Search Our Scientific Publications & Authors

Eur J Hum Genet 2019 Feb 18. Epub 2019 Feb 18.

Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.

Hexokinase 1 (HK1) phosphorylates glucose to glucose-6-phosphate, the first rate-limiting step in glycolysis. Homozygous and heterozygous variants in HK1 have been shown to cause autosomal recessive non-spherocytic hemolytic anemia, autosomal recessive Russe type hereditary motor and sensory neuropathy, and autosomal dominant retinitis pigmentosa (adRP). We report seven patients from six unrelated families with a neurodevelopmental disorder associated with developmental delay, intellectual disability, structural brain abnormality, and visual impairments in whom we identified four novel, de novo missense variants in the N-terminal half of HK1. Read More

Eur J Hum Genet 2019 Feb 18. Epub 2019 Feb 18.

Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.

Beckwith-Wiedemann syndrome (BWS; OMIM #130650) is an imprinting disorder caused by genetic or epigenetic alterations of one or both imprinting control regions on chromosome 11p15.5. Hypomethylation of the centromeric imprinting control region (KCNQ1OT1:TSS-DMR, ICR2) is the most common molecular cause of BWS and is present in about half of the cases. Read More

Eur J Hum Genet 2019 Feb 18. Epub 2019 Feb 18.

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

With the rising demand for clinical genetics services, it is a challenge for clinical geneticists to meet the needs of patients and referring primary care providers in a timely way, using current models of genetics health care delivery. One method of providing primary care providers with greater access to clinical genetics expertise is through an electronic consultation (eConsult) service. We describe here a pilot project of a clinical genetics eConsult service that our genetics centre in Eastern Ontario, Canada provided, using the Champlain Building Access to Specialists through eConsultation (BASE) web-based application. Read More

Eur J Hum Genet 2019 Feb 15. Epub 2019 Feb 15.

School of Neurobiology Biochemistry and Biophysics, Sagol School of Neurosciences, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

Here, we describe a single patient from a consanguineous family, who suffers from developmental delay, intellectual disability, hypermetropia, moderate alternating esotropia, unsteady gait, and peripheral polyneuropathy. Brain MRI revealed basal ganglia disease. Exome analysis disclosed a homozygous variant, c. Read More

Eur J Hum Genet 2019 Feb 14. Epub 2019 Feb 14.

Departament de Ciències Experimentals i de la Salut, Institute of Evolutionary Biology (CSIC-UPF), Universitat Pompeu Fabra, Barcelona, Spain.

In this study, we seek to understand and to correlate the genetic patterns observed in the population of the island of Ibiza in the Western Mediterranean basin with past events. Genome-wide genotypes of 189 samples representing 13 of 17 regions in Spain have been analyzed, in addition to 105 samples from the Levant, 157 samples from North Africa, and one ancient sample from the Phoenician Cas Molí site in Ibiza. Before the Catalans conquered the island in 1235 CE, Ibiza (Eivissa) had already been influenced by several cultures, starting with the Phoenicians, then the Carthaginians, followed by the Umayyads. Read More

Eur J Hum Genet 2019 Feb 14. Epub 2019 Feb 14.

FarGen, The Genetic Biobank of the Faroe Islands, Tórshavn, Faroe Islands.

Long-term collection of dried blood spot (DBS) samples through newborn screening may have retrospective and prospective advantages, especially in combination with advanced analytical techniques. This work concerns whether linked-reads may overcome some of the limitations of short-read sequencing of DBS samples, such as performing molecular phasing. We performed whole-exome sequencing of DNA extracted from DBS and corresponding whole blood (WB) reference samples, belonging to a trio with unaffected parents and a proband affected by primary carnitine deficiency (PCD). Read More

Eur J Hum Genet 2019 Feb 13. Epub 2019 Feb 13.

Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit, Amsterdam, The Netherlands.

The tendency to conceive spontaneous dizygotic (DZ) twins is a complex trait with important contributions from both environmental factors and genetic disposition. In earlier work, we identified the first two genes as maternal susceptibility loci for DZ twinning. The aim of this study was to identify genetic variants influencing multiple births and to genetically correlate the findings across a broad range of traits. Read More

Eur J Hum Genet 2019 Feb 13. Epub 2019 Feb 13.

Sydney Children's Hospital, Randwick, NSW, Australia.

Eur J Hum Genet 2019 Feb 11. Epub 2019 Feb 11.

Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700, RB Groningen, The Netherlands.

Expanded carrier screening (ECS) aims to inform couples' reproductive choice, preferably before conception. As part of an implementation study in which trained general practitioners (GPs) offered a population-based ECS couple-test, we evaluated the feasibility of the test-offer and degree of participant informed choice (IC). Trained GPs from nine practices in the northern Netherlands invited 4295 female patients aged 18-40 to take part in couple-based ECS. Read More

Eur J Hum Genet 2019 Feb 8. Epub 2019 Feb 8.

Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.

Alkaptonuria (AKU) is a rare metabolic disorder caused by a deficient enzyme in the tyrosine degradation pathway, homogentisate 1,2-dioxygenase (HGD). In 172 AKU patients from 39 countries, we identified 28 novel variants of the HGD gene, which include three larger genomic deletions within this gene discovered via self-designed multiplex ligation-dependent probe amplification (MLPA) probes. In addition, using a reporter minigene assay, we provide evidence that three of eight tested variants potentially affecting splicing cause exon skipping or cryptic splice-site activation. Read More

Eur J Hum Genet 2019 Feb 8. Epub 2019 Feb 8.

Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

Analyses in our diagnostic DNA laboratory include genes involved in autosomal recessive (AR) lysosomal storage disorders such as glycogenosis type II (Pompe disease) and mucopolysaccharidosis type I (MPSI, Hurler disease). We encountered 4 cases with apparent homozygosity for a disease-causing sequence variant that could be traced to one parent only. In addition, in a young child with cardiomyopathy, in the absence of other symptoms, a diagnosis of Pompe disease was considered. Read More

Eur J Hum Genet 2019 Feb 5. Epub 2019 Feb 5.

The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev, 84105, Beer Sheva, Israel.

Studies of ciliopathies have served in elucidating much of our knowledge of structure and function of primary cilia. We report humans with Bardet-Biedl syndrome who display intellectual disability, retinitis pigmentosa, obesity, short stature and brachydactyly, stemming from a homozyogous truncation mutation in SCAPER, a gene previously associated with mitotic progression. Our findings, based on linkage analysis and exome sequencing studies of two remotely related large consanguineous families, are in line with recent reports of SCAPER variants associated with intellectual disability and retinitis pigmentosa. Read More

Eur J Hum Genet 2019 Feb 5. Epub 2019 Feb 5.

Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.

Some of the most widely studied variants in psychiatric genetics include variable number tandem repeat variants (VNTRs) in SLC6A3, DRD4, SLC6A4, and MAOA. While initial findings suggested large effects, their importance with respect to psychiatric phenotypes is the subject of much debate with broadly conflicting results. Despite broad interest, these loci remain absent from the largest available samples, such as the UK Biobank, limiting researchers' ability to test these contentious hypotheses rigorously in large samples. Read More

Eur J Hum Genet 2019 Feb 5. Epub 2019 Feb 5.

Department of Human Genetics, Hannover Medical School, Hannover, Germany.

Wilson disease (WD) is an autosomal recessive disease of copper excess due to pathogenic variants in the ATP7B gene coding for a copper-transporting ATPase. We present a 5-year-old girl with the homozygous frame shift variant NM_000053.3: c. Read More

Eur J Hum Genet 2019 Feb 4. Epub 2019 Feb 4.

Yorkshire Regional Genetics Service, Leeds, UK.

Prenatal genetic technologies now are being implemented in LMICs, and while there is much research on the ethical, legal and social implications of such technologies in Western countries, there is a paucity of such research in LMICs, which have diverse cultural, religious, political, financial and health service contexts. This study aimed to explore views about women's autonomous decision-making for antenatal screening held by women, men and healthcare professionals (HCPs) in Pakistan. A Q-methodology study was conducted during June 2016 to January 2018 in Lahore, Pakistan. Read More

Eur J Hum Genet 2019 Feb 4. Epub 2019 Feb 4.

Analytic and Translational Genetics Unit, MGH, Boston, MA, USA.

Along with traditional effects of aging and carcinogen exposure-inherited DNA variation has substantial contribution to cancer risk. Extraordinary progress made in analysis of common variation with GWAS methodology does not provide sufficient resolution to understand rare variation. To fulfill missing classification for rare germline variation we assembled dataset of whole exome sequences from>2000 patients (selected cases tested negative for candidate genes and unselected cases) with different types of cancers (breast cancer, colon cancer, and cutaneous and ocular melanomas) matched to more than 7000 non-cancer controls and analyzed germline variation in known cancer predisposing genes to identify common properties of disease-associated DNA variation and aid the future searches for new cancer susceptibility genes. Read More

Eur J Hum Genet 2019 Feb 1. Epub 2019 Feb 1.

FHU TRANSLAD et équipe GAD INSERM UMR 1231, University of Burgundy Franche-Comté, Dijon, France.

Exome sequencing (ES) has revolutionized diagnostic procedures in medical genetics, particularly for developmental diseases. The variety and complexity of the information produced has raised issues regarding its use in a clinical setting. Of particular interest are patients' expectations regarding the information disclosed, the accompaniment provided, and the value patients place on these. Read More

Eur J Hum Genet 2019 Jan 30. Epub 2019 Jan 30.

HeLEX Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

The purpose of this study was to explore and compare different countries in what motivated research participants' decisions whether to share their de-identified data. We investigated European DIRECT (Diabetes Research on Patient Stratification) research project participants' desire for control over sharing different types of their de-identified data, and with who data could be shared in the future after the project ends. A cross-sectional survey was disseminated among DIRECT project participants. Read More

Eur J Hum Genet 2019 Jan 30. Epub 2019 Jan 30.

Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, 04023-900, São Paulo, Brazil.

Precise breakpoint mapping of balanced chromosomal rearrangements is crucial to identify disease etiology. Ten female patients with X-autosome balanced translocations associated with phenotypic alterations were evaluated, by mapping and sequencing their breakpoints. The rearrangements' impact on the expression of disrupted genes, and inferred mechanisms of formation in each case were assessed. Read More

Eur J Hum Genet 2019 Jan 29. Epub 2019 Jan 29.

Institute of Biochemistry and Molecular Biology, Ulm University, 89081, Ulm, Germany.

Meier-Gorlin syndrome (MGS) is a rare, congenital primordial microcephalic dwarfism disorder. MGS is caused by genetic variants of components of the origin recognition complex (ORC) consisting of ORC1-6 and the pre-replication complex, which together enable origin firing and hence genome replication. In addition, ORC1 has previously been shown to play a role in ciliogenesis. Read More

Eur J Hum Genet 2019 Jan 25. Epub 2019 Jan 25.

Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, Florence, Italy.

Periventricular nodular heterotopia (PNH) is a brain malformation in which nodules of neurons are ectopically retained along the lateral ventricles. Genetic causes include FLNA abnormalities (classical X-linked PNH), rare variants in ARFGEF2, DCHS1, ERMARD, FAT4, INTS8, MAP1B, MCPH1, and NEDD4L, as well as several chromosomal abnormalities. We performed array-CGH in 106 patients with different malformations of cortical development (MCD) and looked for common pathways possibly involved in PNH. Read More

Eur J Hum Genet 2019 Jan 25. Epub 2019 Jan 25.

Department of Health Psychology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Patient empowerment has been identified as a key outcome goal in genetic counselling, and a patient reported outcome measure (PROM) has been developed to measure empowerment in genetic services: the Genetic Counselling Outcome Scale (GCOS). Here we validate the GCOS for a large and diverse Dutch study sample of 2194 patients referred to two clinical genetic centres for counselling about a wide range of conditions (heart disease, neurological disorders, cancer, congenital syndromes, intellectual disability and prenatal pathology). Our results suggest that the GCOS consists of a hierarchical 6-factor structure, with a main scale for empowerment and six subscales: uncertainty about heredity, hope, negative emotions, knowledge about the condition, knowledge about genetic services and uncertainty about the treatment. Read More

Eur J Hum Genet 2019 Jan 25. Epub 2019 Jan 25.

Institute of History and Ethics in Medicine, Technical University of Munich, Munich, Germany.

The research exemption implemented in the new EU General Data Protection Regulation (EU-GDPR) gives member states leeway in determining whether patient consent is required for secondary data use in medical research. However, even though broad consent has become common in data-rich medical research in many EU countries, giving up consent altogether is likely to be controversial. The aim of this study was to examine whether abolishing consent for secondary data use would be acceptable to patients. Read More

Eur J Hum Genet 2019 Jan 25. Epub 2019 Jan 25.

Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, Saint Mary's Hospital, Oxford Road, Manchester, M13 9WL, UK.

Genetic services for individuals affected by cleft lip and/or palate (CL/P) and their families are an important aspect of clinical care; yet debate exists as to how this service should be offered. This study explored the utility, acceptability, and delivery of genetic services from the perspectives of cleft-specialist clinicians, genetic counsellors, and affected families. Analysis of data collected from three focus groups and eleven individual interviews identified two overarching themes "Referring patients and families to genetic services" and "The role of a genetic specialist in the context of CL/P". Read More

Eur J Hum Genet 2019 Jan 25. Epub 2019 Jan 25.

Department of Molecular Biology, Colorado College, Colorado Springs, CO, 80903, USA.

In the present study, 87 unrelated individuals from the Marquesas Archipelago in French Polynesia were typed using mtDNA, Y-chromosome and autosomal (STRs) markers and compared to key target populations from Island South East Asia (ISEA), Taiwan, and West and East Polynesia to investigate their genetic relationships. The Marquesas, located at the eastern-most fringes of the Austronesian expansion, offer a unique opportunity to examine the effects of a protracted population expansion wave on population structure. We explore the contribution of Melanesian, Asian and European heritage to the Marquesan islands of Nuku-Hiva, Hiva-Oa and Tahuata. Read More

Eur J Hum Genet 2019 Jan 25. Epub 2019 Jan 25.

Service of Clinical Biochemistry, Hospital Clínico Universitario de Zaragoza (HCUZ)-IIS Aragón, Zaragoza, Spain.

Transthyretin amyloidosis (ATTR amyloidosis) is a rare disease characterised by extracellular deposition of amyloid fibrils composed by transthyretin. ATTR amyloidosis can be sub-classified as wild-type ATTR (ATTR-wt) or as hereditary amyloidosis (ATTR-m); the prevalence of both types are likely underestimated. There are tools that can help us to study ATTR-m, as gnomAD database. Read More

Eur J Hum Genet 2019 Jan 25. Epub 2019 Jan 25.

Bioinformatics Graduate Program, Boston University, Boston, MA, USA.

Complex diseases are usually associated with multiple correlated phenotypes, and the analysis of composite scores or disease status may not fully capture the complexity (or multidimensionality). Joint analysis of multiple disease-related phenotypes in genetic tests could potentially increase power to detect association of a disease with common SNPs (or genes). Gene-based tests are designed to identify genes containing multiple risk variants that individually are weakly associated with a univariate trait. Read More

Eur J Hum Genet 2019 Jan 25. Epub 2019 Jan 25.

Department of Genetics, Institut Curie, 75005, Paris, France.

Next-generation sequencing (NGS) is routinely used for constitutional genetic analysis. However, cross-contamination between samples constitutes a major risk that could impact the results of the analysis. We have developed ART-DeCo, a tool using the allelic ratio (AR) of the Single Nucleotide Polymorphisms sequenced with regions of interest. Read More

Eur J Hum Genet 2019 Jan 25. Epub 2019 Jan 25.

Service de Génétique, Centre Hospitalier Universitaire, Tours, France.

Name Of The Disease (synonyms): Simpson-Golabi-Behmel syndrome (SGBS). OMIM# OF THE DISEASE: 312870.

Name Of The Analysed Genes Or Dna/chromosome Segments: GPC3. Read More

Eur J Hum Genet 2019 Jan 24. Epub 2019 Jan 24.

Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.

The monogenic etiology of most severe fetal anomaly syndromes is poorly understood. Our objective was to use exome sequencing (ES) to increase our knowledge on causal variants and novel candidate genes associated with specific fetal phenotypes. We employed ES in a cohort of 19 families with one or more fetuses presenting with a distinctive anomaly pattern and/or phenotype recurrence at increased risk for lethal outcomes. Read More

Eur J Hum Genet 2019 Jan 24. Epub 2019 Jan 24.

CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). Read More

Eur J Hum Genet 2019 Jan 24. Epub 2019 Jan 24.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). Read More

Eur J Hum Genet 2019 Jan 21. Epub 2019 Jan 21.

Genetics Education and Health Research, Murdoch Children's Research Institute, Melbourne, Australia.

Personal genomic tests (PGTs) for multiple purposes are marketed to ostensibly healthy people in Australia. These tests are generally marketed and purchased online commercially or can be ordered through a health professional. There has been minimal engagement with Australians about their interest in and experience with ordering a PGT. Read More

Eur J Hum Genet 2019 Jan 21. Epub 2019 Jan 21.

Department of Pediatrics, Centre de Recherche du CHU Ste-Justine, Montreal, Canada.

We review genetic diseases with identified molecular bases that include abnormal, reduced (hypoplasia), or absent (aplasia) patellae as a significant aspect of the phenotype. The known causal genes can be broadly organized according to three major developmental and cellular processes, although some genes may act in more than one of these: limb specification and pattern formation; DNA replication and chromatin structure; bone development and differentiation. There are also several genes whose phenotypes in mice indicate relevance to patellar development, for which human equivalent syndromes have not been reported. Read More

Eur J Hum Genet 2019 Jan 21. Epub 2019 Jan 21.

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

CYFIP2, encoding the evolutionary highly conserved cytoplasmic FMRP interacting protein 2, has previously been proposed as a candidate gene for intellectual disability and autism because of its important role linking FMRP-dependent transcription regulation and actin polymerization via the WAVE regulatory complex (WRC). Recently, de novo variants affecting the amino acid p.Arg87 of CYFIP2 were reported in four individuals with epileptic encephalopathy. Read More

Eur J Hum Genet 2019 Jan 18. Epub 2019 Jan 18.

Clinical Genetics Department, Guy's & St Thomas' NHS Foundation Trust, London, UK.

Eur J Hum Genet 2019 Jan 18. Epub 2019 Jan 18.

Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark.

Genetic interaction is a crucial issue in the understanding of functional pathways underlying complex diseases. However, detecting such interaction effects is challenging in terms of both methodology and statistical power. We address this issue by introducing a disease-concordant twin-case-only design, which applies to both monozygotic and dizygotic twins. Read More

Eur J Hum Genet 2019 Jan 18. Epub 2019 Jan 18.

Oasi Research Institute-IRCCS, Troina, Italy.

In recent years, chromosomal microarray analysis has permitted the discovery of rearrangements underlying several neurodevelopmental disorders and still represents the first diagnostic test for unexplained neurodevelopmental disabilities. Here we report a family of consanguineous parents showing psychiatric disorders and their two sons both affected by intellectual disability, ataxia, and behavioral disorder. SNP/CGH array analysis in this family demonstrated in both siblings a biallelic duplication inherited from the heterozygous parents, disrupting the ADGRB3 gene. Read More

Eur J Hum Genet 2019 Jan 18. Epub 2019 Jan 18.

Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.

To assess the use of plasma free amino acids (PFAAs) as biomarkers for metabolic disorders, it is essential to identify genetic factors that influence PFAA concentrations. PFAA concentrations were absolutely quantified by liquid chromatography-mass spectrometry using plasma samples from 1338 Japanese individuals, and genome-wide quantitative trait locus (QTL) analysis was performed for the concentrations of 21 PFAAs. We next conducted a conditional QTL analysis using the concentration of each PFAA adjusted by the other 20 PFAAs as covariates to elucidate genetic determinants that influence PFAA concentrations. Read More

Eur J Hum Genet 2019 Jan 16. Epub 2019 Jan 16.

Dipartimento di Scienze della Vita e Biotecnologie, Università di Ferrara, 44121, Ferrara, Italy.

From the first century AD, Europe has been interested by population movements, commonly known as Barbarian migrations. Among these processes, the one involving the Longobard culture interested a vast region, but its dynamics and demographic impact remains largely unknown. Here we report 87 new complete mitochondrial sequences coming from nine early-medieval cemeteries located along the area interested by the Longobard migration (Czech Republic, Hungary and Italy). Read More

Eur J Hum Genet 2019 Jan 9. Epub 2019 Jan 9.

Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina.

Among other applications of long-distance haplotype phasing in clinical genetics, determination of linked DNA markers as surrogate for problematic structural variants (e.g., repeat-mediated rearrangements) is essential to perform diagnosis from low-quality DNA samples. Read More

Eur J Hum Genet 2019 Jan 9. Epub 2019 Jan 9.

Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular, Universidad Autónoma de Madrid, CIBERER, IdiPAZ, Madrid, Spain.

The present work describes the value of genetic analysis as a confirmatory measure following the detection of suspected inborn errors of metabolism in the Spanish newborn mass spectrometry screening program. One hundred and forty-one consecutive DNA samples were analyzed by next-generation sequencing using a customized exome sequencing panel. When required, the Illumina extended clinical exome panel was used, as was Sanger sequencing or transcriptional profiling. Read More

Eur J Hum Genet 2019 Jan 9. Epub 2019 Jan 9.

Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Clinical exome sequencing (CES) has become the preferred diagnostic platform for complex pediatric disorders with suspected monogenic etiologies. Despite rapid advancements, the major challenge still resides in identifying the casual variants among the thousands of variants detected during CES testing, and thus establishing a molecular diagnosis. To improve the clinical exome diagnostic efficiency, we developed Phenoxome, a robust phenotype-driven model that adopts a network-based approach to facilitate automated variant prioritization. Read More

Eur J Hum Genet 2019 Jan 8. Epub 2019 Jan 8.

RADEME, EA 7364, Lille University, Lille, France.

Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Read More

Eur J Hum Genet 2019 Jan 8. Epub 2019 Jan 8.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. Read More

Eur J Hum Genet 2019 Jan 8. Epub 2019 Jan 8.

Department of Clinical Genetics, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.

Clinical Genetics services provide a diagnostic, counselling and genetic testing service for children and adults affected by, or at risk of, a genetic condition, most of which are rare, and/or genetically heterogeneous. Appropriate triage of referrals is crucial to ensure that the most urgent referrals are seen as quickly as possible, without negatively impacting the waiting times of less urgent cases. We aimed to examine triage practice in six Clinical Genetic centres across the United Kingdom and Ireland. Read More

Eur J Hum Genet 2019 Jan 8. Epub 2019 Jan 8.

Centre of Genomics and Policy, McGill University, 740 avenue Dr. Penfield, suite 5200, Montréal, QC, H3A 0G1, Canada.

Efforts are underway to harmonise the return of individual results and incidental findings from whole genome sequencing (WGS) across research contexts and countries. We reviewed international, regional and national laws and policies applying to return across 20 countries to identify areas of convergence and divergence. Discrepancies between laws and policies are most problematic where they cannot be reconciled through harmonisation of project-level governance. Read More

Eur J Hum Genet 2019 Jan 8. Epub 2019 Jan 8.

Medical Research, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK.

The centrosomal protein 55 kDa (CEP55 (OMIM 610000)) plays a fundamental role in cell cycle regulation and cytokinesis. However, the precise role of CEP55 in human embryonic growth and development is yet to be fully defined. Here we identified a novel homozygous founder frameshift variant in CEP55, present at low frequency in the Amish community, in two siblings presenting with a lethal foetal disorder. Read More

Eur J Hum Genet 2019 Jan 8. Epub 2019 Jan 8.

Dept. Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA, 94143-2711, USA.

The Integrator complex subunit 1 (INTS1) is a component of the integrator complex that comprises 14 subunits and associates with RPB1 to catalyze endonucleolytic cleavage of nascent snRNAs and assist RNA polymerase II in promoter-proximal pause-release on protein-coding genes. We present five patients, including two sib pairs, with biallelic sequence variants in INTS1. The patients manifested absent or severely limited speech, an abnormal gait, hypotonia and cataracts. Read More

Eur J Hum Genet 2018 Dec 20. Epub 2018 Dec 20.

Department of Medical Genetics, Haukeland University Hospital, 5021, Bergen, Norway.

Missense variants located to the "molecular brake" in the tyrosine kinase hinge region of platelet-derived growth factor receptor-β, encoded by PFGFRB, can cause Penttinen-type (Val665Ala) and Penttinen-like (Asn666His) premature ageing syndromes, as well as infantile myofibromatosis (Asn666Lys and Pro660Thr). We have found the same de novo PDGFRB c.1997A>G p. Read More