A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates genome sequencing outperforms standard of care.

IF 10.8 1区生物学 Q1 GENETICS & HEREDITY

Genome Medicine Pub Date : 2026-10-05 DOI:10.1186/s13073-026-01771-2

Mathilde Geysens, Erika Souche, Maria Chiara Baroni, Valérie Benoit, Tessi Beyltjens, Wouter Bossuyt, Vincent Bours, Marian Crabbé, Didier Croes, Matthias De Smet, Julie Désir, Koenraad Devriendt, Annelies Dheedene, Boyan Ivanov Dimitrov, Katrien Janssens, Candy Kumps, Aimé Lumaka, Björn Menten, Marije Meuwissen, Olivier Monestier, Geert Mortier, Catharina Olsen, Leonor Palmeira, Hilde Peeters, Laura Pölsler, Nicole Revencu, Dominique Roland, Julie Soblet, Yves Sznajer, Sylvia Taziaux, Hilde Van Esch, Geert Vandeweyer, Elise Vantroys, Catherline Vilain, Elsa Wiame, Kris Van Den Bogaert, Joris Robert Vermeesch

{"title":"A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates genome sequencing outperforms standard of care.","authors":"Mathilde Geysens, Erika Souche, Maria Chiara Baroni, Valérie Benoit, Tessi Beyltjens, Wouter Bossuyt, Vincent Bours, Marian Crabbé, Didier Croes, Matthias De Smet, Julie Désir, Koenraad Devriendt, Annelies Dheedene, Boyan Ivanov Dimitrov, Katrien Janssens, Candy Kumps, Aimé Lumaka, Björn Menten, Marije Meuwissen, Olivier Monestier, Geert Mortier, Catharina Olsen, Leonor Palmeira, Hilde Peeters, Laura Pölsler, Nicole Revencu, Dominique Roland, Julie Soblet, Yves Sznajer, Sylvia Taziaux, Hilde Van Esch, Geert Vandeweyer, Elise Vantroys, Catherline Vilain, Elsa Wiame, Kris Van Den Bogaert, Joris Robert Vermeesch","doi":"10.1186/s13073-026-01771-2","DOIUrl":null,"url":null,"abstract":"Background: Exome (ES) or genome (GS) sequencing are recommended as first- or second-tier molecular tests for patients with developmental disorders (DD), but the clinical utility of GS continues to be debated.Methods: This prospective randomized trial involving all Belgian human genetics centers compared the standard of care (SoC) - combining ES and chromosomal microarray analysis or shallow GS - with GS for 567 individuals with unexplained DD. The study was retrospectively registered.Results: The diagnostic yield of GS was 39.8% (113/284) vs. 30% for SoC (85/283) (p = 0.015), mainly due to an increased detection of single nucleotide variants and indels (+ 8.7%). GS also enabled the detection of three non-coding (potential) pathogenic variants. Across both study arms, the diagnostic yield was higher for females (45.5%, 97/213) compared to males (28.5%, 101/354) (p < 0.001). Upon correction for the sex distribution and analytical differences between the study arms, the diagnostic yield difference between GS and SoC was reduced to 7.3% (p = 0.069). De novo variants were found for 23.6% of patients. Analysis of inherited variants in genes associated with autosomal dominant phenotypes contributed more to the diagnostic yield (3.9%) than X-linked variants (1.9%), and to a similar extent as autosomal recessive variants (4.1%).Conclusions: This nationwide study indicates GS outperforms SoC for the diagnosis of patients with DD in a decentralized hospital setting and well-characterized cohort. The results also highlight the importance of evaluating autosomal dominant inherited variants in genomics analyses for DD.Trial registration: ClinicalTrials.gov (NCT07051213, 03-07-2025).","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8000,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637178/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genome Medicine","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13073-026-01771-2","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Exome (ES) or genome (GS) sequencing are recommended as first- or second-tier molecular tests for patients with developmental disorders (DD), but the clinical utility of GS continues to be debated.

Methods: This prospective randomized trial involving all Belgian human genetics centers compared the standard of care (SoC) - combining ES and chromosomal microarray analysis or shallow GS - with GS for 567 individuals with unexplained DD. The study was retrospectively registered.

Results: The diagnostic yield of GS was 39.8% (113/284) vs. 30% for SoC (85/283) (p = 0.015), mainly due to an increased detection of single nucleotide variants and indels (+ 8.7%). GS also enabled the detection of three non-coding (potential) pathogenic variants. Across both study arms, the diagnostic yield was higher for females (45.5%, 97/213) compared to males (28.5%, 101/354) (p < 0.001). Upon correction for the sex distribution and analytical differences between the study arms, the diagnostic yield difference between GS and SoC was reduced to 7.3% (p = 0.069). De novo variants were found for 23.6% of patients. Analysis of inherited variants in genes associated with autosomal dominant phenotypes contributed more to the diagnostic yield (3.9%) than X-linked variants (1.9%), and to a similar extent as autosomal recessive variants (4.1%).

Conclusions: This nationwide study indicates GS outperforms SoC for the diagnosis of patients with DD in a decentralized hospital setting and well-characterized cohort. The results also highlight the importance of evaluating autosomal dominant inherited variants in genomics analyses for DD.

Trial registration: ClinicalTrials.gov (NCT07051213, 03-07-2025).

查看原文本刊更多论文

一项用于诊断发育障碍的全国性前瞻性随机试验表明，基因组测序优于标准护理。

背景：外显子组（ES）或基因组（GS）测序被推荐作为发育障碍（DD）患者的一级或二级分子检测，但GS的临床应用仍存在争议。方法：这项前瞻性随机试验涉及所有比利时人类遗传学中心，比较了567例不明原因DD患者的标准治疗(SoC) -结合ES和染色体微阵列分析或浅GS -与GS。该研究回顾性登记。结果：GS的诊断率为39.8%(113/284)，而SoC的诊断率为30% (85/283)(p = 0.015)，主要是由于单核苷酸变异和indels的检出率增加（+ 8.7%）。GS还能够检测到三种非编码（潜在）致病变异。在两个研究组中，女性的诊断率（45.5%,97/213）高于男性（28.5%,101/354）(p结论：这项全国性的研究表明，在分散的医院环境和特征明确的队列中，GS在诊断DD患者方面优于SoC。该结果还强调了评估常染色体显性遗传变异在dd基因组学分析中的重要性。试验注册：ClinicalTrials.gov （NCT07051213, 03-07-2025）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Genome Medicine GENETICS & HEREDITY-

CiteScore

20.80

自引率

0.80%

发文量

128

审稿时长

6-12 weeks

期刊介绍： Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.