Abstract
AbstractPurposeTo improve molecular diagnostic rates for participants recruited to the UK 100 000 Genomes Project suspected to have congenital malformations caused by ciliopathies.MethodsBespoke variant filtering and analysis strategy.ResultsEighty‐three pre‐screened probands were recruited in the following disease categories: Bardet‐Biedl syndrome (n = 45), Joubert syndrome (n = 14) and Rare Multisystem Ciliopathy Disorders (n = 24). We determined a research molecular diagnosis for n = 43/83 (51.8%) of probands, n = 33 (39.8%) classified as confident or probable diagnoses. The diagnosis rate is 19.3% higher than the n = 27/83 (32.5%) previously reported by Genomics England. Interestingly, 19/43 (44.2%) of diagnoses are not ciliopathies. 4 patients have causative variants in eye disease genes not directly linked to cilia (PRPF8, RHO, PROM1, OPA1) and 15 in genes causative of non‐ciliopathy multisystemic conditions. This may reflect difficulties in clinical recognition of ciliopathies and highlights the importance of looking beyond the initial panel. n = 11/83 probands (13.3%) had at least one causative variant outside of the Tiers 1 and 2 variant annotation categories (defined by the Genomics England Rare Disease Tiering Process), which would otherwise be excluded in standard diagnostic strategies. These include 4 SVs and 3 predicted by SpliceAI to cause non‐canonical splicing defects. We found two homozygous truncating variants in the candidate ciliopathy genes LRRC45 and CFAP45 in a single proband. Identification of further individuals with ciliopathy phenotypes with pathogenic variants in these genes would strengthen confidence in their status as ciliopathy disease genes.ConclusionsThis study shows the value of research collaborations to improve interpretation of genomic data. Improved integration of SV and splice variant analysis tools, such as SpliceAI, will be essential to maximise the diagnostic potential of WGS data beyond coding variants in exons of virtual panels of genes.
Highlights
Ciliopathies represent a group of inherited genetic disorders that arise as a result of defects in the primary cilium, the ‘cell’s antenna’,1 or motile cilia, organelles responsible for the movement of fluid over the surface of cells.[2]
Congenital malformations caused by ciliopathies cohort A total of 83 probands were identified in the CMC cohort
Fifteen participants were recruited as singleton cases, and for 68 individuals at least one additional family member underwent whole genome sequencing (WGS)
Summary
Ciliopathies represent a group of inherited genetic disorders that arise as a result of defects in the primary cilium, the ‘cell’s antenna’,1 or motile cilia, organelles responsible for the movement of fluid over the surface of cells.[2]. There are 24 known genetic causes of the metabolic/obesity ciliopathy Bardet-Biedl syndrome (BBS) (OMIM PS209900) In this same series, Alström syndrome is unusual, because it is a single gene ciliopathy (caused by pathogenic variants in ALMS1). 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). 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. They demonstrate the value of research collaborations in order to maximise interpretation of genomic data
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