A gene-to-patient approach uplifts novel disease gene discovery and identifies 18 putative novel disease genes

Seaby, Eleanor G.; Tavares, Ana Lisa Taylor; Brittain, Helen

doi:10.1016/j.gim.2022.04.019

Cited by 18 publications

(15 citation statements)

References 36 publications

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“…We excluded known autosomal recessive disease genes leaving 293 genes. Variants in novel disease genes represent further potential diagnoses but are beyond the scope of this disease gene focused assessment and have been published elsewhere (Seaby et al 2022).…”

Section: Discussionmentioning

confidence: 99%

Targeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project

et al. 2022

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Background Genome sequencing was first offered clinically in the UK through the 100,000 Genomes Project (100KGP). Analysis was restricted to predefined gene panels associated with the patient’s phenotype. However, panels rely on clearly characterised phenotypes and risk missing diagnoses outside of the panel(s) applied. We propose a complementary method to rapidly identify pathogenic variants, including those missed by 100KGP methods. Methods The Loss-of-function Observed/Expected Upper-bound Fraction (LOEUF) score quantifies gene constraint, with low scores correlated with haploinsufficiency. We applied DeNovoLOEUF, a filtering strategy to sequencing data from 13,949 rare disease trios in the 100KGP, by filtering for rare, de novo, loss-of-function variants in disease genes with a LOEUF score < 0.2. We compared our findings with the corresponding patient’s diagnostic reports. Results 324/332 (98%) of the variants identified using DeNovoLOEUF were diagnostic or partially diagnostic (whereby the variant was responsible for some of the phenotype). We identified 39 diagnoses that were “missed” by 100KGP standard analyses, which are now being returned to patients. Conclusion We have demonstrated a highly specific and rapid method with a 98% positive predictive value that has good concordance with standard analysis, low false-positive rate, and can identify additional diagnoses. Globally, as more patients are being offered genome sequencing, we anticipate that DeNovoLOEUF will rapidly identify new diagnoses and facilitate iterative analyses when new disease genes are discovered.

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Section: Discussionmentioning

confidence: 99%

Targeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project

et al. 2022

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“…Among these 3 genes, HDLBP is the most interesting candidate for developmental phenotypes. Loss-of-function variants of HDLBP have been found in individuals with developmental delay, autism, and macrocephaly [Seaby et al, 2022]. De novo missense variants in HDLBP that were predicted to be damaging by in silico analysis were present in individuals with autism spectrum disorders [O'Roak et al, 2012;Satterstrom et al, 2020], and analysis of predicted-to-bedamaging de novo variants from multiple public databases showed HDLBP enrichment in ASD cohorts [Takata et al, 2018].…”

Section: Discussionmentioning

confidence: 99%

Genotype-Phenotype Correlation of Distal 2q37 Deletions

Iwata‐Otsubo¹,

Darr²,

Torres-Martinez³

et al. 2022

Cytogenet Genome Res

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Brachydactyly mental retardation syndrome (BDMR) typically results from large deletions (>2–9 Mb) in distal 2q37. Haploinsufficiency of HDAC4 with incomplete penetrance has been proposed as the primary genetic cause of BDMR. To date, pure 2q37 deletions distal to HDAC4 were reported only in a limited number of individuals who share a subset of the clinical manifestations seen in cases with 2q37 deletions encompassing HDAC4. Here, we present a 4-year-old African American male who carries the smallest established 2q37.3 deletion distal to HDAC4 (827.1 kb; 16 OMIM genes). His clinical features that overlap with BDMR phenotypes include expressive-receptive language delay, behavioral issues, mild facial dysmorphism such as frontal bossing, and bilateral 5th finger brachydactyly and clinodactyly. The deletion was inherited from his mother with a history of learning difficulties and similar facial dysmorphism. This case provides important genotype-phenotype correlation information and suggests a 2q37 region distal to HDAC4 encompassing the HDLBP gene may contribute to a subset of clinical features overlapping with those seen in individuals with BDMR.

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“…Variants in novel disease genes represent further potential diagnoses but are beyond the scope of this disease-gene focused assessment. 13 We applied LOFTEE v1.0 11 to flag variants as potential false positives but retained variants in the terminal exon. Variants remaining following DeNovoLOEUF filtering steps were considered putative diagnostic variants .…”

Section: Methodsmentioning

confidence: 99%

Targeting de novo loss of function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project

Seaby

Thomas

Webb

et al. 2022

Preprint

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Whole genome sequencing was first offered clinically in the UK through the 100,000 Genomes Project (100KGP); however, data analysis was time and resource intensive with 3 million variants found per patient. Consequently, analysis was restricted to predefined gene panels associated with the patient’s phenotype. However, panels rely on clearly characterised phenotypes and risk missing diagnostic variants outside of the panel(s) applied. We propose a complementary method to rapidly identify diagnostic variants, including those missed by 100KGP methods.The Loss-of-function Observed/Expected Upper-bound Fraction (LOEUF) score quantifies gene constraint, with low scores correlated with haploinsufficiency. We applied DeNovoLOEUF, a filtering strategy to sequencing data from 13,949 rare disease trios in the 100KGP, by filtering for rare, de novo, single nucleotide loss-of-function variants in OMIM disease genes with a LOEUF score <0.2. We conducted our analysis prospectively in 2019 and compared our findings with the corresponding diagnostic reports as returned in 2019 and again in 2021.324/336 (96%) of the variants identified through DeNovoLOEUF were classified as diagnostic or partially diagnostic. We identified 39 diagnoses that were “missed” by 100KGP standard analyses, which are now being returned to patients. We have demonstrated a highly specific and rapid method with a 96% positive predictive value that has good concordance with standard analysis, low false positive rate, and can identify additional diagnoses. Globally, as more patients are being offered genome sequencing, we anticipate that DeNovoLOEUF will rapidly identify new diagnoses and facilitate iterative analyses when new disease genes are discovered.

show abstract

A gene-to-patient approach uplifts novel disease gene discovery and identifies 18 putative novel disease genes

Cited by 18 publications

References 36 publications

Targeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project

Targeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project

Genotype-Phenotype Correlation of Distal 2q37 Deletions

Targeting de novo loss of function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project

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