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Eur J Hum Genet 2019 Apr 17. Epub 2019 Apr 17.

Centre for Biomedicine, EURAC, Bolzano and CRB Uppsala University Sweden, Uppsala, Sweden.

The General Data Protection Regulation (GDPR) came into force in May 2018. The aspiration of providing for a high level of protection to individuals' personal data risked placing considerable constraints on scientific research, which was contrary to various research traditions across the EU. Therefore, along with the set of carefully outlined data subjects' rights, the GDPR provides for a two-level framework to enable derogations from these rights when scientific research is concerned. Read More

Eur J Hum Genet 2019 Apr 17. Epub 2019 Apr 17.

AP-HP, G-H Pitié-Salpêtrière, Centre de Référence des Maladies neuromusculaires, Paris Nord/Est/Ile de france, Paris, France.

Currently only 25-30% of patients with axonal forms of Charcot-Marie-Tooth disease (CMT) receive a genetic diagnosis. We aimed to identify the causative gene of CMT type 2 in 8 non-related French families with a distinct clinical phenotype. We collected clinical, electrophysiological, and laboratory findings and performed genetic analyses in four different French laboratories. Read More

Eur J Hum Genet 2019 Apr 12. Epub 2019 Apr 12.

Our Lady's Children's Hospital Crumlin, Dublin 12, Dublin, Ireland.

Multi-gene testing is useful in genetically heterogeneous conditions, including inherited cardiac pathologies. Increasing the number of genes analysed increases diagnostic yield of variants of certain, likely, or uncertain pathogenicity. Concerns exist regarding management of variants of uncertain/likely pathogenicity in conditions of oligogenic inheritance or variable expressivity. Read More

Eur J Hum Genet 2019 Apr 12. Epub 2019 Apr 12.

Division of Newborn Medicine and Neonatal Genomics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.

Clinical exome sequencing (CES) is increasingly being utilized; however, a large proportion of patients remain undiagnosed, creating a need for a systematic approach to increase the diagnostic yield. We have reanalyzed CES data for a clinically heterogeneous cohort of 102 probands with likely Mendelian conditions, including 74 negative cases and 28 cases with candidate variants, but reanalysis requested by clinicians. Reanalysis was performed by an interdisciplinary team using a validated custom-built pipeline, "Variant Explorer Pipeline" (VExP). Read More

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

Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.

Human leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Read More

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

Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel.

The ATP/GTP-Binding Protein 1 (AGTPBP1) gene (OMIM *606830) catalyzes deglutamylation of polyglutamylated proteins, and its deficiency manifests by cerebellar ataxia and peripheral neuropathy in mice and lower motor neuron-like disease in sheep. In the mutant mice, cerebellar atrophy due to Purkinje cell degeneration is observed, likely due to increased tubulin polyglutamylation in affected brain areas. We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy. Read More

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

Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel.

The transforming growth factor-beta (TGFβ) signaling pathway is essential for palatogenesis and retinal development. Glycoprotein A repetitions predominant (GARP), encoded by LRRC32, is a TGFβ cell surface receptor that has been studied primarily in the context of cellular immunity. We identified a homozygous stop-gain variant in LRRC32 (c. Read More

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

Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.

The DOCK3 gene encodes the Dedicator of cytokinesis 3 (DOCK3) protein, which belongs to the family of guanine nucleotide exchange factors and is expressed almost exclusively in the brain and spinal cord. We used whole exome sequencing (WES) to investigate the molecular cause of developmental delay and hypotonia in three unrelated probands. WES identified truncating and splice site variants in Patient 1 and compound heterozygous and homozygous missense variants in Patients 2 and 3, respectively. Read More

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

Child Language Doctoral Program (CLDP), University of Kansas, Lawrence, KS, USA.

Language is a uniquely human ability, and failure to attain this ability can have a life-long impact on the affected individuals. This is particularly true for individuals with specific language impairment (SLI), which is defined as an impairment in normal language development in the absence of any other developmental disability. Although SLI displays high heritability, family-based linkage studies have been hampered by an unclear mode of Mendelian segregation, variable disease penetrance, and heterogeneity of diagnostic criteria. Read More

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

Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia.

Kalmyks, the only Mongolic-speaking population in Europe, live in the southeast of the European Plain, in Russia. They adhere to Buddhism and speak a dialect of the Mongolian language. Historical and linguistic evidence, as well a shared clan names, suggests a common origin with Oirats of western Mongolia; yet, only a limited number of genetic studies have focused on this topic. Read More

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

Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Systemic healthcare issues and geographical challenges restrict women's access to BRCA1/2 testing to inform the use of tailored treatments for high-grade serous ovarian cancer. Consequently, BRCA1/2 testing in this population is low and improved testing pathways are urgently needed. This study aimed to determine the acceptability and feasibility of telephone genetic counselling (TGC) to facilitate treatment-focused BRCA1/2 testing in Australia for women with high-grade serous ovarian cancer. Read More

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

Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, 171 76, Stockholm, Sweden.

Colorectal cancer (CRC) is one of the major cancer types in the western world including Sweden. However, known genetic risk factors could only explain a limited part of heritability of the disease. Moreover, colon and rectal cancers are habitually discussed as one entity, colorectal cancer, although different carcinogenesis has been recognized. Read More

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

Department of Neurosurgery, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini, 5, 16147, Genoa, Italy.

De novo DDX3X variants account for 1-3% of syndromic intellectual disability (ID) in females and have been occasionally reported in males. Furthermore, somatic DDX3X variants occur in several aggressive cancers, including medulloblastoma. We report three unrelated females with severe ID, dysmorphic features, and a common brain malformative pattern characterized by malformations of cortical development, callosal dysgenesis, basal ganglia anomalies, and midbrain-hindbrain malformations. Read More

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

Medical Genetics Unit, University-Hospital "Santa Maria della Misericordia", Perugia, Italy.

Schilbach-Rott syndrome (SRS, OMIM%164220) is a disorder of unknown aetiology that is characterised by hypotelorism, epichantal folds, cleft palate, dysmorphic face, hypospadia in males and mild mental retardation in some patients. To date, 5 families and 17 patients have exhibited this phenotype, and recurrence in two of these families suggests an autosomal dominant inheritance. SRS overlaps with a mild form of holoprosencephaly (HPE), but array-CGH analysis and sequencing of some HPE-related genes (SEPT9, SHH and TWIST) did not reveal any variants in at least one family. Read More

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

Molecular Immunopathology and Histocompatibility Unit, Division of Molecular Genetics, Onassis Cardiac Surgery Center, Kallithea, 17674, Greece.

Eur J Hum Genet 2019 Mar 28. Epub 2019 Mar 28.

Viapath at King's College Hospital, Haematological Malignancy Diagnostic Centre, Cytogenetics Laboratory, London, UK.

Specialists of human genetic diagnostics can be divided into four groups: Medical Geneticists (MDG), Genetic Nurses and/or Counsellors (GN/GC), Clinical Laboratory Geneticists (CLG) and Laboratory Genetics Technicians (LGT). While the first two groups are in direct patient contact, the work of the latter two, of equal importance for patient care, are often hidden as they work behind the scenes. Herein the first study on the rights and duties of CLGs is presented. Read More

Eur J Hum Genet 2019 Mar 22. Epub 2019 Mar 22.

Survivorship Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.

Since the publication of the article, the authors noticed that 'NFI cohort' and 'NFI-free cohort' columns in the 'Autism and the 'Autism/ADHD' rows had been erroneously interchanged in Table 3. This has now been updated in the HTML and PDF of the original article. Read More

Eur J Hum Genet 2019 Mar 27. Epub 2019 Mar 27.

North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

The Boost Brittle Bones Before Birth (BOOSTB4) clinical trial is investigating the safety and efficacy of transplanting fetal derived mesenchymal stromal cells (MSCs) prenatally and/or in early postnatal life to treat severe Osteogenesis Imperfecta (OI). This study aimed to explore stakeholder views to understand perceived benefits or concerns, identify ethical issues and establish protocols for support and counselling. Semi-structured qualitative interviews were conducted with three groups; 1. Read More

Eur J Hum Genet 2019 Mar 26. Epub 2019 Mar 26.

Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

Intellectual disability (ID), megalencephaly, frontal predominant pachygyria, and seizures, previously called "thin" lissencephaly, are reported to be caused by recessive variants in CRADD. Among five families of different ethnicities identified, one homozygous missense variant, c.509G>A p. Read More

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

Biobank Lab, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Łódź, Poland.

The aim of the present study was to define the mtDNA variability of Polish population and to visualize the genetic relations between Poles. For the first time, the study of Polish population was conducted on such a large number of individuals (5852) representing administrative units of both levels of local administration in Poland (voivodeships and counties). Additionally, clustering was used as a method of population subdivision. Read More

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

Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.

Interpretation of sequence variants is an ongoing challenge and new approaches aim to increase stringency. The reclassification of variants has the potential to alter medical management and elicit psychosocial consequences for patients. The perspective of patients with an inherited cardiac disease and a clinically significant variant reclassification was explored through semi-structured phone interviews. Read More

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

Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen N, 2200, Denmark.

Family studies have established that the heritability of blood pressure is significant and genome-wide association studies (GWAS) have identified numerous susceptibility loci, including one within the non-coding part of Rho GTPase-activating protein 42 gene (ARHGAP42) on chromosome 11q22.1. Arhgap42-deficient mice have significantly elevated blood pressure, but the phenotypic effects of human variants in the coding part of the gene are unknown. Read More

Eur J Hum Genet 2019 Mar 19. Epub 2019 Mar 19.

Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore, Singapore.

A 22-year-old man was referred for continuation of diabetes mellitus treatment. He was first diagnosed with diabetes mellitus 2 months after birth, when he failed to thrive and showed symptoms of diabetic ketoacidosis. There was no family history of diabetes mellitus. Read More

Eur J Hum Genet 2019 Mar 19. Epub 2019 Mar 19.

Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.

Huntington's disease (HD) is a severe neurodegenerative condition that impacts the whole family. Prenatal diagnosis by direct or exclusion testing is available for couples at risk of transmitting HD to their children. An ethical problem can arise after prenatal diagnosis for HD if a known 'high risk' pregnancy is continued to term: international guidelines emphasise that this situation should be avoided where possible, as it removes the resulting child's future right to make an informed, autonomous decision about predictive testing. Read More

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

Cell Biology and Genetics Research Centre, St. George's University of London, London, UK.

Recent studies have demonstrated genetic differences between monozygotic (MZ) twins. To test the hypothesis that early post-twinning mutational events associate with phenotypic discordance, we investigated a cohort of 13 twin pairs (n = 26) discordant for various clinical phenotypes using whole-exome sequencing and screened for copy number variation (CNV). We identified a de novo variant in PLCB1, a gene involved in the hydrolysis of lipid phosphorus in milk from dairy cows, associated with lactase non-persistence, and a variant in the mitochondrial complex I gene MT-ND5 associated with amyotrophic lateral sclerosis (ALS). Read More

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

Department of Medical Genetics and Rare Orthopaedic Diseases, and CLIBI Laboratory, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue and 90% of cases are due to dominant mutations in COL1A1 and COL1A2 genes. To increase OI disease knowledge and contribute to patient follow-up management, a homogeneous Italian cohort of 364 subjects affected by OI types I-IV was evaluated. The study population was composed of 262 OI type I, 24 type II, 39 type III, and 39 type IV patients. Read More

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

Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, CIBERER, Barcelona, Spain.

DPH1 variants have been associated with an ultra-rare and severe neurodevelopmental disorder, mainly characterized by variable developmental delay, short stature, dysmorphic features, and sparse hair. We have identified four new patients (from two different families) carrying novel variants in DPH1, enriching the clinical delineation of the DPH1 syndrome. Using a diphtheria toxin ADP-ribosylation assay, we have analyzed the activity of seven identified variants and demonstrated compromised function for five of them [p. Read More

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

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

Roma are a socially and culturally distinct isolated population with genetically divergent subisolates, residing mainly across Central, Southern, and Eastern Europe. We evaluated the genetic etiology of hearing impairment (HI) in 15 Hungarian Roma families through exome sequencing. A family with autosomal dominant non-syndromic HI segregating a rare variant in the Calponin-homology 2 domain of PLS1, or Plastin 1 [p. Read More

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

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

We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). Read More

Eur J Hum Genet 2019 Mar 7. Epub 2019 Mar 7.

Science Policy Research Unit, University of Sussex, Brighton, United Kingdom.

Recent US Supreme Court decisions have invalidated patent claims on isolated genomic DNA, and testing methods that applied medical correlations using conventional techniques. As a consequence, US genetic testing laboratories have a relatively low risk of infringing patents on naturally occurring DNA or methods for detecting genomic variants. In Europe, however, such claims remain patentable, and European laboratories risk infringing them. Read More

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

University of Toronto, Toronto, ON, Canada.

Guidelines recommend that providers engage patients in shared decision-making about receiving incidental results (IR) prior to genomic sequencing (GS), but this can be time-consuming, given the myriad of IR and variation in patients' preferences. We aimed to develop patient profiles to inform pre-test counseling for IR. We conducted semi-structured interviews with participants as a part of a randomized trial of the GenomicsADvISER. Read More

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

Graduate School of Biomedical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.

Predicting metabolizer phenotype (MP) is typically performed using data from a single gene. Cytochrome p450 family 2 subfamily D polypeptide 6 (CYP2D6) is considered the primary gene for predicting MP in reference to approximately 30% of marketed drugs and endogenous toxins. CYP2D6 predictions have proven clinically effective but also have well-documented inaccuracies due to relatively high genotype-phenotype discordance in certain populations. Read More

Eur J Hum Genet 2019 Feb 28. Epub 2019 Feb 28.

Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

Bicuspid aortic valve (BAV) is the most common congenital heart defect (CHD), affecting 1-2% of the population. BAV is associated with thoracic aortic aneurysms (TAAs). Deleterious copy number variations (CNVs) were found previously in up to 10% of CHD cases. Read More

Eur J Hum Genet 2019 Feb 28. Epub 2019 Feb 28.

Survivorship Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.

Most research on psychosocial consequences of neurofibromatosis type 1 (NF1) has focused on the relationship between disease factors and cognitive functioning. NF1 may impair domains of learning and attention, resulting in low academic performance. This study is the first nationwide population-based cohort study to investigate educational attainment and delay in completing mandatory school by persons with NF1. Read More

Eur J Hum Genet 2019 Feb 26. Epub 2019 Feb 26.

Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA.

Mobile applications (apps) have been increasingly utilized to access the latest and abundant information related to genetics/genomics for resources, risk assessments, and individualized recommendations. Nevertheless, the number and quality of the current apps in genetics/genomics remain unknown. Thus, in this review, we aimed to identify existing genetic/genomic apps, summarize their characteristics, and examine their quality. Read More

Eur J Hum Genet 2019 Feb 26. Epub 2019 Feb 26.

Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA.

SMAD4 pathogenic variants cause juvenile polyposis (JPS) and hereditary hemorrhagic telangiectasia (HHT), and 40% of affected individuals also have thoracic aortic disease. At the same time, SMAD4 pathogenic variants have not been reported in thoracic aortic disease families without JPS-HHT. A SMAD4 heterozygous variant, c. Read More

Eur J Hum Genet 2019 Feb 26. Epub 2019 Feb 26.

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany.

Height is a heritable and highly heterogeneous trait. Short stature affects 3% of the population and in most cases is genetic in origin. After excluding known causes, 67% of affected individuals remain without diagnosis. Read More

Eur J Hum Genet 2019 Feb 22. Epub 2019 Feb 22.

Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

Progressive dilatation of the thoracic aorta leads to thoracic aortic aneurysm (TAA), which is often asymptomatic but predisposes to lethal aortic dissections and ruptures. TAA is a common complication in patients with bicuspid aortic valve (BAV). Recently, rare loss-of-function SMAD6 variants were shown to contribute significantly to the genetic aetiology of BAV/TAA. Read More

Eur J Hum Genet 2019 Feb 20. Epub 2019 Feb 20.

Fondazione IRCCS Casa Sollievo della Sofferenza, Division of Medical Genetics, San Giovanni Rotondo, FG, Italy.

Hartsfield syndrome (HS) is an ultrarare developmental disorder mainly featuring holoprosencephaly and ectrodactyly. It is caused by heterozygous or biallelic variants in FGFR1. Recently, a dominant-negative effect was suggested for FGFR1 variants associated with HS. Read More

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 May 13;27(5):669-670. Epub 2019 Feb 13.

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

Eur J Hum Genet 2019 May 11;27(5):691-700. 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