Evaluating the performance of a clinical genome sequencing program for diagnosis of rare genetic disease, seen through the lens of craniosynostosis

Michael Mueller,Ana Lisa Taylor Tavares,Augusto Rendon,Adam Giess,Susan L Hill,Nirupa Murugaesu,Athanasios Kousathanas,Eleanor Williams,Afshan Siddiq,Andrew O.M Wilkie,Peter O’Donovan,Arianna Tucci,Prabhu Arumugam,Loukas Moutsianas,Andrew Bond,Rebecca S Tooze,Shirley Henderson,Melis Kayikci,Samuel C Smith,Alona Sosinsky,Marta Bleda,Mariana Buongermino Pereira,Alexander Stuckey,Federico Minneci,Christine Patch,Greg Elgar,Tom Fowler,Meriel Mcentagart,Angela Hamblin,Zandra C Deans,Emma Mccann,Astrid Weber,Yang Pei,Helen Brittain,Deirdre Cilliers,J C Ambrose ,Andrew G L Douglas ,D Perez-Gil ,T Rahim ,F Maleady‐Crowe ,L Lahnstein ,I U S Leong ,T Rogers ,C R Boustred ,S M Wood ,C A Odhams ,E R A Thomas ,Javier Ferreiros López ,R Jackson ,Louise Jones ,A Sieghart ,Richard Scott ,Dalia Kasperavičiūtė ,Louise Wilson ,J Pullinger ,K Witkowska ,Jenny Morton ,S R Thompson ,K Savage ,Stephen R F Twigg ,Mark J Caulfield ,Sarah Leigh ,R Bevers ,Anna C Need ,K Sawant ,F Boardman-Pretty ,G C Chan ,M Tanguy ,Tim Hubbard ,M J Welland ,Ruth Mcgowan,Eduardo Calpena,Andrew Wilkie

doi:10.1038/s41436-021-01297-5

Abstract

PurposeGenome sequencing (GS) for diagnosis of rare genetic disease is being introduced into the clinic, but the complexity of the data poses challenges for developing pipelines with high diagnostic sensitivity. We evaluated the performance of the Genomics England 100,000 Genomes Project (100kGP) panel-based pipelines, using craniosynostosis as a test disease.MethodsGS data from 114 probands with craniosynostosis and their relatives (314 samples), negative on routine genetic testing, were scrutinized by a specialized research team, and diagnoses compared with those made by 100kGP.ResultsSixteen likely pathogenic/pathogenic variants were identified by 100kGP. Eighteen additional likely pathogenic/pathogenic variants were identified by the research team, indicating that for craniosynostosis, 100kGP panels had a diagnostic sensitivity of only 47%. Measures that could have augmented diagnoses were improved calling of existing panel genes (+18% sensitivity), review of updated panels (+12%), comprehensive analysis of de novo small variants (+29%), and copy-number/structural variants (+9%). Recent NHS England recommendations that partially incorporate these measures should achieve 85% overall sensitivity (+38%).ConclusionGS identified likely pathogenic/pathogenic variants in 29.8% of previously undiagnosed patients with craniosynostosis. This demonstrates the value of research analysis and the importance of continually improving algorithms to maximize the potential of clinical GS.

Highlights

Evaluations of genome sequencing (GS) of rare disorders in a research setting showed that it could provide diagnostic enhancement of 21–42%, according to clinical context [1,2,3]
Given the substantial investment in sequencing and data patients enrolled into 100kGP to be enriched for rare genetic storage required for clinical GS, assurance that the clinical causes, this heterogeneity presents a substantial challenge for pipeline can efficiently identify clinical grade molecular diag- pipeline-based diagnosis, so we considered that CRS could noses is critical
For each case we determined whether the Genomic Medicine Centres (GMCs) had established a pathogenic or likely pathogenic variant, according to ACMG/AMP criteria [26], which we considered established a molecular diagnosis

Summary

Introduction

Evaluations of genome sequencing (GS) of rare disorders in a research setting showed that it could provide diagnostic enhancement of 21–42%, according to clinical context [1,2,3].

Results

Conclusion