8,403 results match your criteria Journal of Medical Genetics [Journal]


Natural history of renal tumours in von Hippel-Lindau disease: a large retrospective study of Chinese patients.

J Med Genet 2019 Feb 11. Epub 2019 Feb 11.

Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing, China.

Background: Historically, renal cell carcinoma (RCC) is one of the main causes of death in von Hippel-Lindau (VHL) disease. However, the natural history of VHL-related RCC has not been thoroughly elucidated to date. This report described the natural history of VHL-related RCC in a large Chinese VHL cohort and might be helpful in the surveillance and treatment of VHL disease. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105567DOI Listing
February 2019
1 Read

Contribution of spurious transcription to intellectual disability disorders.

J Med Genet 2019 Feb 11. Epub 2019 Feb 11.

Molecular Neurobiology and Neuropathology Unit, Instituto de Neurociencias (UMH-CSIC), San Juan de Alicante, Alicante, Spain.

During the development of multicellular organisms, chromatin-modifying enzymes orchestrate the establishment of gene expression programmes that characterise each differentiated cell type. These enzymes also contribute to the maintenance of cell type-specific transcription profiles throughout life. But what happens when epigenomic regulation goes awry? Genomic screens in experimental models of intellectual disability disorders (IDDs) caused by mutations in epigenetic machinery-encoding genes have shown that transcriptional dysregulation constitutes a hallmark of these conditions. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105668DOI Listing
February 2019

Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC).

J Med Genet 2019 Feb 11. Epub 2019 Feb 11.

Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.

Introduction: Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105361DOI Listing
February 2019

Genetic diagnosis of subfertility: the impact of meiosis and maternal effects.

J Med Genet 2019 Feb 6. Epub 2019 Feb 6.

Reproduction and Genetics Department, Vrije Universiteit Brussel, Brussels, Belgium.

During reproductive age, approximately one in seven couples are confronted with fertility problems. While the aetiology is diverse, including infections, metabolic diseases, hormonal imbalances and iatrogenic effects, it is becoming increasingly clear that genetic factors have a significant contribution. Due to the complex nature of infertility that often hints at a multifactorial cause, the search for potentially causal gene mutations in idiopathic infertile couples has remained difficult. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105513
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http://dx.doi.org/10.1136/jmedgenet-2018-105513DOI Listing
February 2019
1 Read

promoter deletion causes endoactivation and Liebenberg syndrome.

J Med Genet 2019 Feb 2. Epub 2019 Feb 2.

Human Molecular Genomics Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.

Background: Structural variants (SVs) affecting non-coding -regulatory elements are a common cause of congenital limb malformation. Yet, the functional interpretation of these non-coding variants remains challenging. The human Liebenberg syndrome is characterised by a partial transformation of the arms into legs and has been shown to be caused by SVs at the locus leading to its misregulation in the forelimb by its native enhancer element Pen. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105793DOI Listing
February 2019

Features, genetics and their correlation in Jalili syndrome: a systematic review.

J Med Genet 2019 Jan 31. Epub 2019 Jan 31.

Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (the Islamic Republic of).

Jalili syndrome is a rare genetic disorder first identified by Jalili in Gaza. Amelogenesis imperfecta and cone-rode dystrophy are simultaneously seen in Jalili syndrome patients as the main and primary manifestations. Molecular analysis has revealed that the gene is responsible for this rare syndrome. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105716
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http://dx.doi.org/10.1136/jmedgenet-2018-105716DOI Listing
January 2019
2 Reads

Prevalence of germline pathogenic variants in sequential epithelial ovarian cancer cases.

J Med Genet 2019 Jan 25. Epub 2019 Jan 25.

Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.

Introduction: Poly(ADP-ribose) polymerase inhibitors significantly improve progression-free survival in platinum-sensitive high-grade serous and endometrioid ovarian carcinoma, with greatest benefits observed in women with a pathogenic / variant. Consequently, the demand for germline testing in ovarian cancer has increased substantially, leading to the screening of unselected populations of patients. We aimed to determine the prevalence of pathogenic germline variants in women diagnosed with epithelial ovarian cancer, categorised according to the established risk factors for hereditary breast and ovarian cancer syndrome and the Manchester BRCA Score, to inform risk stratification. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105792DOI Listing
January 2019

Diagnosis of 'possible' mitochondrial disease: an existential crisis.

J Med Genet 2019 Jan 25. Epub 2019 Jan 25.

Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK.

Primary genetic mitochondrial diseases are often difficult to diagnose, and the term 'possible' mitochondrial disease is used frequently by clinicians when such a diagnosis is suspected. There are now many known phenocopies of mitochondrial disease. Advances in genomic testing have shown that some patients with a clinical phenotype and biochemical abnormalities suggesting mitochondrial disease may have other genetic disorders. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105800DOI Listing
January 2019
2 Reads

pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium.

J Med Genet 2019 Jan 19. Epub 2019 Jan 19.

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

Background: Pathogenic variants in cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals with variants.

Methods: Aortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105583
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http://dx.doi.org/10.1136/jmedgenet-2018-105583DOI Listing
January 2019
3 Reads

Clinical spectrum and pleiotropic nature of germline mutations.

J Med Genet 2019 Jan 19. Epub 2019 Jan 19.

Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.

encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that genetic alterations cause diffuse gastric cancer and lobular breast cancer-the foremost manifestations of the hereditary diffuse gastric cancer syndrome. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105807
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http://dx.doi.org/10.1136/jmedgenet-2018-105807DOI Listing
January 2019
4 Reads

Longitudinal evaluation of SMN levels as biomarker for spinal muscular atrophy: results of a phase IIb double-blind study of salbutamol.

J Med Genet 2018 Dec 28. Epub 2018 Dec 28.

Muscle Pathology and Neuroimmunology Unit, Neurological Institute Carlo Besta, Milano, Italy.

Background: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, due to the loss of function of the survival motor neuron () gene. The first treatment for the condition, recently approved, is based on the reduction of exon 7 skipping in mRNAs produced by a highly homologous gene (). The primary objective of the present study was to evaluate the applicability of the dosage of SMN gene produts in blood, as biomarker for SMA, and the safety of oral salbutamol, a beta2-adrenergic agonist modulating levels. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105482
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http://dx.doi.org/10.1136/jmedgenet-2018-105482DOI Listing
December 2018
4 Reads

Integrative network and brain expression analysis reveals mechanistic modules in ataxia.

J Med Genet 2018 Dec 27. Epub 2018 Dec 27.

Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands.

Background: Genetic forms of ataxia are a heterogenous group of degenerative diseases of the cerebellum. Many causative genes have been identified. We aimed to systematically investigate these genes to better understand ataxia pathophysiology. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105703DOI Listing
December 2018

Does multilocus inherited neoplasia alleles syndrome have severe clinical expression?

J Med Genet 2018 Dec 22. Epub 2018 Dec 22.

Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.

Importance: Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations.

Objective: To determine the prevalence and clinical features of MINAS in a large cohort of adult patients with hereditary cancer homogeneously tested with the same gene panel. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105700DOI Listing
December 2018
1 Read

Should pretest genetic counselling be required for patients pursuing genomic sequencing? Results from a survey of participants in a large genomic implementation study.

J Med Genet 2018 Dec 22. Epub 2018 Dec 22.

Biomedical Ethics Research Program, Mayo Clinic, Rochester, Minnesota, USA.

Purpose: We assessed the decision-making of individuals pursuing genomic sequencing without a requirement for pretest genetic counselling. We sought to describe the extent to which individuals who decline genetic counselling reported decisional conflict or struggled to make a decision to pursue genomic testing.

Methods: We administered a 100-item survey to 3037 individuals who consented to the Return of Actionable Variants Empirical study, a genomic medicine implementation study supported by the National Institutes of Health (USA) eMERGE consortium. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105577
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http://dx.doi.org/10.1136/jmedgenet-2018-105577DOI Listing
December 2018
5 Reads

Biallelic mutations in encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis.

J Med Genet 2018 Dec 20. Epub 2018 Dec 20.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.

Background: Leber congenital amaurosis (LCA) is the earliest and most severe form of inherited retinal dystrophies. In approximately 56% of Chinese probands, genetic defects can be detected in known LCA-causing genes. In this study, the objective was to identify pathogenic variants in two unsolved Chinese families with LCA. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105709DOI Listing
December 2018

de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome.

J Med Genet 2018 Dec 20. Epub 2018 Dec 20.

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Background: In this study, we aimed to identify the gene abnormality responsible for pathogenicity in an individual with an undiagnosed neurodevelopmental disorder with megalencephaly, ventriculomegaly, hypoplastic corpus callosum, intellectual disability, polydactyly and neuroblastoma. We then explored the underlying molecular mechanism.

Methods: Trio-based, whole-exome sequencing was performed to identify disease-causing gene mutation. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105487DOI Listing
December 2018

Comprehensive genomic variation profiling of cervical intraepithelial neoplasia and cervical cancer identifies potential targets for cervical cancer early warning.

J Med Genet 2018 Dec 19. Epub 2018 Dec 19.

Department of Obstetrics and Gynecology, Southwestern Hospital, Third Military Medical University, Chongqing, China.

Background: To better understand the pathogenesis of cervical cancer (CC), we systematically analysed the genomic variation and human papillomavirus (HPV) integration profiles of cervical intraepithelial neoplasia (CIN) and CC.

Methods: We performed whole-genome sequencing or whole-exome sequencing of 102 tumour-normal pairs and human papillomavirus probe capture sequencing of 45 CCs, 44 CIN samples and 25 normal cervical samples, and constructed strict integrated workflow of genomic analysis.

Results: Mutational analysis identified eight significantly mutated genes in CC including four genes (, , and ), which have not previously been reported in CC. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105745DOI Listing
December 2018
2 Reads

Breast cancer risk in neurofibromatosis type 1 is a function of the type of gene mutation: a new genotype-phenotype correlation.

J Med Genet 2018 Dec 10. Epub 2018 Dec 10.

Inherited Tumour Syndromes Research Group, Institute of Cancer & Genetics, Cardiff University, Cardiff, UK.

Background: Neurofibromatosis type 1 (NF1) predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described.

Methods: Constitutional mutations in 78 patients with NF1 with BC (NF1-BC) were compared with the Leiden Open Variation Database (n=3432).

Results: No cases were observed with whole or partial gene deletions (HR 0. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105599DOI Listing
December 2018
3 Reads
6.335 Impact Factor

CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.

J Med Genet 2018 Dec 5. Epub 2018 Dec 5.

The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel.

Background: Dilated cardiomyopathy (DCM) is a primary myocardial disease leading to contractile dysfunction, progressive heart failure and excessive risk of sudden cardiac death. Around half of DCM cases are idiopathic, and genetic factors seem to play an important role.

Aim: We investigated a possible genetic cause of DCM in two consanguineous children from a Bedouin family. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105498DOI Listing
December 2018
2 Reads

T cell dysfunction in chronic hepatitis B infection and liver cancer: evidence from transcriptome analysis.

J Med Genet 2019 Jan 5;56(1):22-28. Epub 2018 Dec 5.

Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China.

Background: T cell dysfunction occurs in many diseases, especially in chronic virus infection and cancers. However, up to now, little is known on the distinctions in T cell exhaustion between cancer and chronic virus infection. The objective of this study is to explore the transcriptional similarities and differences in exhausted CD8 +T cell between chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105570DOI Listing
January 2019
1 Read

Meiotic chromatid recombination and segregation assessed with human single cell genome sequencing data.

J Med Genet 2018 Dec 4. Epub 2018 Dec 4.

Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China.

Background: The human oocyte transmits one set of haploid genome into female pronucleus (FPN) while discards the remaining genome into the first polar body (PB1) and the second polar body (PB2). The FPN genome carries an assembly of maternal and paternal genome that resulted from homologous recombination during the prophase of the first meiosis. However, how parental genome has been shuffled and transmitted is difficult to assess by analysing only the progeny's genome. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105612DOI Listing
December 2018

Kabuki syndrome: international consensus diagnostic criteria.

J Med Genet 2019 Feb 4;56(2):89-95. Epub 2018 Dec 4.

President, the Research Institute of Personalized Health Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan.

Background: Kabuki syndrome (KS) is a clinically recognisable syndrome in which 70% of patients have a pathogenic variant in or . Understanding the function of these genes opens the door to targeted therapies. The purpose of this report is to propose diagnostic criteria for KS, particularly when molecular genetic testing is equivocal. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105625DOI Listing
February 2019
5 Reads

De novo mutation in causes ichthyosis, , hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy.

J Med Genet 2018 Nov 28. Epub 2018 Nov 28.

NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Background: Very long-chain fatty acids (VLCFAs) are essential for functioning of biological membranes. ELOVL fatty acid elongase 1 catalyses elongation of saturated and monounsaturated C22-C26-VLCFAs. We studied two patients with a dominant mutation. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105711DOI Listing
November 2018

MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive erebellar, cular, cranioacial and enital features (COFG syndrome).

J Med Genet 2018 Nov 28. Epub 2018 Nov 28.

Genome Research Division, Human Genetics Department, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs.

Objective: A homozygous truncating variant in has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105623DOI Listing
November 2018
2 Reads

Biallelic disruption of is associated with a skeletal disorder characterised by rhizomelic shortening of extremities and dysmorphic features.

J Med Genet 2018 Nov 26. Epub 2018 Nov 26.

Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.

Background: During mouse embryonic development the protein kinase domain containing, cytoplasmic () gene, also known as is expressed in several tissues including the ventral midbrain, with particularly strong expression in branchial arches and limb buds. Homozygous knockout mice have dysmorphic features and shortened long bones as the most obvious morphological abnormalities. The human gene has currently not been associated with any disorders. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105639
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http://dx.doi.org/10.1136/jmedgenet-2018-105639DOI Listing
November 2018
1 Read

Screening of deep intronic regions by targeted gene sequencing identifies the first germline variant causing pseudoexon activation in a patient with breast/ovarian cancer.

J Med Genet 2019 Feb 24;56(2):63-74. Epub 2018 Nov 24.

Oncogenetics Group, Vall d'Hebron Institut d'Oncologia, Barcelona, Spain.

Background: Genetic analysis of and for the diagnosis of hereditary breast and ovarian cancer (HBOC) is commonly restricted to coding regions and exon-intron boundaries. Although germline pathogenic variants in these regions explain about ~20% of HBOC cases, there is still an important fraction that remains undiagnosed. We have screened deep intronic regions to identify potential spliceogenic variants that could explain part of the missing HBOC susceptibility. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105606DOI Listing
February 2019

Correction: .

Authors:

J Med Genet 2019 Jan 22;56(1):50-52. Epub 2018 Nov 22.

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http://dx.doi.org/10.1136/jmedgenet-2017-105127corr1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327860PMC
January 2019
5 Reads

mutation affects ER homeostasis, causing neurological syndrome.

J Med Genet 2018 Nov 21. Epub 2018 Nov 21.

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, Beer Sheva, Israel.

Background: Consanguineous kindred presented with an autosomal recessive syndrome of intrauterine growth retardation, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and optic nerve atrophy with no eye fixation. Affected individuals died by the age of 4. Brain MRI demonstrated microcephaly, semilobar holoprosencephaly and agenesis of corpus callosum. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105503DOI Listing
November 2018
7 Reads

Cancer immunotherapy: challenges and clinical applications.

J Med Genet 2019 Jan 21;56(1):1-3. Epub 2018 Nov 21.

Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

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http://dx.doi.org/10.1136/jmedgenet-2018-105852DOI Listing
January 2019
6 Reads

From gestalt to gene: early predictive dysmorphic features of PMM2-CDG.

J Med Genet 2018 Nov 21. Epub 2018 Nov 21.

Genetics and Molecular Medicine Department and Pediatric Institute of Rare Diseases (IPER), Hospital Sant Joan de Déu, Barcelona, Spain.

Introduction: Phosphomannomutase-2 deficiency (PMM2-CDG) is associated with a recognisable facial pattern. There are no early severity predictors for this disorder and no phenotype-genotype correlation. We performed a detailed dysmorphology evaluation to describe facial gestalt and its changes over time, to train digital recognition facial analysis tools and to identify early severity predictors. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105588DOI Listing
November 2018
13 Reads

Practice evaluation of biobank ethics and governance: current needs and future perspectives.

J Med Genet 2018 Nov 21. Epub 2018 Nov 21.

Charité - University Medicine Berlin, QUEST - Center for Transforming Biomedical Research, Berlin Institute of Health (BIH), Berlin, Germany.

Background: Biobank research faces many ethical challenges. Ethics research aims to develop standards for governance to meet these challenges by elaborating overarching normative principles of medical ethics in the context of biobanking. Most ethical standards are widely agreed on among biobank stakeholders and entail specific governance solutions, for example, adoption of consent procedures. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105617DOI Listing
November 2018
6 Reads

Novel homozygous mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella.

J Med Genet 2019 Feb 10;56(2):96-103. Epub 2018 Nov 10.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Background: Male infertility is a major issue of human reproduction health. Asthenoteratospermia can impair sperm motility and cause male infertility. Asthenoteratospermia with multiple morphological abnormalities of the flagella (MMAF) presents abnormal spermatozoa with absent, bent, coiled, short and/or irregular-calibre flagella. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105486
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http://dx.doi.org/10.1136/jmedgenet-2018-105486DOI Listing
February 2019
11 Reads

Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying mutations.

J Med Genet 2018 Dec 10;55(12):814-823. Epub 2018 Nov 10.

Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Background: Mutations in the metalloendopeptidase () gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in . Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105650DOI Listing
December 2018
7 Reads
6.340 Impact Factor

Reclassification of and variants of uncertain significance: a multifactorial analysis of multicentre prospective cohort.

J Med Genet 2018 Dec 10;55(12):794-802. Epub 2018 Nov 10.

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: and () variants classified ambiguously as variants of uncertain significance (VUS) are a major challenge for clinical genetic testing in breast cancer; their relevance to the cancer risk is unclear and the association with the response to specific -targeted agents is uncertain. To minimise the proportion of VUS in , we performed the multifactorial likelihood analysis and validated this method using an independent cohort of patients with breast cancer.

Methods: We used a data set of 2115 patients with breast cancer from the nationwide multicentre prospective Korean Hereditary Breast Cancer study. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105565
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http://dx.doi.org/10.1136/jmedgenet-2018-105565DOI Listing
December 2018
2 Reads

Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy.

J Med Genet 2019 Feb 10;56(2):53-62. Epub 2018 Nov 10.

Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.

Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch-repair genes. Besides very high tumour risks, CMMRD phenotypes are often characterised by the presence of signs reminiscent of neurofibromatosis type 1 (NF1). Because NF1 signs may be present prior to tumour onset, CMMRD is a legitimate differential diagnosis in an otherwise healthy child suspected to have NF1/Legius syndrome without a detectable underlying / germline mutation. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105664
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http://dx.doi.org/10.1136/jmedgenet-2018-105664DOI Listing
February 2019
20 Reads

Expanding the phenotype of COPA syndrome: a kindred with typical and atypical features.

J Med Genet 2018 Nov 1. Epub 2018 Nov 1.

Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Copa syndrome is a rare autosomal dominant disorder with abnormal intracellular vesicle trafficking. The objective of this work is to expand the knowledge about this disorder by delineating phenotypic features of an unreported COPA family.

Methods And Results: A heterozygous missense variant (c. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105560
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http://dx.doi.org/10.1136/jmedgenet-2018-105560DOI Listing
November 2018
13 Reads

Assessment of parental mosaicism in -related epilepsy by single-molecule molecular inversion probes and next-generation sequencing.

J Med Genet 2019 Feb 27;56(2):75-80. Epub 2018 Oct 27.

Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Dravet syndrome is a severe genetic encephalopathy, caused by pathogenic variants in Low-grade parental mosaicism occurs in a substantial proportion of families (7%-13%) and has important implications for recurrence risks. However, parental mosaicism can remain undetected by methods regularly used in diagnostics. In this study, we use single-molecule molecular inversion probes (smMIP), a technique with high sensitivity for detecting low-grade mosaic variants and high cost-effectiveness, to investigate the incidence of parental mosaicism of variants in a cohort of 90 families and assess the feasibility of this technique. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105672
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http://dx.doi.org/10.1136/jmedgenet-2018-105672DOI Listing
February 2019
7 Reads

Chemoresistant pleomorphic rhabdomyosarcoma: whole exome sequencing reveals underlying cancer predisposition and therapeutic options.

J Med Genet 2018 Oct 23. Epub 2018 Oct 23.

Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France.

Background: Rhabdomyosarcoma (RMS) is rare cancer affecting children and adults. Pleomorphic RMS histology is almost exclusive to adult patients and often resistant to chemotherapy.

Objective: We report the case of a 19-year-old patient who presented with a metastatic chemoresistant pleomorphic RMS. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105594
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http://dx.doi.org/10.1136/jmedgenet-2018-105594DOI Listing
October 2018
7 Reads

Mapping of breakpoints in balanced chromosomal translocations by shallow whole-genome sequencing points to , and as novel candidates for genes causing human Mendelian disorders.

J Med Genet 2019 Feb 23;56(2):104-112. Epub 2018 Oct 23.

Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.

Background: Mapping the breakpoints in de novo balanced chromosomal translocations (BCT) in symptomatic individuals provides a unique opportunity to identify in an unbiased way the likely causative genetic defect and thus find novel human disease candidate genes. Our aim was to fine-map breakpoints of de novo BCTs in a case series of nine patients.

Methods: Shallow whole-genome mate pair sequencing (SGMPS) together with long-range PCR and Sanger sequencing. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105527
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http://dx.doi.org/10.1136/jmedgenet-2018-105527DOI Listing
February 2019
15 Reads

Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank.

J Med Genet 2018 Oct 20. Epub 2018 Oct 20.

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.

Background: Genomic CNVs increase the risk for early-onset neurodevelopmental disorders, but their impact on medical outcomes in later life is still poorly understood. The UK Biobank allows us to study the medical consequences of CNVs in middle and old age in half a million well-phenotyped adults.

Methods: We analysed all Biobank participants for the presence of 54 CNVs associated with genomic disorders or clinical phenotypes, including their reciprocal deletions or duplications. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105477DOI Listing
October 2018
3 Reads

Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood.

J Med Genet 2018 Oct 16. Epub 2018 Oct 16.

Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Dandy-Walker malformation features agenesis/hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of posterior fossa. Although Dandy-Walker malformation is relatively common and several genes were linked to the syndrome, the genetic cause in the majority of cases is unknown.

Objective: To identify the mutated gene responsible for Dandy-Walker malformation, kidney disease and bone marrow failure in four patients from two unrelated families. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105421
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http://dx.doi.org/10.1136/jmedgenet-2018-105421DOI Listing
October 2018
11 Reads

Novel mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures.

J Med Genet 2018 Oct 16. Epub 2018 Oct 16.

Departement of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Inserm U1258, CNRS UMR7104, Université de Strasbourg, Illkirch, France.

Background: The activating signal cointegrator 1 (ASC-1) complex acts as a transcriptional coactivator for a variety of transcription factors and consists of four subunits: ASCC1, ASCC2, ASCC3 and TRIP4. A single homozygous mutation in has recently been reported in two families with a severe muscle and bone disorder.

Objective: We aim to contribute to a better understanding of the ASCC1-related disorder. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105390
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http://dx.doi.org/10.1136/jmedgenet-2018-105390DOI Listing
October 2018
7 Reads

De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy.

J Med Genet 2019 Feb 15;56(2):113-122. Epub 2018 Oct 15.

Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.

Background: Early infantile epileptic encephalopathies are severe disorders consisting of early-onset refractory seizures accompanied often by significant developmental delay. The increasing availability of next-generation sequencing has facilitated the recognition of single gene mutations as an underlying aetiology of some forms of early infantile epileptic encephalopathies.

Objectives: This study was designed to identify candidate genes as a potential cause of early infantile epileptic encephalopathy, and then to provide genetic and functional evidence supporting patient variants as causative. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105322
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http://dx.doi.org/10.1136/jmedgenet-2018-105322DOI Listing
February 2019
1 Read

Specific combinations of biallelic variants cause Wiedemann-Rautenstrauch syndrome.

J Med Genet 2018 Dec 15;55(12):837-846. Epub 2018 Oct 15.

Department of Paediatrics, Amsterdam UMC - location AMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Wiedemann-Rautenstrauch syndrome (WRS) is a form of segmental progeria presenting neonatally, characterised by growth retardation, sparse scalp hair, generalised lipodystrophy with characteristic local fatty tissue accumulations and unusual face. We aimed to understand its molecular cause.

Methods: We performed exome sequencing in two families, targeted sequencing in 10 other families and performed in silico modelling studies and transcript processing analyses to explore the structural and functional consequences of the identified variants. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105528
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http://dx.doi.org/10.1136/jmedgenet-2018-105528DOI Listing
December 2018
26 Reads

10q23.31 microduplication encompassing decreases mTOR signalling activity and is associated with autosomal dominant primary microcephaly.

J Med Genet 2018 Oct 9. Epub 2018 Oct 9.

Department of Genetics and Evolutionary Biology, Human Genome and Stem-Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.

Background: Hereditary primary microcephaly (MCPH) is mainly characterised by decreased occipitofrontal circumference and variable degree of intellectual disability. MCPH with a dominant pattern of inheritance is a rare condition, so far causally linked to pathogenic variants in the , , and genes.

Objective: This study aimed at identifying the causative variant of the autosomal dominant form of MCPH in a Brazilian family with three affected members. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105471DOI Listing
October 2018
2 Reads

Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline mutations.

J Med Genet 2018 Oct 5. Epub 2018 Oct 5.

Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden.

Background: Inherited mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in mutation carriers with metastatic melanoma were evaluated. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105610
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http://dx.doi.org/10.1136/jmedgenet-2018-105610DOI Listing
October 2018
11 Reads

Investigation of clinically relevant germline variants detected by next-generation sequencing in patients with childhood cancer: a review of the literature.

J Med Genet 2018 Dec 4;55(12):785-793. Epub 2018 Oct 4.

Children's Cancer Research Unit, Kids Research and Discipline of Child and Adolescent Health, University of Sydney, Westmead, New South Wales, Australia.

Genetic predisposition is an important underlying cause of childhood cancer, although the proportion of patients with childhood cancer carrying predisposing pathogenic germline variants is uncertain. This review considers the pathogenic or likely pathogenic germline variants reported by six studies that used next-generation sequencing to investigate genetic predisposition in selected cohorts of patients with childhood cancer and used incompletely overlapping gene sets for analysis and interpretation. These six studies reported that 8. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105488DOI Listing
December 2018

Correction: SLC26A4.

Authors:

J Med Genet 2018 Dec 4;55(12):846. Epub 2018 Oct 4.

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http://dx.doi.org/10.1136/jmedgenet-2017-104721corr1DOI Listing
December 2018
1 Read

Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study.

J Med Genet 2018 Oct 4. Epub 2018 Oct 4.

Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Technical University of Munich, at Klinikum rechts der Isar, Munich-Neuherberg, Germany.

Background: Progression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown.

Methods: In 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression.

Results: Islet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105532
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http://dx.doi.org/10.1136/jmedgenet-2018-105532DOI Listing
October 2018
2 Reads

Haemophagocytic lymphohistiocytosis complicating pembrolizumab treatment for metastatic breast cancer in a patient with the gene polymorphism.

J Med Genet 2019 Jan 4;56(1):39-42. Epub 2018 Oct 4.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.

Background: Immune checkpoint inhibitor therapy is a modern breakthrough in medical oncology, but it can precipitate inflammatory and autoimmune adverse effects. Among the most serious of these toxicities is haemophagocytic lymphohistiocytosis (HLH), a life-threatening disorder of unbridled immune activation that results in injury to multiple organ systems.

Objective: Description of a case of pembrolizumab-associated HLH in a patient with a proposed underlying genetic risk factor for its occurrence. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105485
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http://dx.doi.org/10.1136/jmedgenet-2018-105485DOI Listing
January 2019
2 Reads