple complement and coagulation pathway genes known to be associated with disease. However, the diagnostic yield is undefined in routine clinical practice. Historic studies relied on case-control cohorts, did not apply current guidelines for variant pathogenicity assessment, and used targeted gene enrichment combined with next-generation sequencing. A clinically enhanced exome, targeting ~54?Mb, was sequenced for 73 patients. Variant analysis and interpretation were performed on genes with biological relevance in thrombotic microangiopathy (C3,CD46, CFB, CFH, CFI, DGKE, and THBD). CFHR3-CFHR1 deletion status was also assessed using multiplex ligation-dependent probe amplification. Variants were classified using American College of Medical Genetics and Genomics guidelines. We identified 5 unique novel and 14 unique rare variants in 25% (18/73) of patients, including a total of 5 pathogenic, 4 likely pathogenic, and 15 variants of uncertain clinical significance. Nine patients had homozygous deletions in CFHR3-CFHR1. The diagnostic yield, defined as the presence of a pathogenic variant, likely pathogenic variant or homozygous deletion of CFHR3-CFHR1, was 25% for all patients tested. Variants of uncertain clinical significance were identified in 21% (15/73) of patients.These results illustrate the expected diagnositic yield in the setting of thrombotic microangiopathies through the application of standardized variant interpretation, and highlight the utility of such an approach. Sequencing a clinically enhanced exome to enable targeted, disease-specific variant analysis is a viable approach. The moderate rate of variants of uncertain clinical significance highlights the paucity of data surrounding the variants in our cohort and illustrates the need for expanded variant curation resources to aid in thrombotic microangiopathy-related disease variant classification.

Dataset Information

Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

Publications

Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

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