4.5 Article

Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project

Journal

JOURNAL OF MEDICAL GENETICS
Volume 59, Issue 8, Pages 737-747

Publisher

BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2021-108065

Keywords

genetics; medical; genomics; congenital; hereditary; and neonatal diseases and abnormalities; diagnosis

Funding

  1. Wellcome Trust 4Ward North Clinical PhD Academy [203914/Z/16/Z]
  2. Wellcome Trust [204378/Z/16/Z]
  3. MRC [MR/M000532/1, MR/T017503/1]
  4. NIHR [DB NIHR RP-2016-07-011]
  5. UKRI Future Leader Fellowship [MR/T02044X/1]
  6. MRC [MR/T017503/1, MR/M000532/1] Funding Source: UKRI
  7. Wellcome Trust [204378/Z/16/Z] Funding Source: Wellcome Trust

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This study linked large-scale genome sequence with phenotype information to achieve a molecular diagnosis for 51.8% of probands suspected to have primary ciliopathies, higher than previously reported. A significant proportion of diagnoses were due to variants in non-ciliopathy disease genes, indicating clinical difficulties in recognizing ciliopathies.
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.

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