Unlocking the potential of the <scp>UK</scp> 100,000 Genomes Project—lessons learned from analysis of the “Congenital Malformations caused by Ciliopathies” cohort

Best, Sunayna; Inglehearn, Chris F.; Watson, Christopher M.; Toomes, Carmel; Wheway, Gabrielle; Johnson, Colin A.

doi:10.1002/ajmg.c.31965

Cited by 4 publications

(5 citation statements)

References 6 publications

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“…Similar difficulties were also noted in a recent commentary, where a response rate of 20% was noted. 74 The reasons for this are often due to the time gap between recruitment and the research finding being uncovered (>5 years for several participants). In that time an appreciable turnover of clinicians is to be expected.…”

Section: Discussionmentioning

confidence: 99%

The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

Pagnamenta,

Yu,

Walker

et al. 2024

The American Journal of Human Genetics

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Section: Discussionmentioning

confidence: 99%

The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

Pagnamenta,

Yu,

Walker

et al. 2024

The American Journal of Human Genetics

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“…We have discussed the challenges of 100K analyses more extensively in our recent commentary article and suggest potential improvements for future use of 100K data. 33 Clearly, open dialogue between researchers, clinicians and clinical scientists is essential to fully exploit the available data for patient benefit in the postgenomic era.…”

Section: Discussionmentioning

confidence: 99%

“…The Genomics England Rare Disease Tiering Process includes an automated variant triaging algorithm to classify variants on virtual PanelApp panel(s) selected according to entered HPO terms into a series of ‘Tiered’ categories, which have been described previously 2 33. Tiered variants are primarily limited to those variants affecting coding sequences, and splice donor or acceptor sites.…”

Section: Discussionmentioning

confidence: 99%

“…Our findings suggest that diagnoses may be missed when screening of limited gene panels is directed by incorrect or incomplete HPO term entry, and that inaccurate phenotyping may prevent participants from accessing clinically valuable findings. We have discussed the challenges of 100K analyses more extensively in our recent commentary article and suggest potential improvements for future use of 100K data 33. Clearly, open dialogue between researchers, clinicians and clinical scientists is essential to fully exploit the available data for patient benefit in the postgenomic era.…”

Section: Discussionmentioning

confidence: 99%

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Uncovering the burden of hidden ciliopathies in the 100 000 Genomes Project: a reverse phenotyping approach

Best

Lord

et al. 2022

J Med Genet

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BackgroundThe 100 000 Genomes Project (100K) recruited National Health Service patients with eligible rare diseases and cancer between 2016 and 2018. PanelApp virtual gene panels were applied to whole genome sequencing data according to Human Phenotyping Ontology (HPO) terms entered by recruiting clinicians to guide focused analysis.MethodsWe developed a reverse phenotyping strategy to identify 100K participants with pathogenic variants in nine prioritised disease genes (BBS1, BBS10, ALMS1, OFD1, DYNC2H1, WDR34, NPHP1, TMEM67, CEP290), representative of the full phenotypic spectrum of multisystemic primary ciliopathies. We mapped genotype data ‘backwards’ onto available clinical data to assess potential matches against phenotypes. Participants with novel molecular diagnoses and key clinical features compatible with the identified disease gene were reported to recruiting clinicians.ResultsWe identified 62 reportable molecular diagnoses with variants in these nine ciliopathy genes. Forty-four have been reported by 100K, 5 were previously unreported and 13 are new diagnoses. We identified 11 participants with unreportable, novel molecular diagnoses, who lacked key clinical features to justify reporting to recruiting clinicians. Two participants had likely pathogenic structural variants and one a deep intronic predicted splice variant. These variants would not be prioritised for review by standard 100K diagnostic pipelines.ConclusionReverse phenotyping improves the rate of successful molecular diagnosis for unsolved 100K participants with primary ciliopathies. Previous analyses likely missed these diagnoses because incomplete HPO term entry led to incorrect gene panel choice, meaning that pathogenic variants were not prioritised. Better phenotyping data are therefore essential for accurate variant interpretation and improved patient benefit.

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“…Best and colleagues make numerous helpful suggestions arising from their experience working with 100,000 Genomes Project data, noting that the dataset they were using is now 16 months old, a period in which many changes have been implemented which we believe resolve several of the issues raised (Best et al, 2022).…”

mentioning

confidence: 99%

Re: Best et al., ‘Unlocking the potential of the UK 100,000 Genomes Project – Lessons learned from analysis of the “Congenital malformations caused by ciliopathies” cohort’

Brown

Wigley

Walker

et al. 2022

American J of Med Genetics Pt A

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Unlocking the potential of the UK 100,000 Genomes Project—lessons learned from analysis of the “Congenital Malformations caused by Ciliopathies” cohort

Cited by 4 publications

References 6 publications

The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

Uncovering the burden of hidden ciliopathies in the 100 000 Genomes Project: a reverse phenotyping approach

Re: Best et al., ‘Unlocking the potential of the UK 100,000 Genomes Project – Lessons learned from analysis of the “Congenital malformations caused by ciliopathies” cohort’

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