Oyediran Akinrinade

Aims Despite our increased understanding of the genetic basis of dilated cardiomyopathy (DCM), the clinical utility and yield of clinically meaningful findings of comprehensive next-generation sequencing (NGS)-based genetic diagnostics in DCM has been poorly described. We utilized a high-quality oligonucleotide-selective sequencing (OS-Seq)-based t...

Background: Truncating titin (TTN) mutations, especially in A-band region, represent the most common cause of dilated cardiomyopathy (DCM). Clinical interpretation of these variants can be challenging, as these variants are also present in reference populations. We carried out systematic analyses of TTN truncating variants (TTNtv) in publicly avai...

Dilated cardiomyopathy (DCM), a genetically heterogeneous cardiac disease characterized by left ventricular dilatation and systolic dysfunction, is caused majorly by truncations of titin (TTN), especially in A-band region. Clinical interpretation of TTN truncating variants (TTNtv) has been challenged by the existing inaccurate variant assessment st...

Cardiomyopathy has variable penetrance. We analyzed age and sex-related genetic differences in 1,397 cardiomyopathy patients (Ontario, UK) with whole genome sequencing. Pediatric cases (n = 471) harbored more deleterious protein-coding variants in Tier 1 cardiomyopathy genes compared to adults (n = 926) (34.6% vs 25.9% respectively, p = 0.0015), wi...

Recent advancements in next generation sequencing (NGS) technology have led to the identification of the giant sarcomere gene, titin (TTN), as a major human disease gene. Truncating variants of TTN (TTNtv) especially in the A-band region account for 20% of dilated cardiomyopathy (DCM) cases. Much attention has been focused on assessment and interpr...

A 44-year-old female patient presented with weight loss, diarrhea and intermittent episodes of left upper quadrant (LUQ) pain lasting for 3 years, accompanied by acute episodes of focal LUQ pain, dizziness, tachycardia, borborygmi and bloating, occurring approximately 60 min after meals. The patient developed chronic acalculous cholecystitis and tr...

Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patient...

Aims: Cardiomyopathy is a clinically and genetically heterogeneous disorder with age and sex-related differences in severity and outcomes. The aim of our study was to identify age and sex-related differences in the genetic architecture of cardiomyopathy. Methods and Results: We analyzed whole genome sequence data from 471 pediatric and 926 adult ca...

Successful portoenterostomy (SPE) improves the short‐term outcome of patients with biliary atresia (BA) by relieving cholestasis and extending survival with native liver. Despite SPE, hepatic fibrosis progresses in most patients, leading to cirrhosis and a deterioration of liver function. The goal of this study was to characterize the effects of SP...

Background Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. Objectives This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. Methods We performed exome sequencing in 289 childhood cancer survivors at least 3 years f...

Background: Despite known clinical and genetic risk factors, predicting anthracycline cardiotoxicity remains challenging. Objective: To develop a risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. Methods: We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure....

Cardiomyopathy (CMP) is a heritable genetic disorder. Protein-coding variants account for 20-30% of cases. The contribution of variants in non-coding DNA elements that regulate gene expression has not been explored. We performed whole-genome sequencing (WGS) of 228 unrelated CMP families. Besides pathogenic protein-coding variants in known CMP gene...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Objective Elastin gene deletion or mutation leads to arterial stenoses due to vascular smooth muscle cell (SMC) proliferation. Human induced pluripotent stem cells–derived SMCs can model the elastin insufficiency phenotype in vitro but show only partial rescue with rapamycin. Our objective was to identify drug candidates with superior efficacy in r...

Background: Whole-genome sequencing (WGS) is becoming an increasingly important tool for detecting genomic variation. Blood derived DNA is the current standard for WGS for research or clinical purposes but may not always be feasible to acquire. The usability of DNA from saliva for WGS is not known. We compared the quality of WGS between blood vers...

Background: Assess process, uptake, validity and resource needs for return of actionable research findings to biobank participants. Methods: Participants were prospectively enrolled in a multicenter biorepository of childhood onset heart disease. Clinically actionable research findings were reviewed by a Return of Research Results Committee (RRR...

Purpose: Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous showing progressive retinal cell death which results in vision loss. IRDs include a wide spectrum of disorders, such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), cone-rod dystrophy (CRD), and Stargardt disease (STGD1). Methods: In this stud...

Whole-genome sequencing (WGS) is becoming an increasingly important tool for detecting genomic variation. Blood derived DNA is the current standard for WGS for research or clinical purposes. We compared the level of microbial contamination, sequencing coverage, as well as yield and concordance of single-nucleotide polymorphism (SNP) and copy number...

GATA4, a transcription factor crucial for early liver development, has been implicated in the pathophysiology of hepatoblastoma, an embryonal tumor of childhood. However, the molecular and phenotypic consequences of GATA4 expression in hepatoblastoma are not fully understood. We surveyed GATA4 expression in 24 hepatoblastomas using RNA in situ hybr...

Campylobacter jejuni is an important foodborne pathogen and the most commonly reported bacterial cause of gastroenteritis. C. jejuni is occasionally found in blood, although mechanisms important for invasiveness have remained unclear. C. jejuni is divided into many different lineages, of which the ST21 clonal complex (CC) is widely distributed. Her...

Next generation sequencing (NGS) technologies provide the potential for developing high-throughput and low-cost platforms for medical research and diagnostics, which is expected to accelerate the findings of root causes and treatments of human diseases. In addition to short read lengths of NGS technology; another limiting factor to clinical applica...

Conditional deletion of Gata4 in Sertoli cells (SCs) of adult mice has been shown to increase permeability of the blood-testis barrier (BTB) and disrupt spermatogenesis. To gain insight into the molecular underpinnings of these phenotypic abnormalities, we assessed the impact of Gata4 gene silencing in cell culture models. Microarray hybridization...

Tie2 promoter-mediated loss of peroxisome proliferator-activated receptor gamma (PPARγ) in mice leads to osteopetrosis and pulmonary arterial hypertension. Vascular disease is associated with loss of PPARγ in pulmonary microvascular endothelial cells (PMVEC), we evaluated the role of PPARγ in PMVEC functions, such as angiogenesis and migration. The...

Truncating TTN mutations identified in 1000 Genomes Project Cohort (P1V2). Marked (†) are the false positives that were filtered out in the subsequent version. Abbreviations: P1V2 –phase 1 version 2; GMAF–Global minor allele frequency. (DOCX)

Truncating TTN mutations identified in 1000 Genomes Project Cohort (P1V1). Marked (†) are the false positives that were filtered out in the subsequent version. Abbreviations: P1V1 –phase 1 version 1; GMAF–Global minor allele frequency. (DOCX)

Truncating TTN mutations identified in 1000 Genomes Project Cohort (P1V3). Marked (†) are the variants that were not detected in the phase 3 integrated variant data. Abbreviations: P1V3 –phase 1 version 3; GMAF–Global minor allele frequency. (DOCX)

Campylobacter jejuni is a major pathogen in bacterial gastroenteritis worldwide and can cause bacteremia in severe cases. C. jejuni is highly structured into clonal lineages of which the ST677CC lineage has been overrepresented among C. jejuni isolates derived from blood. In this study, we characterized the genomes of 31 C. jejuni blood isolates an...

Background: The inherited factors that predispose individuals to prostate cancer (PrCa) remain largely unknown. The aim of this study was to identify germline copy number variants (CNVs) in Finnish individuals that could contribute to an increased PrCa risk. Methods: Genome-wide CNV screening was performed by analyzing single nucleotide polymorp...

Background – Truncating titin (TTN) mutations account for 25% and 18% of familial and sporadic cases of dilated cardiomyopathy (DCM) respectively. However, distinguishing true pathogenic TTN truncating variants (TTNtv) from benign variants in clinical diagnostics and in research setting is challenging, as these variants are also present in control...

Transcription factor GATA4 is expressed in somatic cells of the mammalian testis. Gene targeting studies in mice have shown that GATA4 is essential for proper differentiation and function of Sertoli cells. The role of GATA4 in Leydig cell development, however, remains controversial because targeted mutagenesis experiments in mice have not shown a c...

The genetic basis of idiopathic dilated cardiomyopathy (DCM) is recognised but still not widely utilised in diagnostics. Hundreds of mutations in coding exons of over 50 genes have been reported to associate with DCM. Comprehensive genetic testing can improve diagnostics, prognostics and treatment optimisation but it also allows effective screening...

Cardiomyopathies are genetically heterogeneous group of diseases of the myocardium. Mutations in multiple genes have been associated with cardiomyopathy and many cases of cardiomyopathy have a genetic component. Genetic factors may be responsible for 30-50% of cases of dilated cardiomyopathy (DCM), and about 90% of cases of Hypertrophic cardiomyopa...

Inherited factors predisposing individuals to breast and ovarian cancer are largely unidentified in a majority of families with hereditary breast and ovarian cancer (HBOC). We aimed to identify germline copy number variations (CNVs) contributing to HBOC susceptibility in the Finnish population. A cohort of 84 HBOC individuals (negative for BRCA1/2-...

BRCA1 deletion (exons 1A-13) confirmation by MLPA. (PDF)

Clinical characteristics of 20 additional HBOC individuals utilised for CNV validation analysis. (PDF)

All of the identified 545 copy number variations (CNVs) at 273 different genomic regions (listed according to P -values). (PDF)

Clinical characteristics of three additional individuals. (PDF)

Copy number variation validation protocol by quantitative RT-PCR. (PDF)

Enriched GO term categories and pathways ( P -value less than 0.05) involving EPHA3 , ERBB4 and BRCA1. (PDF)