Genome sequencing and comprehensive rare-variant analysis of 465 families with neurodevelopmental disorders

Alba Sanchis-Juan; Karyn Megy; Jonathan Stephens; Camila Armirola Ricaurte; Eleanor Dewhurst; Kayyi Low; Courtney E French; Detelina Grozeva; Kathleen Stirrups; Marie Erwood; Amy McTague; Christopher J Penkett; Olga Shamardina; Salih Tuna; Louise C Daugherty; Nicholas Gleadall; Sofia T Duarte; Antonio Hedrera-Fernández; Julie Vogt; Gautam Ambegaonkar; Manali Chitre; Dragana Josifova; Manju A Kurian; Alasdair Parker; Julia Rankin; Evan Reid; Emma Wakeling; Evangeline Wassmer; C Geoffrey Woods; NIHR BioResource; F Lucy Raymond; Keren J Carss

doi:10.1016/j.ajhg.2023.07.007

Genome sequencing and comprehensive rare-variant analysis of 465 families with neurodevelopmental disorders

Am J Hum Genet. 2023 Aug 3;110(8):1343-1355. doi: 10.1016/j.ajhg.2023.07.007.

Authors

Alba Sanchis-Juan¹, Karyn Megy², Jonathan Stephens³, Camila Armirola Ricaurte³, Eleanor Dewhurst³, Kayyi Low³, Courtney E French⁴, Detelina Grozeva⁵, Kathleen Stirrups³, Marie Erwood³, Amy McTague⁶, Christopher J Penkett³, Olga Shamardina³, Salih Tuna³, Louise C Daugherty³, Nicholas Gleadall³, Sofia T Duarte⁷, Antonio Hedrera-Fernández⁸, Julie Vogt⁹, Gautam Ambegaonkar¹⁰, Manali Chitre⁴, Dragana Josifova¹¹, Manju A Kurian¹², Alasdair Parker¹³, Julia Rankin¹⁴, Evan Reid¹⁵, Emma Wakeling¹⁶, Evangeline Wassmer¹⁷, C Geoffrey Woods¹⁸; NIHR BioResource; F Lucy Raymond¹⁹, Keren J Carss²⁰

Affiliations

¹ Department of Haematology, University of Cambridge, Cambridge, UK; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Department of Haematology, University of Cambridge, Cambridge, UK; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
³ Department of Haematology, University of Cambridge, Cambridge, UK; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁴ Clinical Medical School, University of Cambridge, Cambridge, UK.
⁵ Department of Medical Genetics, University of Cambridge, Cambridge, UK; Centre for Trials Research, Cardiff University, Cardiff, UK.
⁶ Molecular Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, UK; Department of Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁷ Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.
⁸ Pediatric Neurology Department, Hospital Universitario Central de Asturias, Asturias, Spain.
⁹ West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Birmingham, UK.
¹⁰ Child Development Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹¹ Guy's and St Thomas' Hospital, London, UK.
¹² Molecular Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, UK.
¹³ Clinical Medical School, University of Cambridge, Cambridge, UK; Child Development Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁴ Department of Clinical Genetics, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
¹⁵ Cambridge Institute for Medical Research and Department of Medical Genetics, University of Cambridge, Cambridge, UK.
¹⁶ North West Thames Regional Genetics Service, Harrow, UK.
¹⁷ Neurology Department, Birmingham Women and Children's Hospital, Birmingham, UK.
¹⁸ Clinical Medical School, University of Cambridge, Cambridge, UK; Department of Medical Genetics, University of Cambridge, Cambridge, UK.
¹⁹ Department of Haematology, University of Cambridge, Cambridge, UK; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Medical Genetics, University of Cambridge, Cambridge, UK. Electronic address: flr24@cam.ac.uk.
²⁰ Department of Haematology, University of Cambridge, Cambridge, UK; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. Electronic address: keren.carss@astrazeneca.com.

Abstract

Despite significant progress in unraveling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis after microarray and/or exome sequencing. Here, we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in participants with NDD from the National Institute for Health and Care Research (NIHR) BioResource project. Short-read GS was conducted on 692 individuals (489 affected and 203 unaffected relatives) from 465 families. Additionally, long-read GS was performed on five affected individuals who had structural variants (SVs) in technically challenging regions, had complex SVs, or required distal variant phasing. Causal variants were identified in 36% of affected individuals (177/489), and a further 23% (112/489) had a variant of uncertain significance after multiple rounds of re-analysis. Among all reported variants, 88% (333/380) were coding nuclear SNVs or insertions and deletions (indels), and the remainder were SVs, non-coding variants, and mitochondrial variants. Furthermore, long-read GS facilitated the resolution of challenging SVs and invalidated variants of difficult interpretation from short-read GS. This study demonstrates the value of short-read GS, complemented with long-read GS, in investigating the genetic causes of NDDs. GS provides a comprehensive and unbiased method of identifying all types of variants throughout the nuclear and mitochondrial genomes in individuals with NDD.

Keywords: long-read sequencing; neurodevelopmental disorders; structural variants; whole-genome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence
Chromosome Mapping
Genome, Human* / genetics
Humans
INDEL Mutation
Neurodevelopmental Disorders* / genetics

Abstract

Publication types

MeSH terms

Grants and funding