Refinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood
Courtney E. French,
Helen Dolling,
Karyn Mégy,
Alba Sanchis-Juan,
Ajay Kumar,
Isabelle Delon,
Matthew Wakeling,
Lucy Mallin,
Shruti Agrawal,
Topun Austin,
Florence Walston,
Soo-Mi Park,
Alasdair Parker,
Chinthika Piyasena,
Kimberley Bradbury,
Sian Ellard,
David H. Rowitch,
F. Lucy Raymond
Affiliations
Courtney E. French
School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK; Boston Children’s Hospital, Boston, MA 02115, USA
Helen Dolling
School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; NIHR Bioresource, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Centre for Family Research, Department of Psychology, University of Cambridge, Cambridge CB2 3RQ, UK
Karyn Mégy
School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK; NIHR Bioresource, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
Alba Sanchis-Juan
School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK; NIHR Bioresource, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
Ajay Kumar
School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK
Isabelle Delon
Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
Matthew Wakeling
Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Exeter EX4 4PY, UK
Lucy Mallin
Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK
Shruti Agrawal
Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
Topun Austin
School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
Florence Walston
Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich NR4 7UY, UK
Soo-Mi Park
Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
Alasdair Parker
Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
Chinthika Piyasena
Guy’s and St Thomas’ NHS Foundation Trust, London SE1 9RT, UK
Kimberley Bradbury
Guy’s and St Thomas’ NHS Foundation Trust, London SE1 9RT, UK
Sian Ellard
Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Exeter EX4 4PY, UK; Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK
David H. Rowitch
School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; NIHR Bioresource, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
F. Lucy Raymond
School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; NIHR Bioresource, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Corresponding author
Summary: To facilitate early deployment of whole-genome sequencing (WGS) for severely ill children, a standardized pipeline for WGS analysis with timely turnaround and primary care pediatric uptake is needed. We developed a bioinformatics pipeline for comprehensive gene-agnostic trio WGS analysis of children suspected of having an undiagnosed monogenic disease that included detection and interpretation of primary genetic mechanisms of disease, including SNVs/indels, CNVs/SVs, uniparental disomy (UPD), imprinted genes, short tandem repeat expansions, mobile element insertions, SMN1/2 copy number calling, and mitochondrial genome variants. We assessed primary care practitioner experience and competence in a large cohort of 521 families (comprising 90% WGS trios). Children were identified by primary practitioners for recruitment, and we used the UK index of multiple deprivation to confirm lack of patient socio-economic status ascertainment bias. Of the 521 children sequenced, 176 (34%) received molecular diagnoses, with rates as high as 45% for neurology clinics. Twenty-three of the diagnosed cases (13%) required bespoke methods beyond routine SNV/CNV analysis. In our multidisciplinary clinician user experience assessment, both pediatricians and clinical geneticists expressed strong support for rapid WGS early in the care pathway, but requested further training in determining patient selection, consenting, and variant interpretation. Rapid trio WGS provides an efficacious single-pass screening test for children when deployed by primary practitioners in clinical settings that carry high a priori risk for rare pediatric disease presentations.
