Identification of clinically actionable variants from genome sequencing of families with congenital heart disease

Alankarage, Dimuthu; Ip, Eddie; Szot, Justin O.; Munro, Jacob E.; Blue, Gillian M.; Harrison, Katrina; Cuny, Hartmut; Enriquez, Annabelle; Troup, Michael; Humphreys, David T.; Wilson, Meredith; Harvey, Richard P.; Sholler, Gary F.; Graham, Robert M.; Ho, Joshua W. K.; Kirk, Edwin P.; Pachter, Nicholas; Chapman, Gavin; Winlaw, David S.; Giannoulatou, Eleni; Dunwoodie, Sally L.

doi:10.1038/s41436-018-0296-x

Cited by 64 publications

(58 citation statements)

References 41 publications

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“…Even when applying established guidelines, 10 the evaluation of genomic variation is subjective and potentially discordant among analysts. 38 With stringent application of the ACMG guidelines, we consider our interpretation to be conservative, compared with CHD studies with higher diagnostic yields 5,8 (Table S3). As for other heterogeneous diseases with incomplete penetrance, the contribution of rare, inherited variants is most likely underestimated.…”

Section: Discussionmentioning

confidence: 99%

“…High-throughput (exome or genome) sequencing studies of cohorts with CHD had reported remarkably disparate diagnostic rates (5.2-43.3%), which also correlated with the stringency in variant interpretation. [5][6][7][8] Compared with less comprehensive techniques, genome sequencing allows for an unbiased analysis of most types of genomic variation, and had a higher yield than standard of care genetic testing in clinically heterogeneous cohorts. 9 However, variant interpretation may be challenging, particularly for sporadic disease with limited genotype-phenotype correlations and incomplete penetrance.…”

Section: Introductionmentioning

confidence: 99%

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The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease

Reuter

Chaturvedi

Liston

et al. 2020

Genetics in Medicine

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Purpose This study investigated the diagnostic utility of nontargeted genomic testing in patients with pediatric heart disease. Methods We analyzed genome sequencing data of 111 families with cardiac lesions for rare, disease-associated variation. Results In 14 families (12.6%), we identified causative variants: seven were de novo (ANKRD11, KMT2D, NR2F2, POGZ, PTPN11, PURA, SALL1) and six were inherited from parents with no or subclinical heart phenotypes (FLT4, DNAH9, MYH11, NEXMIF, NIPBL, PTPN11). Outcome of the testing was associated with the presence of extracardiac features (p = 0.02), but not a positive family history for cardiac lesions (p = 0.67). We also report novel plausible gene–disease associations for tetralogy of Fallot/pulmonary stenosis (CDC42BPA, FGD5), hypoplastic left or right heart (SMARCC1, TLN2, TRPM4, VASP), congenitally corrected transposition of the great arteries (UBXN10), and early-onset cardiomyopathy (TPCN1). The identified candidate genes have critical functions in heart development, such as angiogenesis, mechanotransduction, regulation of heart size, chromatin remodeling, or ciliogenesis. Conclusion This data set demonstrates the diagnostic and scientific value of genome sequencing in pediatric heart disease, anticipating its role as a first-tier diagnostic test. The genetic heterogeneity will necessitate large-scale genomic initiatives for delineating novel gene–disease associations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease

Reuter

Chaturvedi

Liston

et al. 2020

Genetics in Medicine

View full text Add to dashboard Cite

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“…The quantification of this phenotype confirmed the visual inspection of the homozygous lungs. At E17.5 when the greatest difference in lung size was observed, lung volume of the R184P/R184P embryos (mean ± SD; 0.007 ± 0.001 mm 3 ) remained consistently below the volumes of the heterozygous (0.019 ± 0.003 mm 3 ) and wild-type embryos (0.020 ± 0.003 mm 3 ) ( Figure 4B).…”

Section: Phenotypic Analysis Of the R184p Knock-in Mouse Modelmentioning

confidence: 96%

“…Sporadic incidence of CHD, in families with no history of heart defects, is higher than familial cases of CHD (2). Evidence that there is a genetic basis to CHD has been growing over decades of research, however currently a clinically actionable genetic diagnosis is achieved for only 30% of cases (3). The clinical utility of a genetic diagnosis is highlighted by the vital role it plays in management of the patient's phenotypic diagnosis and prognosis in cases of syndromic CHD (4), as well as calculating the recurrence risk.…”

Section: Introductionmentioning

confidence: 99%

“…The utilisation of massively parallel sequencing techniques such as whole exome sequencing and whole genome sequencing has provided an opportunity for novel CHD gene discovery in an unbiased manner. Recent studies have put forward many genes with variants identified in CHD patients that have predicted-pathogenicity in silico but so far have not been verified functionally (3,5,6).…”

Section: Introductionmentioning

confidence: 99%

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Functional characterization of a novel PBX1 de novo missense variant identified in a patient with syndromic congenital heart disease

Alankarage

Szot

Pachter

et al. 2019

Human Molecular Genetics

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Pre-B cell leukemia factor 1 (PBX1) is an essential developmental transcription factor, mutations in which have recently been associated with CAKUTHED syndrome, characterized by multiple congenital defects including congenital heart disease (CHD). During analysis of a whole-exome-sequenced cohort of heterogeneous CHD patients, we identified a de novo missense variant, PBX1:c.551G>C p.R184P, in a patient with tetralogy of Fallot with absent pulmonary valve and extra-cardiac phenotypes. Functional analysis of this variant by creating a CRISPR-Cas9 gene-edited mouse model revealed multiple congenital anomalies. Congenital heart defects (persistent truncus arteriosus and ventricular septal defect), hypoplastic lungs, hypoplastic/ectopic kidneys, aplastic adrenal glands and spleen, as well as atretic trachea and palate defects were observed in the homozygous mutant embryos at multiple stages of development. We also observed developmental anomalies in a proportion of heterozygous embryos, suggestive of a dominant mode of inheritance. Analysis of gene expression and protein levels revealed that although Pbx1 transcripts are higher in homozygotes, amounts of PBX1 protein are significantly decreased. Here, we have presented the first functional model of a missense PBX1 variant and provided strong evidence that p.R184P is disease-causal. Our findings also expand the phenotypic spectrum associated with pathogenic PBX1 variants in both humans and mice.

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European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases

Arthur

Semsarian

Manlio

et al. 2022

Journal of Arrhythmia

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Identification of clinically actionable variants from genome sequencing of families with congenital heart disease

Cited by 64 publications

References 41 publications

The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease

The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease

Functional characterization of a novel PBX1 de novo missense variant identified in a patient with syndromic congenital heart disease

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases

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