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Whole-exome analysis of 177 pediatric patients with undiagnosed diseases
Kotaro Narita1, Hideki Muramatsu1, Satoshi Narumi2,3
1Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Insights
Whole-exome sequencing (WES) achieved a 44% genetic diagnosis rate in 177 undiagnosed Japanese patients. This advanced genetic testing identified single-nucleotide and copy number variants, aiding rare disease diagnosis.
Area of Science:
- Genetics
- Rare Diseases
- Genomic Medicine
Background:
- Whole-exome sequencing (WES) is a valuable tool for diagnosing rare and undiagnosed conditions.
- Previous genetic diagnostic yields from WES in undiagnosed patient cohorts range from 24-35%.
- The Initiative on Rare and Undiagnosed Diseases (IRUD) aims to diagnose patients lacking a genetic etiology.
Purpose of the Study:
- To evaluate the diagnostic yield of WES in a cohort of Japanese patients with undiagnosed conditions.
- To identify genetic variants, including single-nucleotide variants (SNVs) and copy number variants (CNVs), causative of rare diseases.
- To assess the effectiveness of specialist review meetings in interpreting WES results for genetic diagnosis.
Main Methods:
- Whole-exome sequencing (WES) was performed on 177 Japanese patients with previously undiagnosed conditions.
- Patients included had not undergone prior genome-wide testing.
- Genetic diagnoses were confirmed through expert review meetings, adhering to American College of Medical Genetics and Genomics guidelines, with a focus on SNVs, CNVs, and uniparental disomy (UPD).
Main Results:
- WES identified diagnostic SNVs in 66 patients and CNVs in 11 patients, achieving a 44% (78/177) overall genetic diagnosis rate.
- A complex case diagnosed with Angelman syndrome involved paternally derived uniparental disomy [upd(15)pat] and a homozygous DUOX2 variant, confirmed as loss-of-function and causative of congenital hypothyroidism.
- The diagnostic yield was significantly higher than previously reported, attributed to detailed specialist discussions and enhanced CNV detection.
Conclusions:
- WES, combined with expert review, significantly improves the genetic diagnosis rate for patients with rare and undiagnosed diseases.
- The study highlights the importance of detecting both SNVs and CNVs, as well as complex genetic mechanisms like UPD, for comprehensive diagnosis.
- This approach offers a higher diagnostic yield, providing etiological clarity for a substantial proportion of previously undiagnosed patients.
Abstract:
Recently, whole-exome sequencing (WES) has been used for genetic diagnoses of patients who remain otherwise undiagnosed. WES was performed in 177 Japanese patients with undiagnosed conditions who were referred to the Tokai regional branch of the Initiative on Rare and Undiagnosed Diseases (IRUD) (TOKAI-IRUD). This study included only patients who had not previously received genome-wide testing. Review meetings with specialists in various medical fields were held to evaluate the genetic diagnosis in each case, which was based on the guidelines of the American College of Medical Genetics and Genomics. WES identified diagnostic single-nucleotide variants in 66 patients and copy number variants (CNVs) in 11 patients. Additionally, a patient was diagnosed with Angelman syndrome with a complex clinical phenotype upon detection of a paternally derived uniparental disomy (UPD) [upd(15)pat] wherein the patient carried a homozygous DUOX2 p.E520D variant in the UPD region. Functional analysis confirmed that this DUOX2 variant was a loss-of-function missense substitution and the primary cause of congenital hypothyroidism. A significantly higher proportion of genetic diagnoses was achieved compared to previous reports (44%, 78/177 vs. 24-35%, respectively), probably due to detailed discussions and the higher rate of CNV detection.
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