The morbid genome of ciliopathies: an update

Shamseldin, Hanan E.; Shaheen, Ranad; Ewida, Nour; Bubshait, Dalal; Alkuraya, Hisham; Almardawi, Elham; Howaidi, Ali; Sabr, Yasser; Abdalla, Ebtesam; Alfaifi, Abdullah Y; Alghamdi, Jameel; Alsagheir, Afaf; Alfares, Ahmed; Morsy, Heba; Hussein, Maged H.; Al–Muhaizea, Mohammad A.; Shagrani, Mohammad; Sabban, Essam Al; Salih, Mustafa A.; Meriki, Neama; Khan, Rubina; Almugbel, Maisoon; Qari, Alya; Tulba, Maha; Mahnashi, Mohammed; Alhazmi, Khalid; Alsalamah, Abrar K.; Nowilaty, Sawsan R.; Alhashem, Amal; Hashem, Mais; Abdulwahab, Firdous; Ibrahim, Niema; Alshidi, Tarfa; Alobeid, Eman; Alenazi, Mona M; Alzaidan, Hamad; Rahbeeni, Zuhair; Al‐Owain, Mohammed; Sogaty, Sameera; Seidahmed, Mohammed Zain; Alkuraya, Fowzan S.

doi:10.1016/j.gim.2022.01.019

Cited by 11 publications

(16 citation statements)

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“…nNO was in the normal range, but HSVM analysis showed reduced amplitude of ciliary beating and some long cilia, with 19% of cilia showing microtubular disorganisation, mostly rearrangements. CEP164 is not recognised as a PCD gene, but has been reported in a case of dual Bardet-Biedl syndrome (BBS) and PCD presentation [40] and our patient had some features of BBS. We are investigating this further as a research case.…”

Section: Results Of Snv Analysis In Non-cf Bronchiectasis Cohortmentioning

confidence: 59%

Whole genome sequencing in the diagnosis of primary ciliary dyskinesia

et al. 2021

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Background It is estimated that 1–13% of cases of bronchiectasis in adults globally are attributable to primary ciliary dyskinesia (PCD) but many adult patients with bronchiectasis have not been investigated for PCD. PCD is a disorder caused by mutations in genes required for motile cilium structure or function, resulting in impaired mucociliary clearance. Symptoms appear in infancy but diagnosis is often late or missed, often due to the lack of a “gold standard” diagnostic tool and non-specific symptoms. Mutations in > 50 genes account for around 70% of cases, with additional genes, and non-coding, synonymous, missense changes or structural variants (SVs) in known genes presumed to account for the missing heritability. Methods UK patients with no identified genetic confirmation for the cause of their PCD or bronchiectasis were eligible for whole genome sequencing (WGS) in the Genomics England Ltd 100,000 Genomes Project. 21 PCD probands and 52 non-cystic fibrosis (CF) bronchiectasis probands were recruited in Wessex Genome Medicine Centre (GMC). We carried out analysis of single nucleotide variants (SNVs) and SVs in all families recruited in Wessex GMC. Results 16/21 probands in the PCD cohort received confirmed (n = 9), probable (n = 4) or possible (n = 3) diagnosis from WGS, although 13/16 of these could have been picked up by current standard of care gene panel testing. In the other cases, SVs were identified which were missed by panel testing. We identified variants in novel PCD candidate genes (IFT140 and PLK4) in 2 probands in the PCD cohort. 3/52 probands in the non-CF bronchiectasis cohort received a confirmed (n = 2) or possible (n = 1) diagnosis of PCD. We identified variants in novel PCD candidate genes (CFAP53 and CEP164) in 2 further probands in the non-CF bronchiectasis cohort. Conclusions Genetic testing is an important component of diagnosing PCD, especially in cases of atypical disease history. WGS is effective in cases where prior gene panel testing has found no variants or only heterozygous variants. In these cases it may detect SVs and is a powerful tool for novel gene discovery.

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Section: Results Of Snv Analysis In Non-cf Bronchiectasis Cohortmentioning

confidence: 59%

Whole genome sequencing in the diagnosis of primary ciliary dyskinesia

et al. 2021

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“…One variant (NM_014956.5 c.1726C > T; R576*) was a known allele, previously found homozygous in CEP164 patients with NPHP-RC and motile ciliary defects. 7,12 The second variant (c.4228C > T; Q1410*) is a stop gain within the penultimate exon, not previously described in CEP164ciliopathy patients, however mutations in the final exon of CEP164 have been previously identified. 7 Although this second variant is annotated with 'conflicting interpretation of pathogenicity' in ClinVar and has a relatively high gnomAD frequency (0.0008, no homozygotes recorded), the patient's NB and ALI-cultured epithelial cells demonstrated loss of CEP164 at the base of the motile cilia brush border, supporting the pathogenicity of the identified CEP164 variants.…”

Section: Discussionmentioning

confidence: 97%

“…More recently, CEP164 variants have been associated with motile-ciliary phenotypes. 12 Here we describe a patient with bronchiectasis in whom we identified biallelic CEP164 mutations as the likely cause of an atypical motile ciliary phenotype. This finding has important consequences for the investigation, management, and prognosis of patients with CEP164 mutations, and for the diagnostic work up of those with PCD.…”

Section: Introductionmentioning

confidence: 90%

Biallelic variants in CEP164 cause a motile ciliopathy‐like syndrome

et al. 2022

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Ciliopathies may be classed as primary or motile depending on the underlying ciliary defect and are usually considered distinct clinical entities. Primary ciliopathies are associated with multisystem syndromes typically affecting the brain, kidney, and eye, as well as other organ systems such as the liver, skeleton, auditory system, and metabolism. Motile ciliopathies are a heterogenous group of disorders with defects in specialised motile ciliated tissues found within the lung, brain, and reproductive system, and are associated with primary ciliary dyskinesia, bronchiectasis, infertility and rarely hydrocephalus. Primary and motile cilia share defined core ultra-structures with an overlapping proteome, and human disease phenotypes can reflect both primary and motile ciliopathies. CEP164 encodes a centrosomal distal appendage protein vital for primary ciliogenesis. Human CEP164 mutations are typically described in patients with nephronophthisis-related primary ciliopathies but have also been implicated in

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“…Using targeted gene panel, or whole exome sequencing (WES) approaches, genetic diagnosis rates for syndromic primary (non-motile) ciliopathies are typically 40%-70% and for motile (respiratory ciliopathies) are approximately 70% (studies summarised in online supplemental table 1). A recent large whole genome sequencing (WGS) study in 125 families with ciliopathies achieved an 87% diagnosis rate, 16 and a further increase was achieved following the inclusion of structural variant (SV) analysis and RNA sequencing in carefully phenotyped cohorts. 19 The 100,000 Genomes project is a hybrid clinical/research initiative, launched in 2012 and overseen by Genomics England Ltd (GEL), a company set up and wholly owned by the UK Government Department of Health and Social Care.…”

Section: Diagnosticsmentioning

confidence: 99%

Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100 000 genomes project

Best

Lord

Roche

et al. 2022

Acta Ophthalmologica

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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. ResultsWe 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 nonciliopathy 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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The morbid genome of ciliopathies: an update

Cited by 11 publications

References 0 publications

Whole genome sequencing in the diagnosis of primary ciliary dyskinesia

Whole genome sequencing in the diagnosis of primary ciliary dyskinesia

Biallelic variants in CEP164 cause a motile ciliopathy‐like syndrome

Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100 000 genomes project

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