Publications by authors named "Wolfgang Berger"

109 Publications

Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases.

Int J Mol Sci 2021 Feb 3;22(4). Epub 2021 Feb 3.

Institute of Medical Molecular Genetics, University of Zurich, 8952 Schlieren, Switzerland.

The purpose of this study was to develop a flexible, cost-efficient, next-generation sequencing (NGS) protocol for genetic testing. Long-range polymerase chain reaction (PCR) amplicons of up to 20 kb in size were designed to amplify entire genomic regions for a panel ( = 35) of inherited retinal disease (IRD)-associated loci. Amplicons were pooled and sequenced by NGS. The analysis was applied to 227 probands diagnosed with IRD: (A) 108 previously molecularly diagnosed, (B) 94 without previous genetic testing, and (C) 25 undiagnosed after whole-exome sequencing (WES). The method was validated with 100% sensitivity on cohort A. Long-range PCR-based sequencing revealed likely causative variant(s) in 51% and 24% of proband from cohorts B and C, respectively. Breakpoints of 3 copy number variants (CNVs) could be characterized. Long-range PCR libraries spike-in extended coverage of WES. Read phasing confirmed compound heterozygosity in 5 probands. The proposed sequencing protocol provided deep coverage of the entire gene, including intronic and promoter regions. Our method can be used (i) as a first-tier assay to reduce genetic testing costs, (ii) to elucidate missing heritability cases, (iii) to characterize breakpoints of CNVs at nucleotide resolution, (iv) to extend WES data to non-coding regions by spiking-in long-range PCR libraries, and (v) to help with phasing of candidate variants.
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http://dx.doi.org/10.3390/ijms22041508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913364PMC
February 2021

Whole Exome Sequencing in Coloboma/Microphthalmia: Identification of Novel and Recurrent Variants in Seven Genes.

Genes (Basel) 2021 Jan 6;12(1). Epub 2021 Jan 6.

Institute of Medical Molecular Genetics, University of Zurich, 8952 Schlieren, Switzerland.

Coloboma and microphthalmia (C/M) are related congenital eye malformations, which can cause significant visual impairment. Molecular diagnosis is challenging as the genes associated to date with C/M account for only a small percentage of cases. Overall, the genetic cause remains unknown in up to 80% of patients. High throughput DNA sequencing technologies, including whole-exome sequencing (WES), are therefore a useful and efficient tool for genetic screening and identification of new mutations and novel genes in C/M. In this study, we analyzed the DNA of 19 patients with C/M from 15 unrelated families using singleton WES and data analysis for 307 genes of interest. We identified seven novel and one recurrent potentially disease-causing variants in , , , , , , and in 47% of our families, three of which occurred de novo. The detection rate in patients with ocular and extraocular manifestations (67%) was higher than in patients with an isolated ocular phenotype (46%). Our study highlights the significant genetic heterogeneity in C/M cohorts and emphasizes the diagnostic power of WES for the screening of patients and families with C/M.
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http://dx.doi.org/10.3390/genes12010065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825129PMC
January 2021

Application of WES Towards Molecular Investigation of Congenital Cataracts: Identification of Novel Alleles and Genes in a Hospital-Based Cohort of South India.

Int J Mol Sci 2020 Dec 16;21(24). Epub 2020 Dec 16.

Department of Genetics, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Tamil Nadu 600 113, India.

Congenital cataracts are the prime cause for irreversible blindness in children. The global incidence of congenital cataract is 2.2-13.6 per 10,000 births, with the highest prevalence in Asia. Nearly half of the congenital cataracts are of familial nature, with a predominant autosomal dominant pattern of inheritance. Over 38 of the 45 mapped loci for isolated congenital or infantile cataracts have been associated with a mutation in a specific gene. The clinical and genetic heterogeneity of congenital cataracts makes the molecular diagnosis a bit of a complicated task. Hence, whole exome sequencing (WES) was utilized to concurrently screen all known cataract genes and to examine novel candidate factors for a disease-causing mutation in probands from 11 pedigrees affected with familial congenital cataracts. Analysis of the WES data for known cataract genes identified causative mutations in six pedigrees (55%) in (two variants), and an additional likely causative mutation in a novel gene , which represents the first dominant mutation in this gene. This study identifies a novel cataract gene not yet linked to human disease. NCOA6 is a transcriptional coactivator that interacts with nuclear hormone receptors to enhance their transcriptional activator function.
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http://dx.doi.org/10.3390/ijms21249569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765966PMC
December 2020

Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria.

Circ Genom Precis Med 2021 Feb 24;14(1):e003047. Epub 2020 Nov 24.

Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Switzerland (S.C., A.G., D.A., F.R., C.B.B., F.D., A.M.S.).

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with ARVC and to assess the impact on ARVC diagnosis.

Methods: This study included patients from the Multicenter Zurich ARVC Registry who hosted a genetic variant deemed to be associated with the disease. Reclassification of pathogenicity was performed according to the modified 2015 American College of Medical Genetics criteria. ARVC diagnosis (categories: definite, borderline, possible) based on the 2010 Task Force Criteria was reclassified after genetic readjudication.

Results: In 79 patients bearing 80 unique genetic variants, n=47 (58.8%) genetic variants were reclassified, and reclassification was judged to be clinically relevant in n=33 (41.3%). Variants in plakophilin-2 () were shown to reclassify less frequently as compared with other genes (, n=1, 8.3%; desmosomal non-, n=20, 66.7%; nondesmosomal, n=26, 68.4%; =0.001for overall comparison; versus desmosomal non-=0.001; versus nondesmosomal, <0.001). Genetic reclassification impacted ARVC diagnosis. Eight patients (10.1%) were downgraded from definite to borderline/possible disease at the time of initial genetic testing as well as last follow-up, respectively. Separate genetic reclassification in family members led to downgrading of n=5 (38.5%) variants.

Conclusions: Given that approximately half of genetic variants were reclassified, with 10.1% of patients losing their definite disease status, accurate determination of variant pathogenicity is of utmost importance in the diagnosis of ARVC.
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http://dx.doi.org/10.1161/CIRCGEN.120.003047DOI Listing
February 2021

Genotype-phenotype spectrum in isolated and syndromic nanophthalmos.

Acta Ophthalmol 2020 Sep 30. Epub 2020 Sep 30.

Department of Ophthalmology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Purpose: To (i) describe a series of patients with isolated or syndromic nanophthalmos with the underlying genetic causes, including novel pathogenic variants and their functional characterization and (ii) to study the association of retinal dystrophy in patients with MFRP variants, based on a detailed literature review of genotype-phenotype correlations.

Methods: Patients with nanophthalmos and available family members received a comprehensive ophthalmological examination. Genetic analysis was based on whole-exome sequencing and variant calling in core genes including MFRP, BEST1, TMEM98, PRSS56, CRB1, GJA1, C1QTNF5, MYRF and FAM111A. A minigene assay was performed for functional characterization of a splice site variant.

Results: Seven patients, aged between three and 65 years, from five unrelated families were included. Novel pathogenic variants in MFRP (c.497C>T, c.899-3C>A, c.1180G>A), and PRSS56 (c.1202C>A), and a recurrent de novo variant in FAM111A (c.1706G>A) in a patient with Kenny-Caffey syndrome type 2, were identified. In addition, we report co-inheritance of MFRP-related nanophthalmos and ADAR-related Aicardi-Goutières syndrome.

Conclusion: Nanophthalmos is a genetically heterogeneous condition, and the severity of ocular manifestations appears not to correlate with variants in a specific gene. However, retinal dystrophy is only observed in patients harbouring pathogenic MFRP variants. Furthermore, heterozygous carriers of MFRP and PRSS56 should be screened for the presence of high hyperopia. Identifying nanophthalmos as an isolated condition or as part of a syndrome has implications for counselling and can accelerate the interdisciplinary care of patients.
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http://dx.doi.org/10.1111/aos.14615DOI Listing
September 2020

Exome Sequencing in a Swiss Childhood Glaucoma Cohort Reveals and Variants as Most Frequent Causes.

Transl Vis Sci Technol 2020 06 30;9(7):47. Epub 2020 Jun 30.

Department of Ophthalmology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Purpose: The aim of this study was to investigate the molecular basis of childhood glaucoma in Switzerland to recommend future targeted genetic analysis in the Swiss population.

Methods: Whole-exome sequencing and copy number variation (CNV) analysis was performed in a Swiss cohort of 18 patients from 14 unrelated families. Identified variants were validated by Sanger sequencing and multiplex ligation-dependent probe amplification. Breakpoints of structural variants were determined by a microarray. A minigene assay was conducted for functional analysis of a splice site variant.

Results: A diagnosis of primary congenital glaucoma was made in 14 patients, of which six (43%) harbored pathogenic variants in , one (7%) a frameshift variant in , and seven (50%) remained without a genetic diagnosis. Three patients were diagnosed with glaucoma associated with nonacquired ocular anomalies, of which two patients with mild ocular features of Axenfeld-Rieger syndrome harbored a duplication plus an additional missense variant, and one patient with a Barkan membrane remained without genetic diagnosis. A diagnosis of juvenile open-angle glaucoma was made in one patient, and genetic analysis revealed a duplication.

Conclusions: Sequencing of and as well as analysis of CNVs in , should be performed before extended gene panel sequencing.

Translational Relevance: The identification of the molecular cause of childhood glaucoma is a prerequisite for genetic counseling and personalized care for patients and families.
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http://dx.doi.org/10.1167/tvst.9.7.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414719PMC
June 2020

De Novo Assembly-Based Analysis of Exon ORF15 in an Indigenous African Cohort Overcomes Limitations of a Standard Next-Generation Sequencing (NGS) Data Analysis Pipeline.

Genes (Basel) 2020 07 15;11(7). Epub 2020 Jul 15.

University of Cape Town/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa.

exon ORF15 variants are one of the most frequent causes for inherited retinal disorders (IRDs), in particular retinitis pigmentosa. The low sequence complexity of this mutation hotspot makes it prone to indels and challenging for sequence data analysis. Whole-exome sequencing generally fails to provide adequate coverage in this region. Therefore, complementary methods are needed to avoid false positives as well as negative results. In this study, next-generation sequencing (NGS) was used to sequence long-range PCR amplicons for an IRD cohort of African ancestry. By developing a novel secondary analysis pipeline based on de novo assembly, we were able to avoid the miscalling of variants generated by standard NGS analysis tools. We identified pathogenic variants in 11 patients (13% of the cohort), two of which have not been reported previously. We provide a novel and alternative end-to-end secondary analysis pipeline for targeted NGS of ORF15 that is less prone to false positive and negative variant calls.
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http://dx.doi.org/10.3390/genes11070800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396994PMC
July 2020

Haplotype of the astrocytic water channel AQP4 is associated with slow wave energy regulation in human NREM sleep.

PLoS Biol 2020 05 5;18(5):e3000623. Epub 2020 May 5.

Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Cerebrospinal fluid (CSF) flow through the brain parenchyma is facilitated by the astrocytic water channel aquaporin 4 (AQP4). Homeostatically regulated electroencephalographic (EEG) slow waves are a hallmark of deep non-rapid eye movement (NREM) sleep and have been implicated in the regulation of parenchymal CSF flow and brain clearance. The human AQP4 gene harbors several single nucleotide polymorphisms (SNPs) associated with AQP4 expression, brain-water homeostasis, and neurodegenerative diseases. To date, their role in sleep-wake regulation is unknown. To investigate whether functional variants in AQP4 modulate human sleep, nocturnal EEG recordings and cognitive performance were investigated in 123 healthy participants genotyped for a common eight-SNP AQP4-haplotype. We show that this AQP4-haplotype is associated with distinct modulations of NREM slow wave energy, strongest in early sleep and mirrored by changes in sleepiness and reaction times during extended wakefulness. The study provides the first human evidence for a link between AQP4, deep NREM sleep, and cognitive consequences of prolonged wakefulness.
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http://dx.doi.org/10.1371/journal.pbio.3000623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199924PMC
May 2020

The Expression of Decidual Protein Induced by Progesterone (DEPP) is Controlled by Three Distal Consensus Hypoxia Responsive Element (HRE) in Hypoxic Retinal Epithelial Cells.

Genes (Basel) 2020 01 18;11(1). Epub 2020 Jan 18.

Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, 8952 Schlieren, Switzerland.

Hypoxia affects the development and/or progression of several retinopathies. Decidual protein induced by progesterone () has been identified as a hypoxia-responsive gene that may be part of cellular pathways such as autophagy and connected to retinal diseases. To increase our understanding of regulation in the eye, we defined its expression pattern in mouse and human retina and retinal pigment epithelium (RPE). Interestingly, expression was increased in an age-dependent way in the central human RPE. We showed that was regulated by hypoxia in the mouse retina and eyecup and that this regulation was controlled by hypoxia-inducible transcription factors 1 and 2 (HIF1 and HIF2). Furthermore, we identified three hypoxia response elements (HREs) about 3.5 kb proximal to the transcriptional start site that were responsible for hypoxic induction of in a human RPE cell line. Comparative genomics analysis suggested that one of the three HREs resides in a highly conserved genomic region. Collectively, we defined the molecular elements controlling hypoxic induction of in an RPE cell line, and provided evidence for an enrichment of in the aged RPE of human donors. This makes an interesting gene to study with respect to aging and age-related retinal pathologies.
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http://dx.doi.org/10.3390/genes11010111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016973PMC
January 2020

Integrin-linked kinase controls retinal angiogenesis and is linked to Wnt signaling and exudative vitreoretinopathy.

Nat Commun 2019 11 20;10(1):5243. Epub 2019 Nov 20.

Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, University of Münster, Faculty of Medicine, D-48149, Münster, Germany.

Familial exudative vitreoretinopathy (FEVR) is a human disease characterized by defective retinal angiogenesis and associated complications that can result in vision loss. Defective Wnt/β-catenin signaling is an established cause of FEVR, whereas other molecular alterations contributing to the disease remain insufficiently understood. Here, we show that integrin-linked kinase (ILK), a mediator of cell-matrix interactions, is indispensable for retinal angiogenesis. Inactivation of the murine Ilk gene in postnatal endothelial cells results in sprouting defects, reduced endothelial proliferation and disruption of the blood-retina barrier, resembling phenotypes seen in established mouse models of FEVR. Retinal vascularization defects are phenocopied by inducible inactivation of the gene for α-parvin (Parva), an interactor of ILK. Screening genomic DNA samples from exudative vitreoretinopathy patients identifies three distinct mutations in human ILK, which compromise the function of the gene product in vitro. Together, our data suggest that defective cell-matrix interactions are linked to Wnt signaling and FEVR.
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http://dx.doi.org/10.1038/s41467-019-13220-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868140PMC
November 2019

Atonal homolog 7 (ATOH7) loss-of-function mutations in predominant bilateral optic nerve hypoplasia.

Hum Mol Genet 2020 01;29(1):132-148

Institute of Medical Molecular Genetics, University of Zurich, Schlieren 8952, Switzerland.

Optic nerve hypoplasia (ONH) is a congenital optic nerve abnormality caused by underdevelopment of retinal ganglion cells (RGCs). Despite being a rare disease, ONH is the most common optic disk anomaly in ophthalmological practice. So far, mutations in several genes have been identified as causative; however, many cases of ONH remain without a molecular explanation. The early transcription factor atonal basic-helix-loop-helix (bHLH) transcription factor 7 (ATOH7) is expressed in retinal progenitor cells and has a crucial role in RGC development. Previous studies have identified several mutations in the ATOH7 locus in cases of eye developmental diseases such as non-syndromic congenital retinal non-attachment and persistent hyperplasia of the primary vitreous. Here we present two siblings with a phenotype predominated by bilateral ONH, with additional features of foveal hypoplasia and distinct vascular abnormalities, where whole-exome sequencing identified two compound heterozygous missense mutations affecting a conserved amino acid residue within the bHLH domain of ATOH7 (NM_145178.3:c.175G>A; p.(Ala59Thr) and c.176C>T; p.(Ala59Val)). ATOH7 expression constructs with patient single nucleotide variants were cloned for functional characterization. Protein analyses revealed decreased protein amounts and significantly enhanced degradation in the presence of E47, a putative bHLH dimerization partner. Protein interaction assays revealed decreased heterodimerization and DNA-binding of ATOH7 variants, resulting in total loss of transcriptional activation of luciferase reporter gene expression. These findings strongly support pathogenicity of the two ATOH7 mutations, one of which is novel. Additionally, this report highlights the possible impact of altered ATOH7 dimerization on protein stability and function.
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http://dx.doi.org/10.1093/hmg/ddz268DOI Listing
January 2020

Genotype-Phenotype Analysis of a Novel Recessive and a Recurrent Dominant SNRNP200 Variant Causing Retinitis Pigmentosa.

Invest Ophthalmol Vis Sci 2019 07;60(8):2822-2835

Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland.

Purpose: To compare phenotype variability in retinitis pigmentosa patients with recessive and dominant mutations in the SNRNP200 gene.

Methods: In a retrospective study, patients of two unrelated families were identified: family A, five patients aged 36 to 77 years; family B, one patient aged 9 years and his asymptomatic parents and sister. All patients received a comprehensive eye examination with a detailed retinal functional and morphologic assessment. Genetic testing was performed by whole exome sequencing (WES) in the index patient from each family. Genes described to be involved in eye diseases (n > 450) were screened for rare variants and segregation analysis was performed.

Results: A known heterozygous missense variant (c.3260C>T, p.(Ser1087Leu)) in the SNRNP200 gene was identified in the index patient of family A while a novel homozygous missense mutation (c.1634G>A, p.(Arg545His)) was found in the index patient of family B. Nyctalopia and photophobia were reported by 6/6 and 2/6 patients, respectively. The phenotype associated with the dominant mutation was characterized by variable disease onset (early childhood to the sixth decade of life), disease severity (visual acuity of 20/20-20/200 in the seventh to eighth decade), and advanced rod-cone dysfunction. Characteristics of recessive disease included distinct fundus changes of dot-like hypopigmentation together with retinal atrophy and severe rod-cone dysfunction.

Conclusions: The phenotype characteristics in autosomal dominant and recessive SNRNP200 mutations show distinct features, with earlier severe disease in the recessive case and a variable disease expression in the dominant inheritance pattern.
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http://dx.doi.org/10.1167/iovs.18-25643DOI Listing
July 2019

Dysfunctional LAT2 Amino Acid Transporter Is Associated With Cataract in Mouse and Humans.

Front Physiol 2019 4;10:688. Epub 2019 Jun 4.

Institute of Medical Molecular Genetics, University of Zurich, Zurich, Switzerland.

Cataract, the loss of ocular lens transparency, accounts for ∼50% of worldwide blindness and has been associated with water and solute transport dysfunction across lens cellular barriers. We show that neutral amino acid antiporter LAT2 ) and uniporter TAT1 () are expressed on mouse ciliary epithelium and LAT2 also in lens epithelium. Correspondingly, deletion of LAT2 induced a dramatic decrease in lens essential amino acid levels that was modulated by TAT1 defect. Interestingly, the absence of LAT2 led to increased incidence of cataract in mice, in particular in older females, and a synergistic effect was observed with simultaneous lack of TAT1. Screening in patients diagnosed with congenital or age-related cataract yielded one homozygous single nucleotide deletion segregating in a family with congenital cataract. Expressed in HeLa cells, this LAT2 mutation did not support amino acid uptake. Heterozygous LAT2 variants were also found in patients with cataract some of which showed a reduced transport function when expressed in HeLa cells. Whether heterozygous LAT2 variants may contribute to the pathology of cataract needs to be further investigated. Overall, our results suggest that defects of amino acid transporter LAT2 are implicated in cataract formation, a situation that may be aggravated by TAT1 defects.
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http://dx.doi.org/10.3389/fphys.2019.00688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558864PMC
June 2019

Cystoid edema, neovascularization and inflammatory processes in the murine Norrin-deficient retina.

Sci Rep 2018 04 13;8(1):5970. Epub 2018 Apr 13.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, D-50931, Cologne, Germany.

Mutations in the Norrin (NDP) gene cause severe developmental blood vessel defects in the retina leading to congenital blindness. In the retina of Ndph-knockout mice only the superficial capillary network develops. Here, a detailed characterization of this mouse model at late stages of the disease using in vivo retinal imaging revealed cystoid structures that closely resemble the ovoid cysts in the inner nuclear layer of the human retina with cystoid macular edema (CME). In human CME an involvement of Müller glia cells is hypothesized. In Ndph-knockout retinae we could demonstrate that activated Müller cells were located around and within these cystoid spaces. In addition, we observed extensive activation of retinal microglia and development of neovascularization. Furthermore, ex vivo analyses detected extravasation of monocytic cells suggesting a breakdown of the blood retina barrier. Thus, we could demonstrate that also in the developmental retinal vascular pathology present in the Ndph-knockout mouse inflammatory processes are active and may contribute to further retinal degeneration. This observation delivers a new perspective for curative treatments of retinal vasculopathies. Modulation of inflammatory responses might reduce the symptoms and improve visual acuity in these diseases.
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http://dx.doi.org/10.1038/s41598-018-24476-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899099PMC
April 2018

Effects of COMT genotype and tolcapone on lapses of sustained attention after sleep deprivation in healthy young men.

Neuropsychopharmacology 2018 06 5;43(7):1599-1607. Epub 2018 Feb 5.

Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.

Tolcapone, a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties, improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT. The impact of this common genetic variant on behavioral and neurophysiological markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of sleep homeostasis in humans. We first quantified in 73 young male volunteers the impact of COMT genotype on the evolution of attentional lapses during 40 h of extended wakefulness. Subsequently, we tested in an independent group of 30 young men whether selective inhibition of COMT activity with tolcapone counteracts attentional and neurophysiological markers of elevated sleep need in a genotype-dependent manner. Neither COMT genotype nor tolcapone affected brain electrical activity in wakefulness and sleep. By contrast, COMT genotype and tolcapone modulated the sleep loss-induced impairment of vigilant attention. More specifically, Val/Met heterozygotes produced twice as many lapses after a night without sleep than Met/Met homozygotes. Unexpectedly, tolcapone further deteriorated the sleep loss-induced performance deficits when compared to placebo, particularly in Val/Met and Met/Met genotypes. The findings suggest that PFC dopaminergic tone regulates sustained attention after sleep loss according to an inverse U-shape relationship, independently of neurophysiological markers of elevated sleep need.
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http://dx.doi.org/10.1038/s41386-018-0018-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983551PMC
June 2018

Exome analysis in 34 sudden unexplained death (SUD) victims mainly identified variants in channelopathy-associated genes.

Int J Legal Med 2018 Jul 19;132(4):1057-1065. Epub 2018 Jan 19.

Zurich Institute of Forensic Medicine, Forensic Genetics, University of Zurich, Winterthurerstrasse 190/52, 8057, Zurich, Switzerland.

Sudden cardiac death (SCD) is one of the major causes of mortality worldwide, mostly involving coronary artery disease in the elderly. In contrary, sudden death events in young victims often represent the first manifestation of undetected genetic cardiac diseases, which remained without any symptoms during lifetime. Approximately 30% of these sudden death cases have no definite cardiac etiology after a comprehensive medicolegal investigation and are therefore termed as sudden unexplained death (SUD) cases. Advances in high-throughput sequencing approaches have provided an efficient diagnostic tool to identify likely pathogenic variants in cardiovascular disease-associated genes in otherwise autopsy-negative SUD cases. The aim of this study was to genetically investigate a cohort of 34 unexplained death cases by focusing on candidate genes associated with cardiomyopathies and channelopathies. Exome analysis identified potentially disease-causing sequence alterations in 29.4% of the 34 SUD cases. Six (17.6%) individuals had variants with likely functional effects in the channelopathy-associated genes AKAP9, KCNE5, RYR2, and SEMA3A. Interestingly, four of these six SUD individuals were younger than 18 years of age. Since the total SUD cohort of this study included five children and adolescents, post-mortem molecular autopsy screening indicates a high diagnostic yield within this age group. Molecular genetic testing represents a valuable approach to uncover the cause of death in some of the SUD victims; however, 70-80% of the cases still remain elusive, emphasizing the importance of additional research to better understand the pathological mechanisms leading to a sudden death event.
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http://dx.doi.org/10.1007/s00414-018-1775-yDOI Listing
July 2018

Absence of Goniodysgenesis in Patients with Chromosome 13Q Microdeletion-Related Microcoria.

Ophthalmol Glaucoma 2018 Sep - Oct;1(2):145-147. Epub 2018 Sep 11.

Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1016/j.ogla.2018.08.003DOI Listing
September 2018

Abnormal creatine transport of mutations in monocarboxylate transporter 12 (MCT12) found in patients with age-related cataract can be partially rescued by exogenous chaperone CD147.

Hum Mol Genet 2017 11;26(21):4203-4214

Institute of Medical Molecular Genetics, University Zurich, Zurich, Switzerland.

Membrane transporters influence biological functions in the ocular lens. Here, we investigate the monocarboxylate transporter 12 (MCT12), also called creatine transporter 2 (CRT2), which is found in the ocular lens and is involved in cataract. As the age-related form affects about half of the population world-wide, understanding relevant pathomechanisms is a prerequisite for exploring non-invasive treatments. We screened the coding exons of the gene SLC16A12 in 877 patients from five cohorts, including Caucasian and Asian ethnicities. A previously identified risk factor, SNP rs3740030, displayed different frequencies in the Asian cohorts but risk could not be established. In 15 patients 13 very rare heterozygous nucleotide substitutions were identified, of which eight led to non-synonymous and four to synonymous amino acid exchanges and one mapped to the canonical splice site in intron 3. Their impact on creatine transport was tested in Xenopus laevis oocytes and human HEK293T cells. Four variants (p.Ser158Pro, p.Gly205Val, p.Pro395Gln and p.Ser453Arg) displayed severe reduction in both model systems, indicating conserved function. Two of these, p.Gly205Val, and p.Ser453Arg, did not localize to the oocyte membrane, suggesting possible impacts on protein interactions for transporter processing. In support, exogenously supplied excess of MCT12's chaperone CD147 in HEK293T cells led to a partial recovery of the defective uptake activity from p.Gly205Val and also from mutant p.Pro395Gln, which did localize to the membrane. Our findings provide first insight in the molecular requirements of creatine transporter, with particular emphasis on rescuing effects by its chaperone CD147, which can provide useful pharmacological information for substrate delivery.
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http://dx.doi.org/10.1093/hmg/ddx310DOI Listing
November 2017

Unusual retinopathy in a child with severe combined immune deficiency.

Ophthalmic Genet 2018 Jan-Feb;39(1):92-94. Epub 2017 Aug 16.

b Institute of Medical Molecular Genetics , University of Zurich , Schlieren , Switzerland.

We describe a case of an infant diagnosed with severe combined immune deficiency (Adenosine Deaminase (ADA), SCID) with severe retinopathy and associated low vision in both eyes at first examination. An extensive infectious work up revealed an enterovirus infection, which suggested an early infectious and severe retinopathy. Genetic causes of congenital retinitis pigmentosa/ Leber's congenital amaurosis could be excluded by whole exome sequencing.
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http://dx.doi.org/10.1080/13816810.2017.1350721DOI Listing
March 2018

C2orf71 Mutations as a Frequent Cause of Autosomal-Recessive Retinitis Pigmentosa: Clinical Analysis and Presentation of 8 Novel Mutations.

Invest Ophthalmol Vis Sci 2017 08;58(10):3840-3850

Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland 11Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland 12Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland.

Purpose: To define the phenotype of C2orf71 associated retinopathy and to present novel mutations in this gene.

Methods: A retrospective multicenter study of patients with retinopathy and identified C2orf71 mutations was performed. Ocular function (visual acuity, visual fields, electroretinogram [ERG] responses); retinal morphology (fundus, optical coherence tomography); and underlying mutations were analyzed.

Results: Thirteen patients from 11 families, who were aged 7 to 63 years (mean: 32.1 years) at their first examination with presumed compound heterozygous (6/13 patients) or homozygous (7/13 patients) C2orf71 mutations were identified. Eight of the mutations were novel. Truncation mutations were responsible in all cases. Nyctalopia was observed in less than 50% of patients. Visual acuity ranged from 20/20 to light perception. Severe visual loss was associated with atrophic maculopathy. Full-field ERG responses showed severe progressive cone-rod or rod-cone dysfunction. Typical fundus changes were progressive symmetrical retinopathy with an early mild maculopathy and patchy circular midperipheral RPE atrophy. Normal retinal lamination was preserved despite early disruption of the ellipsoid zone and RPE irregularities. Outer retinal tubulations were associated with better-preserved visual acuity.

Conclusions: On the basis of our multicenter analysis, C2orf71 might represent a more frequently mutated gene in autosomal recessive retinitis pigmentosa in some populations. The phenotype analysis over a wide age range showed a variable and progressive retinal degeneration with early onset maculopathy and a better visual potential before the age of 30 years.
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http://dx.doi.org/10.1167/iovs.17-21597DOI Listing
August 2017

Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease.

PLoS One 2017 2;12(6):e0178753. Epub 2017 Jun 2.

Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, Tuebingen, Germany.

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178753PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456345PMC
September 2017

Functional Polymorphisms in Dopaminergic Genes Modulate Neurobehavioral and Neurophysiological Consequences of Sleep Deprivation.

Sci Rep 2017 04 10;7:45982. Epub 2017 Apr 10.

Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.

Sleep deprivation impairs cognitive performance and reliably alters brain activation in wakefulness and sleep. Nevertheless, the molecular regulators of prolonged wakefulness remain poorly understood. Evidence from genetic, behavioral, pharmacologic and imaging studies suggest that dopaminergic signaling contributes to the behavioral and electroencephalographic (EEG) consequences of sleep loss, although direct human evidence thereof is missing. We tested whether dopamine neurotransmission regulate sustained attention and evolution of EEG power during prolonged wakefulness. Here, we studied the effects of functional genetic variation in the dopamine transporter (DAT1) and the dopamine D receptor (DRD2) genes, on psychomotor performance and standardized waking EEG oscillations during 40 hours of wakefulness in 64 to 82 healthy volunteers. Sleep deprivation consistently enhanced sleepiness, lapses of attention and the theta-to-alpha power ratio (TAR) in the waking EEG. Importantly, DAT1 and DRD2 genotypes distinctly modulated sleep loss-induced changes in subjective sleepiness, PVT lapses and TAR, according to inverted U-shaped relationships. Together, the data suggest that genetically determined differences in DAT1 and DRD2 expression modulate functional consequences of sleep deprivation, supporting the hypothesis that striato-thalamo-cortical dopaminergic pathways modulate the neurobehavioral and neurophysiological consequences of sleep loss in humans.
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http://dx.doi.org/10.1038/srep45982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385564PMC
April 2017

Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases.

Eur J Hum Genet 2017 04 11;25(4):404-409. Epub 2017 Jan 11.

Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland.

Sudden infant death syndrome (SIDS) is described as the sudden and unexplained death of an apparently healthy infant younger than one year of age. Genetic studies indicate that up to 35% of SIDS cases might be explained by familial or genetic diseases such as cardiomyopathies, ion channelopathies or metabolic disorders that remained undetected during conventional forensic autopsy procedures. Post-mortem genetic testing by using massive parallel sequencing (MPS) approaches represents an efficient and rapid tool to further investigate unexplained death cases and might help to elucidate pathogenic genetic variants and mechanisms in cases without a conclusive cause of death. In this study, we performed whole-exome sequencing (WES) in 161 European SIDS infants with focus on 192 genes associated with cardiovascular and metabolic diseases. Potentially causative variants were detected in 20% of the SIDS cases. The majority of infants had variants with likely functional effects in genes associated with channelopathies (9%), followed by cardiomyopathies (7%) and metabolic diseases (1%). Although lethal arrhythmia represents the most plausible and likely cause of death, the majority of SIDS cases still remains elusive and might be explained by a multifactorial etiology, triggered by a combination of different genetic and environmental risk factors. As WES is not substantially more expensive than a targeted sequencing approach, it represents an unbiased screening of the exome, which could help to investigate different pathogenic mechanisms within the genetically heterogeneous SIDS cohort. Additionally, re-analysis of the datasets provides the basis to identify new candidate genes in sudden infant death.
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http://dx.doi.org/10.1038/ejhg.2016.199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386419PMC
April 2017

A case-control field study on the relationships among type 2 diabetes, sleepiness and habitual caffeine intake.

J Psychopharmacol 2017 02 27;31(2):233-242. Epub 2016 Sep 27.

1 Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.

Objectives: The purpose of this study was to examine the possible links between type 2 diabetes, daytime sleepiness, sleep quality and caffeine consumption.

Methods: In this case-control field study, comparing type 2 diabetic ( n=134) and non-type 2 diabetic ( n=230) participants, subjects completed detailed and validated questionnaires to assess demographic status, health, daytime sleepiness, sleep quality and timing, diurnal preference, mistimed circadian rhythms and habitual caffeine intake. All participants gave saliva under standardised conditions for CYP1A2 genotyping and quantification of caffeine concentration. Hierarchical linear regression analyses examined whether type 2 diabetes status was associated with caffeine consumption.

Results: Type 2 diabetic participants reported greater daytime sleepiness ( p=0.001), a higher prevalence of sleep apnoea ( p=0.005) and napping ( p=0.008), and greater habitual caffeine intake ( p<0.001), derived from the consumption of an extra cup of coffee each day. This finding was confirmed by higher saliva caffeine concentration at bedtime ( p=0.01). Multiple regression analyses revealed that type 2 diabetes status was associated with higher self-reported caffeine consumption ( p<0.02) and higher salivary caffeine ( p<0.02). Next to male sex, type 2 diabetes status was the strongest predictor of caffeine intake. Subjective sleep and circadian estimates were similar between case and control groups.

Conclusions: Type 2 diabetic patients may self-medicate with caffeine to alleviate daytime sleepiness. High caffeine intake reflects a lifestyle factor that may be considered when promoting type 2 diabetes management.
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http://dx.doi.org/10.1177/0269881116668595DOI Listing
February 2017

Identification of Novel and Recurrent Disease-Causing Mutations in Retinal Dystrophies Using Whole Exome Sequencing (WES): Benefits and Limitations.

PLoS One 2016 8;11(7):e0158692. Epub 2016 Jul 8.

Institute of Medical Molecular Genetics, University of Zurich, Wagistrasse 12, CH-8952, Schlieren, Switzerland.

Inherited retinal dystrophies (IRDs) are Mendelian diseases with tremendous genetic and phenotypic heterogeneity. Identification of the underlying genetic basis of these dystrophies is therefore challenging. In this study we employed whole exome sequencing (WES) in 11 families with IRDs and identified disease-causing variants in 8 of them. Sequence analysis of about 250 IRD-associated genes revealed 3 previously reported disease-associated variants in RHO, BEST1 and RP1. We further identified 5 novel pathogenic variants in RPGRIP1 (p.Ser964Profs*37), PRPF8 (p.Tyr2334Leufs*51), CDHR1 (p.Pro133Arg and c.439-17G>A) and PRPF31 (p.Glu183_Met193dup). In addition to confirming the power of WES in genetic diagnosis of IRDs, we document challenges in data analysis and show cases where the underlying genetic causes of IRDs were missed by WES and required additional techniques. For example, the mutation c.439-17G>A in CDHR1 would be rated unlikely applying the standard WES analysis. Only transcript analysis in patient fibroblasts confirmed the pathogenic nature of this variant that affected splicing of CDHR1 by activating a cryptic splice-acceptor site. In another example, a 33-base pair duplication in PRPF31 missed by WES could be identified only via targeted analysis by Sanger sequencing. We discuss the advantages and challenges of using WES to identify mutations in heterogeneous diseases like IRDs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158692PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938416PMC
August 2017

Next generation sequencing based identification of disease-associated mutations in Swiss patients with retinal dystrophies.

Sci Rep 2016 06 29;6:28755. Epub 2016 Jun 29.

Institute of Medical Molecular Genetics, University of Zürich, Wagistrasse 12, CH-8952, Schlieren, Switzerland.

Inherited monogenic diseases of the retina and vitreous affect approximately 1 in 2000 individuals. They are characterized by tremendous genetic heterogeneity and clinical variability involving mutations in approximately 250 genes and more than 20 different clinical phenotypes. Clinical manifestations of retinal dystrophies (RDs) range from mild retinal dysfunctions to severe congenital forms of blindness. A detailed clinical diagnosis and the identification of causative mutations are crucial for genetic counseling of affected patients and their families, for understanding genotype-phenotype correlations and developing therapeutic approaches. Using whole exome sequencing (WES) we have established a reliable and efficient high-throughput analysis pipeline to identify disease-causing mutations. Our data indicate that this approach enables us to genetically diagnose approximately 64% of the patients (n = 58) with variant(s) in known disease-associated genes. We report 20 novel and 26 recurrent variants in genes associated with RDs. We also identified a novel phenotype for mutations in C2orf71 and provide functional evidence for exon skipping due to a splice-site variant identified in FLVCR1. In conclusion, WES can rapidly identify variants in various families affected with different forms of RDs. Our study also expands the clinical and allelic spectrum of genes associated with RDs in the Swiss population.
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http://dx.doi.org/10.1038/srep28755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926080PMC
June 2016

Biallelic Mutations in CRB1 Underlie Autosomal Recessive Familial Foveal Retinoschisis.

Invest Ophthalmol Vis Sci 2016 05;57(6):2637-46

Program of Genetics and Genome Biology The Hospital for Sick Children, Toronto, Canada 2Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Canada 3Department of Ophthalmology and Vision Science.

Purpose: To identify the genetic cause of autosomal recessive familial foveal retinoschisis (FFR).

Methods: A female sibship with FFR was identified (Family-A; 17 and 16 years, respectively); panel based genetic sequencing (132 genes) and comparative genome hybridization (142 genes) were performed. Whole-exome sequencing (WES) was performed on both siblings using the Illumina-HiSeq-2500 platform. A sporadic male (Family-B; 35 years) with FFR underwent WES using Illumina NextSeq500. All three affected subjects underwent detailed ophthalmologic evaluation including fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinogram (ERG).

Results: Panel-based genetic testing identified two presumed disease causing variants in CRB1 (p.Gly123Cys and p.Cys948Tyr) in Family-A sibship; no deletion or duplication was detected. WES analysis in the sibship identified nine genes with two or more shared nonsynonymous rare coding sequence variants; CRB1 remained a strong candidate gene, and CRB1 variants segregated with the disease. WES in Family-B identified two presumed disease causing variants in CRB1 (p.Ile167_Gly169del and p.Arg764Cys) that segregated with the disease phenotype. Distance visual acuity was 20/40 or better in all three affected except for the left eye of the older subject (Family-B), which showed macular atrophy. Fundus evaluation showed spoke-wheel appearance at the macula in five eyes. The SD-OCT showed macular schitic changes in inner and outer nuclear layers in all cases. The ERG responses were normal in all subjects.

Conclusions: This is the first report to implicate CRB1 as the underlying cause of FFR. This phenotype forms the mildest end of the spectrum of CRB1-related diseases.
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http://dx.doi.org/10.1167/iovs.15-18281DOI Listing
May 2016

Arrhythmogenic right ventricular cardiomyopathy: implications of next-generation sequencing in appropriate diagnosis.

Europace 2017 Jun;19(6):1063-1069

Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland.

Aims: To evaluate potential differences in the genetic profile of cases with 'definite', 'borderline', and 'possible' arrhythmogenic right ventricular cardiomyopathy (ARVC) phenotype by 2010 task force criteria using a custom genetic panel after whole-exome analysis.

Methods And Results: We performed whole-exome sequencing in 14 cases with the clinical diagnosis ARVC using an 'Illumina HighSeq 2000' system. We presented our initial results focused on 96 known cardiomyopathy and channelopathy genes. According to the 2010 task force criteria, 7/14 cases (50%) were classified as 'definite' phenotype, 4/14 (29%) were 'borderline', and 3/14 (21%) were diagnosed with the 'possible' phenotype. Nine out of 14 patients (64%) were males, and all were Caucasians, with an average age at genetic diagnosis of 50 ± 15 years. Among the seven cases with the 'definite' phenotype, six (86%) had a putative desmosomal mutation, while none of the seven patients with a 'possible' or borderline task force classification phenotype hosted putative mutations in desmosomal genes. Four (57%) of them had rare variants in other dilated cardiomyopathy (DCM) genes.

Conclusions: Most of the patients with 'definite' ARVC phenotype by task force 2010 host mutations in desmosomal genes. Weaker ARVC phenotypes host variants/mutations in other DCM genes and result in a disease spectrum, including DCM or phenocopies of ARVC.
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http://dx.doi.org/10.1093/europace/euw098DOI Listing
June 2017

Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases.

Int J Legal Med 2016 Jul 4;130(4):1011-1021. Epub 2016 Feb 4.

Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland.

Sudden death of healthy young adults in the absence of any medical reason is generally categorised as autopsy-negative sudden unexplained death (SUD). Approximately 30 % of all SUD cases can be explained by lethal sequence variants in cardiac genes causing disturbed ion channel functions (channelopathies) or minimal structural heart abnormalities (cardiomyopathies). The aim of this study was to perform whole-exome sequencing (WES) in five young SUD cases in order to identify potentially disease-causing mutations with a focus on 184 genes associated with cardiac diseases or sudden death. WES analysis enabled the identification of damaging-predicted cardiac sequence alterations in three out of five SUD cases. Two SUD victims carried disease-causing variants in long QT syndrome (LQTS)-associated genes (KCNH2, SCN5A). In a third case, WES identified variants in two genes involved in mitral valve prolapse and thoracic aortic aneurism (DCHS1, TGFβ2). The genome of a fourth case carried several minor variants involved in arrhythmia pointing to a multigene influence that might have contributed to sudden death. Our results confirm that post-mortem genetic testing in SUD cases in addition to the conventional autopsy can help to identify familial cardiac diseases and can contribute to the identification of genetic risk factors for sudden death.
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http://dx.doi.org/10.1007/s00414-016-1317-4DOI Listing
July 2016