This study investigated the diagnostic utility of nontargeted genomic testing in patients with pediatric heart disease.
We analyzed genome sequencing data of 111 families with cardiac lesions for ...rare, disease-associated variation.
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.
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.
The range of genetic variation with potential clinical implications in schizophrenia, beyond rare copy number variants (CNVs), remains uncertain. We therefore analyzed genome sequencing data for 259 ...unrelated adults with schizophrenia from a well-characterized community-based cohort previously examined with chromosomal microarray for CNVs (none with 22q11.2 deletions). We analyzed these genomes for rare high-impact variants considered causal for neurodevelopmental disorders, including single-nucleotide variants (SNVs) and small insertions/deletions (indels), for potential clinical relevance based on findings for neurodevelopmental disorders. Also, we investigated a novel variant type, tandem repeat expansions (TREs), in 45 loci known to be associated with monogenic neurological diseases. We found several of these variants in this schizophrenia population suggesting that these variants have a wider clinical spectrum than previously thought. In addition to known pathogenic CNVs, we identified 11 (4.3%) individuals with clinically relevant SNVs/indels in genes converging on schizophrenia-relevant pathways. Clinical yield was significantly enriched in females and in those with broadly defined learning/intellectual disabilities. Genome analyses also identified variants with potential clinical implications, including TREs (one in DMPK; two in ATXN8OS) and ultra-rare loss-of-function SNVs in ZMYM2 (a novel candidate gene for schizophrenia). Of the 233 individuals with no pathogenic CNVs, we identified rare high-impact variants (i.e., clinically relevant or with potential clinical implications) for 14 individuals (6.0%); some had multiple rare high-impact variants. Mean schizophrenia polygenic risk score was similar between individuals with and without clinically relevant rare genetic variation; common variants were not sufficient for clinical application. These findings broaden the individual and global picture of clinically relevant genetic risk in schizophrenia, and suggest the potential translational value of genome sequencing as a single genetic technology for schizophrenia.
Commercial pharmacogenetic testing panels capture a fraction of the genetic variation underlying medication metabolism and predisposition to adverse reactions. In this study we compared variation in ...six pharmacogenes detected by whole genome sequencing (WGS) to a targeted commercial panel in a cohort of 308 individuals with family history of pediatric heart disease. In 1% of the cohort, WGS identified rare variants that altered the interpretation of metabolizer status and would thus prevent potential errors in gene-based dosing.
Recent genome-wide studies of rare genetic variants have begun to implicate novel mechanisms for tetralogy of Fallot (TOF), a severe congenital heart defect (CHD). To provide statistical support for ...case-only data without parental genomes, we re-analyzed genome sequences of 231 individuals with TOF (
n
= 175) or related CHD. We adapted a burden test originally developed for
de novo
variants to assess ultra-rare variant burden in individual genes, and in gene-sets corresponding to functional pathways and mouse phenotypes, accounting for highly correlated gene-sets and for multiple testing. For truncating variants, the gene burden test confirmed significant burden in
FLT4
(Bonferroni corrected
p
-value < 0.01). For missense variants, burden in
NOTCH1
achieved genome-wide significance only when restricted to constrained genes (i.e., under negative selection, Bonferroni corrected
p
-value = 0.004), and showed enrichment for variants affecting the extracellular domain, especially those disrupting cysteine residues forming disulfide bonds (OR = 39.8 vs. gnomAD). Individuals with
NOTCH1
ultra-rare missense variants, all with TOF, were enriched for positive family history of CHD. Other genes not previously implicated in CHD had more modest statistical support in gene burden tests. Gene-set burden tests for truncating variants identified a cluster of pathways corresponding to VEGF signaling (
FDR
= 0%), and of mouse phenotypes corresponding to abnormal vasculature (
FDR
= 0.8%); these suggested additional candidate genes not previously identified (e.g.,
WNT5A
and
ZFAND5
). Results for the most promising genes were driven by the TOF subset of the cohort. The findings support the importance of ultra-rare variants disrupting genes involved in VEGF and NOTCH signaling in the genetic architecture of TOF, accounting for 11–14% of individuals in the TOF cohort. These proof-of-principle data indicate that this statistical methodology could assist in analyzing case-only sequencing data in which ultra-rare variants, whether
de novo
or inherited, contribute to the genetic etiopathogenesis of a complex disorder.
Variant interpretation is the main bottleneck in medical genomic sequencing efforts. This usually involves genome analysts manually searching through a multitude of independent databases, often with ...the aid of several, mostly independent, computational tools. To streamline variant interpretation, we developed the GeneTerpret platform which collates data from current interpretation tools and databases, and applies a phenotype-driven query to categorize the variants identified in the genome(s). The platform assigns quantitative validity scores to genes by query and assembly of the genotype-phenotype data, sequence homology, molecular interactions, expression data, and animal models. It also uses the American College of Medical Genetics and Genomics (ACMG) criteria to categorize variants into five tiers of pathogenicity. The final output is a prioritized list of potentially causal variants/genes.
We tested GeneTerpret by comparing its performance to expert-curated genes (ClinGen's gene-validity database) and variant pathogenicity reports (DECIPHER database). Output from GeneTerpret was 97.2% and 83.5% concordant with the expert-curated sources, respectively. Additionally, similar concordance was observed when GeneTerpret's performance was compared with our internal expert-interpreted clinical datasets.
GeneTerpret is a flexible platform designed to streamline the genome interpretation process, through a unique interface, with improved ease, speed and accuracy. This modular and customizable system allows the user to tailor the component-programs in the analysis process to their preference. GeneTerpret is available online at https://geneterpret.com .
Abstract only
Introduction:
Pulmonary vein stenosis (PVS) is a rare and progressive disease of the vasculature, characterized by neointimal proliferation and is frequently lethal in pediatric ...patients. PVS is clinically heterogeneous, and its etiology remains unknown. Insight into the genetic basis of PVS can help to direct treatment interventions and improve clinical outcomes.
Objectives:
To examine the genetic mechanisms underlying PVS and to compare the genetic architecture in patients with severe disease to patients with disease stabilization.
Methods:
We performed genome sequencing in a cohort of 18 pediatric patients with PVS. The genomic data was analyzed for clinically reportable variants and biologically plausible candidates. We used a statistical overrepresentation test to investigate the overrepresentation of gene ontology (GO) terms in patients with aggressive disease compared with stabilized patients.
Results:
Seven patients (38.9%) had aggressive disease, resulting in death or lung transplant, 16 patients (88.9%) had concomitant congenital heart disease, and 11 patients (61.1%) had extracardiac anomalies. In two patients (11.1%) with a syndromic presentation, we identified Pathogenic/Likely Pathogenic variants in three genes:
ANKRD11,
associated with KBG syndrome,
FOXP1
, and
DYNC1H1
, associated with intellectual developmental disorders. In search of novel candidate genes, we identified
de novo
variants in
PAK4
,
AMBRA1
, and
ANKRD50
, involved in cytoskeletal remodeling, mTOR-regulated autophagy, and protein trafficking, respectively. In patients with severe PVS, we found an overrepresentation of rare (minor allele frequency <0.15%) coding variants in genes involved in blood vessel morphogenesis (FDR <0.05), protein phosphorylation (FDR <0.05), dynein intermediate chain binding (FDR <0.05), and ATP binding (FDR <0.05). No GO terms were overrepresented in the patients with stabilized disease.
Conclusions:
This exploratory cohort of patients with PVS provides further insight into the genetic contributions to PVS. These results suggest distinct genetic landscapes between progressive and stabilized disease. Genetic testing in larger cohorts is needed to further define the molecular pathology of pediatric PVS.
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