Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100, 000 Genomes Project. Issue 8 (29th October 2021)

• Record Type: Journal Article
• Authors: Best, Sunayna; Lord, Jenny; Roche, Matthew; Watson, Christopher M; Poulter, James A; Bevers, Roel P J; Stuckey, Alex; Szymanska, Katarzyna; Ellingford, Jamie M; Carmichael, Jenny; Brittain, Helen; Toomes, Carmel; Inglehearn, Chris; Johnson, Colin A; Wheway, Gabrielle
• Other Names: author non-byline.; Ambrose John C author non-byline.; Arumugam Prabhu author non-byline.; Bevers Roel author non-byline.; Bleda Marta author non-byline.; Boardman-Pretty Freya author non-byline.; Boustred Christopher R author non-byline.; Brittain Helen author non-byline.; Caulfield Mark J author non-byline.; Chan Georgia C author non-byline.; Elgar Greg author non-byline.; Fowler Tom author non-byline.; Giess Adam author non-byline.; Hamblin Angela author non-byline.; Henderson Shirley author non-byline.; Hubbard Tim JP author non-byline.; Jackson Rob author non-byline.; Jones Louise J author non-byline.; Kasperaviciute Dalia author non-byline.; Kayikci Melis author non-byline.; Kousathanas Athanasios author non-byline.; Lahnstein Lea author non-byline.; Leigh Sarah E A author non-byline.; Leong Ivonne US author non-byline.; Lopez Javier F author non-byline.; Maleady-Crowe Fiona author non-byline.; McEntagart Meriel author non-byline.; Minneci Federico author non-byline.; Moutsianas Loukas author non-byline.; Mueller Michael author non-byline.; Murugaesu Nirupa author non-byline.; Need Anna C author non-byline.; O'Donovan Peter author non-byline.; Odhams Chris A author non-byline.; Patch Christine author non-byline.; Pereira Mariana Buongermino author non-byline.; Perez-Gil Daniel author non-byline.; Pullinger John author non-byline.; Rendon TahrimaRahim; Augusto author non-byline.; Rogers Tim author non-byline.; Savage Kevin author non-byline.; Sawant Kushmita author non-byline.; Scott Richard H author non-byline.; Siddiq Afshan author non-byline.; Sieghart Alexander author non-byline.; Smith Samuel C author non-byline.; Sosinsky Alona author non-byline.; Stuckey Alexander author non-byline.; Tanguy Mélanie author non-byline.; Tavares Ana Taylor author non-byline.; Thomas Ellen RA author non-byline.; Thompson Simon R author non-byline.; Tucci Arianna author non-byline.; Welland Matthew J author non-byline.; Williams Eleanor author non-byline.; Witkowska Katarzyna author non-byline.; Wood Suzanne M author non-byline.;
• Is Part Of: Journal of medical genetics. Volume 59:Issue 8(2022)
• Page Start: 737
• Page End: 747
• Publication Date: 2021-10-29
• Subjects: genetics -- medical -- genomics -- congenital -- hereditary -- and neonatal diseases and abnormalities -- diagnosis; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2021-108065
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Primary ciliopathies represent a group of inherited disorders due to defects in the primary cilium, the 'cell's antenna'. The 100, 000 Genomes Project was launched in 2012 by Genomics England (GEL), recruiting National Health Service (NHS) patients with eligible rare diseases and cancer. Sequence data were linked to Human Phenotype Ontology (HPO) terms entered by recruiting clinicians. Methods: Eighty-three prescreened probands were recruited to the 100, 000 Genomes Project suspected to have congenital malformations caused by ciliopathies in the following disease categories: Bardet-Biedl syndrome (n=45), Joubert syndrome (n=14) and 'Rare Multisystem Ciliopathy Disorders' (n=24). We implemented a bespoke variant filtering and analysis strategy to improve molecular diagnostic rates for these participants. Results: We determined a research molecular diagnosis for n=43/83 (51.8%) probands. This is 19.3% higher than previously reported by GEL (n=27/83 (32.5%)). A high proportion of diagnoses are due to variants in non-ciliopathy disease genes (n=19/43, 44.2%) which may reflect difficulties in clinical recognition of ciliopathies. n=11/83 probands (13.3%) had at least one causative variant outside the tiers 1 and 2 variant prioritisation categories (GEL's automated triaging procedure), which would not be reviewed in standard 100, 000 Genomes Project diagnostic strategies. These include four structural variants and three predicted to cause non-canonical splicing defects. Two unrelated participants have biallelic likely pathogenic variants in LRRC45, a putative novel ciliopathy disease gene. Conclusion: These data illustrate the power of linking large-scale genome sequence to phenotype information. They demonstrate the value of research collaborations in order to maximise interpretation of genomic data.