Publications by authors named "Najim Lahrouchi"

31 Publications

Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot.

Genet Med 2021 Oct 10;23(10):1952-1960. Epub 2021 Jun 10.

University of Nottingham, Queen's Medical Centre, Nottingham, UK.

Purpose: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear.

Methods: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF.

Results: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10).

Conclusion: Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.
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http://dx.doi.org/10.1038/s41436-021-01212-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486653PMC
October 2021

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.

Circulation 2021 Jul 5;144(1):7-19. Epub 2021 May 5.

Department of Genetics, University Medical Center Utrecht, University of Utrecht, The Netherlands (J.P.v.T.).

Background: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.

Methods: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.

Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (, , , , , , , , , , ) or strong () evidence. Seven genes (14%; , , , , , , ) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence.

Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.053033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247549PMC
July 2021

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.

J Clin Invest 2021 03;131(5)

Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.
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http://dx.doi.org/10.1172/JCI142148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919725PMC
March 2021

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

Nat Genet 2021 02 25;53(2):128-134. Epub 2021 Jan 25.

Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
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http://dx.doi.org/10.1038/s41588-020-00762-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611259PMC
February 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Genet Med 2021 01 7;23(1):47-58. Epub 2020 Sep 7.

Member of the European Reference Network for rare, low prevalence and/or complex diseases of the heart: ERN GUARD-Heart, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Circulation 2020 07 20;142(4):324-338. Epub 2020 May 20.

Masonic Medical Research Institute, Utica, NY (R.P.).

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.

Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.

Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).

Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382531PMC
July 2020

Genome-wide association studies of cardiac electrical phenotypes.

Cardiovasc Res 2020 07;116(9):1620-1634

Department of Clinical and Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

The genetic basis of cardiac electrical phenotypes has in the last 25 years been the subject of intense investigation. While in the first years, such efforts were dominated by the study of familial arrhythmia syndromes, in recent years, large consortia of investigators have successfully pursued genome-wide association studies (GWAS) for the identification of single-nucleotide polymorphisms that govern inter-individual variability in electrocardiographic parameters in the general population. We here provide a review of GWAS conducted on cardiac electrical phenotypes in the last 14 years and discuss the implications of these discoveries for our understanding of the genetic basis of disease susceptibility and variability in disease severity. Furthermore, we review functional follow-up studies that have been conducted on GWAS loci associated with cardiac electrical phenotypes and highlight the challenges and opportunities offered by such studies.
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http://dx.doi.org/10.1093/cvr/cvaa144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341169PMC
July 2020

Predicting Risk for Adult-Onset Sudden Cardiac Death in the Population.

J Am Coll Cardiol 2019 11 11;74(21):2635-2637. Epub 2019 Nov 11.

Amsterdam University Medical Center, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands. Electronic address: https://twitter.com/NajimLahrouchi.

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http://dx.doi.org/10.1016/j.jacc.2019.09.024DOI Listing
November 2019

The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy.

Eur J Hum Genet 2020 01 18;28(1):17-22. Epub 2019 Sep 18.

Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.

Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during autopsy. This study sought to compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy. We evaluated 57 SCD cases with structural findings at cardiac autopsy. Next-generation sequencing using a panel of 77 primary electrical disorder and cardiomyopathy genes was performed. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. In 29 cases (51%) autopsy findings of uncertain significance were identified whereas in 28 cases (49%) a diagnosis of cardiomyopathy was established. We identified a pathogenic or likely pathogenic variant in 10 cases (18%); in 1 (3%) case with non-specific autopsy findings compared with 9 (32%) cases with autopsy findings diagnostic of cardiomyopathy (p = 0.0054). The yield of genetic testing in SCD cases with autopsy findings consistent with cardiomyopathy is comparable with the yield in cardiomyopathy patients that are alive. Genetic testing in cases with findings of uncertain significance offers lower clinical utility than in cardiomyopathy, with lower yields than detected previously. This highlights the need for stringent evaluation of variant pathogenicity.
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http://dx.doi.org/10.1038/s41431-019-0500-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906523PMC
January 2020

Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores.

Eur Heart J 2019 10;40(37):3097-3107

Department of Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, Meibergdreef 9, AZ Amsterdam, The Netherlands.

Aims: Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG).

Methods And Results: In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose-response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P < 0.01 for all). PRSBrS, baseline QRS duration, presence of Type II or III BrS ECG at baseline, and family history of BrS are independently associated with the occurrence of a Type I BrS ECG, with good predictive accuracy (optimism-corrected C-statistic 0.74).

Conclusion: We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a diagnostic drug-induced Type I BrS ECG with clinically relevant accuracy. These findings could lead to the use of PRS in the diagnosis of BrS and, if confirmed in population studies, to identify patients at risk for toxicity when given SCB.
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http://dx.doi.org/10.1093/eurheartj/ehz435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769824PMC
October 2019

Blood Pressure-Associated Genetic Variants in the Natriuretic Peptide Receptor 1 Gene Modulate Guanylate Cyclase Activity.

Circ Genom Precis Med 2019 08 20;12(8):e002472. Epub 2019 Aug 20.

Center for Genomic Medicine (N.L., C.N.-C.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston.

Background: Human genetic variation in the NPR1 (natriuretic peptide receptor 1 gene, encoding NPR-A, atrial natriuretic peptide receptor 1) was recently shown to affect blood pressure (BP). NPR-A catalyzes the intracellular conversion of guanosine triphosphate to cGMP (cyclic 3',5'-guanosine monophosphate) on binding of ANP, BNP (atrial or brain natriuretic peptide). Increased levels of cGMP decrease BP by inducing natriuresis, diuresis, and vasodilation.

Methods: We performed a meta-analysis of low-frequency and rare NPR1 variants for BP association in up to 491 584 unrelated individuals. To examine whether the identified BP-associated variants affect NPR-A function, the cGMP response to ANP and BNP was measured in cells expressing wild-type NPR1 and cells expressing the NPR1 variants.

Results: In this study, we identified BP associations of 3 amino acid altering variants of NPR1. The minor alleles of rs35479618 (p.E967K, gnomAD non-Finnish European allele frequency 0.017) and rs116245325 (p.L1034F, allele frequency 0.0007) were associated with higher BP (P=4.0×10 and P=9.9×10, respectively), while the minor allele of rs61757359 (p.G541S, allele frequency 0.003) was associated with lower BP (P=1.8×10). Cells transiently expressing 967K or 1034F NPR-A displayed decreased cGMP production in response to ANP and BNP (all P<10), while cells expressing 541S NPR-A produced more cGMP compared with cells expressing wild-type NPR-A (P≤4.13×10 for ANP and P≤4.24×10 for BNP).

Conclusions: In summary, the loss or gain of guanylate cyclase activity for these NPR1 allelic variants could explain the higher or lower BP observed for carriers in large population-based studies.
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http://dx.doi.org/10.1161/CIRCGEN.119.002472DOI Listing
August 2019

GATA6 mutations: Characterization of two novel patients and a comprehensive overview of the GATA6 genotypic and phenotypic spectrum.

Am J Med Genet A 2019 09 12;179(9):1836-1845. Epub 2019 Jul 12.

Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

The first human mutations in GATA6 were described in a cohort of patients with persistent truncus arteriosus, and the phenotypic spectrum has expanded since then. This study underscores the broad phenotypic spectrum by presenting two patients with de novo GATA6 mutations, both exhibiting complex cardiac defects, pancreatic, and other abnormalities. Furthermore, we provided a detailed overview of all published human genetic variation in/near GATA6 published to date and the associated phenotypes (n = 78). We conclude that the most common phenotypes associated with a mutation in GATA6 were structural cardiac and pancreatic abnormalities, with a penetrance of 87 and 60%, respectively. Other common malformations were gallbladder agenesis, congenital diaphragmatic hernia, and neurocognitive abnormalities, mostly developmental delay. Fifty-eight percent of the mutations were de novo, and these patients more often had an anomaly of intracardiac connections, an anomaly of the great arteries, and hypothyroidism, compared with those with inherited mutations. Functional studies mostly support loss-of-function as the pathophysiological mechanism. In conclusion, GATA6 mutations give a wide range of phenotypic defects, most frequently malformations of the heart and pancreas. This highlights the importance of detailed clinical evaluation of identified carriers to evaluate their full phenotypic spectrum.
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http://dx.doi.org/10.1002/ajmg.a.61294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6772993PMC
September 2019

Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.

Eur Heart J 2019 09;40(35):2964-2975

Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.

Aims: Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome.

Methods And Results: A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively.

Conclusion: Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.
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http://dx.doi.org/10.1093/eurheartj/ehz311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748747PMC
September 2019

Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly.

Nat Commun 2019 03 12;10(1):1180. Epub 2019 Mar 12.

Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, 1105AZ, The Netherlands.

A failure in optic fissure fusion during development can lead to blinding malformations of the eye. Here, we report a syndrome characterized by facial dysmorphism, colobomatous microphthalmia, ptosis and syndactyly with or without nephropathy, associated with homozygous frameshift mutations in FAT1. We show that Fat1 knockout mice and zebrafish embryos homozygous for truncating fat1a mutations exhibit completely penetrant coloboma, recapitulating the most consistent developmental defect observed in affected individuals. In human retinal pigment epithelium (RPE) cells, the primary site for the fusion of optic fissure margins, FAT1 is localized at earliest cell-cell junctions, consistent with a role in facilitating optic fissure fusion during vertebrate eye development. Our findings establish FAT1 as a gene with pleiotropic effects in human, in that frameshift mutations cause a severe multi-system disorder whereas recessive missense mutations had been previously associated with isolated glomerulotubular nephropathy.
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http://dx.doi.org/10.1038/s41467-019-08547-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414540PMC
March 2019

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.

Nat Genet 2019 01 21;51(1):51-62. Epub 2018 Dec 21.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
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http://dx.doi.org/10.1038/s41588-018-0303-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365102PMC
January 2019

Inherited dilated cardiomyopathy in a large Moroccan family caused by LMNA mutation.

Anatol J Cardiol 2018 Jul;20(1):65-68

Research Center in Genomics of Human Pathologies (GENOPATH), Faculty of Medicine and Pharmacy, Mohammed V University in Rabat; Rabat-Morocco.

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http://dx.doi.org/10.14744/AnatolJCardiol.2018.69639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237802PMC
July 2018

Yield and Pitfalls of Ajmaline Testing in the Evaluation of Unexplained Cardiac Arrest and Sudden Unexplained Death: Single-Center Experience With 482 Families.

JACC Clin Electrophysiol 2017 12 28;3(12):1400-1408. Epub 2017 Jun 28.

Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands. Electronic address:

Objectives: This study evaluated the yield of ajmaline testing and assessed the occurrence of confounding responses in a large cohort of families with unexplained cardiac arrest (UCA) or sudden unexplained death (SUD).

Background: Ajmaline testing to diagnose Brugada syndrome (BrS) is routinely used in the evaluation of SUD and UCA, but its yield, limitations, and appropriate dosing have not been studied in a large cohort.

Methods: We assessed ajmaline test response and genetic testing results in 637 individuals from 482 families who underwent ajmaline testing for SUD or UCA.

Results: Overall, 89 individuals (14%) from 88 families (18%) had a positive ajmaline test result. SCN5A mutations were identified in 9 of 86 ajmaline-positive cases (10%). SCN5A mutation carriers had positive test results at significantly lower ajmaline doses than noncarriers (0.75 [range: 0.64 to 0.98] mg/kg vs. 1.03 [range: 0.95 to 1.14] mg/kg, respectively; p < 0.01). In 7 of 88 families (8%), it was concluded that the positive ajmaline response was a confounder, either in the presence of an alternative genetic diagnosis accounting for UCA/SUD (5 cases) or noncosegregation of positive ajmaline response and arrhythmia (2 cases). The rate of confounding responses was significantly higher in positive ajmaline responses obtained at >1 mg/kg than in those obtained at ≤1 mg/kg (7 of 48 vs. 0 of 41 individuals; Fisher's exact test: p = 0.014).

Conclusions: In line with previous, smaller studies, a positive ajmaline response was observed in a large proportion of UCA/SUD families. Importantly, our data emphasize the potential for confounding possibly false-positive ajmaline responses in this population, particularly at high doses, which could possibly lead to a misdiagnosis. Clinicians should consider all alternative causes in UCA/SUD and avoid ajmaline doses >1 mg/kg.
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http://dx.doi.org/10.1016/j.jacep.2017.04.005DOI Listing
December 2017

Risk of arrhythmic events in drug-induced Brugada syndrome.

Heart Rhythm 2017 10 27;14(10):1434-1435. Epub 2017 Jun 27.

Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Cardiovascular Genetics Center, Montreal Heart Institute, Montreal, Quebec, Canada; Department of Medicine, Université de Montréal, Montreal, Quebec, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2017.06.033DOI Listing
October 2017

Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome.

J Am Coll Cardiol 2017 May;69(17):2134-2145

Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, United Kingdom; Cardiology Clinical Academic Group, St. George's University Hospitals NHS Foundation Trust, London, United Kingdom. Electronic address:

Background: Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.

Objectives: This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives.

Methods: We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls.

Results: A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%.

Conclusions: Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.
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http://dx.doi.org/10.1016/j.jacc.2017.02.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405216PMC
May 2017

Exome sequencing identifies primary carnitine deficiency in a family with cardiomyopathy and sudden death.

Eur J Hum Genet 2017 06 15;25(6):783-787. Epub 2017 Mar 15.

Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Pediatric cardiomyopathy is a rare but severe disease with high morbidity and mortality. The causes are poorly understood and can only be established in one-third of cases. Recent advances in genetic technologies, specifically next-generation sequencing, now allow for the detection of genetic causes of cardiomyopathy in a systematic and unbiased manner. This is particularly important given the large clinical variability among pediatric cardiomyopathy patients and the large number of genes (>100) implicated in the disorder. We report on the performance of whole-exome sequencing in members of a consanguineous family with a history of pediatric hypertrophic cardiomyopathy and sudden cardiac death, which led to the identification of a homozygous stop variant in the SLC22A5 gene, implicated in primary carnitine deficiency, as the likely genetic cause. Targeted carnitine tandem mass spectrometry analysis in the patient revealed complete absence of plasma-free carnitine and only trace levels of total carnitine, further supporting the causality of the SLC22A5 variant. l-carnitine supplementation in the proband led to a rapid and marked clinical improvement. This case illustrates the use of exome sequencing as a systematic and unbiased diagnostic tool in pediatric cardiomyopathy, providing an efficient route to the identification of the underlying cause, which lead to appropriate treatment and prevention of premature death.
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http://dx.doi.org/10.1038/ejhg.2017.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477358PMC
June 2017

GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability.

Am J Hum Genet 2016 09 11;99(3):704-710. Epub 2016 Aug 11.

Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.

GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.
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http://dx.doi.org/10.1016/j.ajhg.2016.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010642PMC
September 2016

Next-Generation Sequencing in Post-mortem Genetic Testing of Young Sudden Cardiac Death Cases.

Front Cardiovasc Med 2016 30;3:13. Epub 2016 May 30.

Department of Clinical and Experimental Cardiology, Heart Center, AMC , Amsterdam , Netherlands.

Sudden cardiac death (SCD) in the young (<40 years) occurs in the setting of a variety of rare inherited cardiac disorders and is a disastrous event for family members. Establishing the cause of SCD is important as it permits the pre-symptomatic identification of relatives at risk of SCD. Sudden arrhythmic death syndrome (SADS) is defined as SCD in the setting of negative autopsy findings and toxicological analysis. In such cases, reaching a diagnosis is even more challenging and post-mortem genetic testing can crucially contribute to the identification of the underlying cause of death. In this review, we will discuss the current achievements of "the molecular autopsy" in young SADS cases and provide an overview of key challenges in assessing pathogenicity (i.e., causality) of genetic variants identified through next-generation sequencing.
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http://dx.doi.org/10.3389/fcvm.2016.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885007PMC
June 2016

Prognostic significance of fever-induced Brugada syndrome.

Heart Rhythm 2016 07 23;13(7):1515-20. Epub 2016 Mar 23.

Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. Electronic address:

Background: In Brugada syndrome (BrS), spontaneous type 1 electrocardiogram (ECG) is an established risk marker for fatal arrhythmias whereas drug-induced type 1 ECG shows a relatively benign prognosis. No study has analyzed the prognosis of fever-induced type 1 ECG (F-type1) in a large BrS cohort.

Objectives: The objectives of this study were to assess the prognosis of F-type1 in asymptomatic BrS and to compare the effects of fever and drugs on ECG parameters.

Methods: One hundred twelve patients with BrS who developed F-type1 were retrospectively enrolled. Prognosis was evaluated in 88 asymptomatic patients. In a subgroup (n = 52), ECG parameters of multiple ECGs (at baseline, during fever, and after drug challenge) were analyzed.

Results: Eighty-eight asymptomatic patients had a mean age of 45.8 ± 18.7 years, and 71.6% (67 of 88) were men. Twenty-one percent (18 of 88) had a family history of sudden cardiac death, and 26.4% (14 of 53) carried a pathogenic SCN5A mutation. Drug challenge was positive in 29 of 36 patients tested (80.6%). The risk of ventricular fibrillation in asymptomatic patients was 0.9%/y (3 of 88; 43.6 ± 37.4 months). ST-segment elevation in lead V2 during fever and after drug challenge was not significantly different (0.41 ± 0.21 ms during fever and 0.40 ± 0.30 ms after drug challenge; P > .05). Fever shortened the PR interval compared to baseline, whereas drug challenge resulted in prolonged PR interval and QRS duration (PR interval: 169 ± 29 ms at baseline, 148 ± 45 ms during fever, and 202 ± 35 ms after drug challenge; QRS duration: 97 ± 18 ms at baseline, 92 ± 28 ms during fever, and 117 ± 21 ms after drug challenge).

Conclusion: Patients with BrS who develop F-type1 are at risk of arrhythmic events. F-type1 appears to develop through a more complex mechanism as compared with drug-induced type 1 ECG.
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http://dx.doi.org/10.1016/j.hrthm.2016.03.044DOI Listing
July 2016

Genetics of sudden cardiac death.

Circ Res 2015 Jun;116(12):1919-36

From the Department of Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (C.R.B., N.L.); Molecular Cardiology, Fondazione Salvatore Maugeri, Pavia, Italy (S.G.P.); and Department of Molecular Medicine, University of Pavia, Pavia Italy (S.G.P.).

Sudden cardiac death occurs in a broad spectrum of cardiac pathologies and is an important cause of mortality in the general population. Genetic studies conducted during the past 20 years have markedly illuminated the genetic basis of the inherited cardiac disorders associated with sudden cardiac death. Here, we review the genetic basis of sudden cardiac death with a focus on the current knowledge on the genetics of the primary electric disorders caused primarily by mutations in genes encoding ion channels, and the cardiomyopathies, which have been attributed to mutations in genes encoding a broader category of proteins, including those of the sarcomere, the cytoskeleton, and desmosomes. We discuss the challenges currently faced in unraveling genetic factors that predispose to sudden cardiac death in the setting of sequela of coronary artery disease and present the genome-wide association studies conducted in recent years on electrocardiographic parameters, highlighting their potential in uncovering new biological insights into cardiac electric function.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.304030DOI Listing
June 2015

A child with a white pupil.

JAMA 2014 May;311(17):1799-800

Department of Ophthalmology, VU University Medical Center, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1001/jama.2013.286248DOI Listing
May 2014

Ruptured aneurysm of the right coronary sinus of Valsalva in a child with Down syndrome.

Cardiol Young 2014 Apr 18;24(2):376-8. Epub 2013 Apr 18.

1 Department of Pediatric Cardiology, VU University Medical Center, Amsterdam, The Netherlands.

Aneurysms of one of the aortic sinuses of Valsalva are rare congenital or acquired lesions. Here we present the case of an adolescent with Down syndrome with ruptured aneurysm of the right coronary sinus into the right atrium. All sinuses of Valsalva were normal during cardiological screening owing to Down syndrome at the age of 2 weeks. Paediatricians should have a low threshold for referring patients with Down syndrome for cardiac re-evaluation because of the new onset of cardiac symptoms or cardiac physical findings, even in the situation in which there are normal echocardiographic findings in the past.
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http://dx.doi.org/10.1017/S1047951113000450DOI Listing
April 2014
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