The impact of routine next generation sequencing testing for familial hypercholesterolaemia – 5 months service experience

Yarram-Smith, Laura; Dean, P.D.G.; O’Shea, Siobhan; Dennis, Gretchen; Bayly, Graham; Taylor, Andrew; Day, A.; Watson, Mark; Giles, P.; Ayling, Ruth M; Haralambos, K.; Whatley, Sharon D.; McDowell, I.F.W.; Williams, Mark R.

doi:10.1016/j.atherosclerosis.2014.08.002

Cited by 6 publications

(5 citation statements)

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“…The technical advances realized during the Human Genome project has enabled significant increases in the speed of return for diagnostic test results and significant reductions in the costs. DNA diagnostic laboratories have now developed NGS protocols whereby all the protein coding regions for all the four known autosomal dominant FH genes as well as LDLRAP1 , a gene showing autosomal recessive inheritance (two pathogenic variants required to cause the condition) ( 32 ), can be captured and sequenced together ( 33 , 34 , 35 , 36 ). With the addition of small “barcoding” sequence identifiers into primers used for PCR amplification, it is also possible to batch samples from up to 96 individuals and analyze them in one run with high accuracy ( 34 ).…”

Section: Ngs Methodsmentioning

confidence: 99%

“…DNA diagnostic laboratories have now developed NGS protocols whereby all the protein coding regions for all the four known autosomal dominant FH genes as well as LDLRAP1 , a gene showing autosomal recessive inheritance (two pathogenic variants required to cause the condition) ( 32 ), can be captured and sequenced together ( 33 , 34 , 35 , 36 ). With the addition of small “barcoding” sequence identifiers into primers used for PCR amplification, it is also possible to batch samples from up to 96 individuals and analyze them in one run with high accuracy ( 34 ). This economy of scale has reduced costs so that now a full FH diagnostic screen including copy number assessment (deletions and duplications found in 5% of cases) can be completed for under £300.…”

Section: Ngs Methodsmentioning

confidence: 99%

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Genetic testing for familial hypercholesterolemia—past, present, and future

Futema

Taylor-Beadling

Williams

et al. 2021

Journal of Lipid Research

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Ngs Methodsmentioning

confidence: 99%

Section: Ngs Methodsmentioning

confidence: 99%

Genetic testing for familial hypercholesterolemia—past, present, and future

Futema

Taylor-Beadling

Williams

et al. 2021

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…DNA diagnostic labs have now developed NGS methods whereby all the protein coding and splicing regions of the genome for the known FH genes can be captured and sequenced together as a gene "panel" with high accuracy [29e32], and with the addition of small 'barcoding' sequences attached to the primers used to PCRamplify the regions of interest, it is now possible to mix the samples from up to 95 individuals (keeping one slot for a no-template control) and analyse them in one run with high accuracy [30]. This economy of scale is helping to drive down prices so that now a full FH diagnostic scan can be completed for around £250, and the data can also be used to review if an individual has a large duplication or deletion of the gene, which occurs in about 5e10% of patients.…”

Section: Variants Of Unknown Significance (Vus)mentioning

confidence: 99%

Clinical utility of the polygenic LDL-C SNP score in familial hypercholesterolemia

et al. 2018

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Mutations in any of three genes (LDLR, APOB and PCSK9) are known to cause autosomal dominant FH, but a mutation can be found in only~40% of patients with a clinical diagnosis of FH. In the remainder, a polygenic aetiology may be the cause of the phenotype, due to the co-inheritance of common LDL-C raising variants. In 2013, we reported the development of a 12-SNP LDL-C "SNP-Score" based on common variants identified as LDL-C raising from genome wide association consortium studies, and have confirmed the validity of this score in samples of no-mutation FH adults and children from more than six countries with European-Caucasian populations. In more than 80% of those with a clinical diagnosis of FH but with no detectable mutation in LDLR/APOB/PCSK9, the polygenic explanation is the most likely for their hypercholesterolaemia. Those with a low score (in the bottom two deciles) may have a mutation in a novel gene, and further research including whole exome or whole genome sequencing is warranted. Only in families where the index case has a monogenic cause should cascade testing be carried out, using DNA tests for an unambiguous identification of affected relatives. The clinical utility of the polygenic explanation is that it supports a more conservative (less aggressive) treatment care pathway for those with no mutation. The ability to distinguish those with a clinical diagnosis of FH who have a monogenic or a polygenic cause of their hypercholesterolaemia is a paradigm example of the use of genomic information to inform Precision Medicine using lipid lowering agents with different efficacy and costs.

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“…A previous study [10] suggested that 88% of the general population in the US (age >40 years) with TC > 9.3 mmol/L (and/or LDL-C >6.8 mmol/L) and normal triglycerides (TG < 2.3 mmol/L) are expected to have an FH-causing mutation. We aimed to test this hypothesis using targeted next generation sequencing (NGS) (Illumina TruSeq Custom Amplicon and MiSeq Illumina sequencer) methods for genetic diagnosis of FH [11] in the Whitehall II prospective cohort study (WHII) of British civil servants [12] . The criteria of our standard variant calling pipeline were: coverage ≥30×, minimum of five reads for an altered allele, Phred quality ≥20, and a strand bias filter.…”

Section: Hypothesis and Methodsmentioning

confidence: 99%

Would raising the total cholesterol diagnostic cut-off from 7.5 mmol/L to 9.3 mmol/L improve detection rate of patients with monogenic familial hypercholesterolaemia?

et al. 2015

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A previous report suggested that 88% of individuals in the general population with total cholesterol (TC) > 9.3 mmol/L have familial hypercholesterolaemia (FH). We tested this hypothesis in a cohort of 4896 UK civil servants, mean (SD) age 44 (±6) years, using next generation sequencing to achieve a comprehensive genetic diagnosis. 25 (0.5%) participants (mean age 49.2 years) had baseline TC > 9.3 mmol/L, and overall we found an FH-causing mutation in the LDLR gene in seven (28%) subjects. The detection rate increased to 39% by excluding eight participants with triglyceride levels over 2.3 mmol/L, and reached 75% in those with TC > 10.4 mmol/L. By extrapolation, the detection rate would be ∼25% by including all participants with TC > 8.6 mmol/L (2.5 standard deviations from the mean). Based on the 1/500 FH frequency, 30% of all FH-cases in this cohort would be missed using the 9.3 mmol/L cut-off. Given that an overall detection rate of 25% is considered economically acceptable, these data suggest that a diagnostic TC cut-off of 8.6 mmol/L, rather than 9.3 mmol/L would be clinically useful for FH in the general population.

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The impact of routine next generation sequencing testing for familial hypercholesterolaemia – 5 months service experience

Cited by 6 publications

References 0 publications

Genetic testing for familial hypercholesterolemia—past, present, and future

Genetic testing for familial hypercholesterolemia—past, present, and future

Clinical utility of the polygenic LDL-C SNP score in familial hypercholesterolemia

Would raising the total cholesterol diagnostic cut-off from 7.5 mmol/L to 9.3 mmol/L improve detection rate of patients with monogenic familial hypercholesterolaemia?

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