8,429 results match your criteria Journal of Medical Genetics [Journal]


Mutation-specific Fabry disease patient-derived cell model to evaluate the amenability to chaperone therapy.

J Med Genet 2019 Apr 22. Epub 2019 Apr 22.

Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.

Background: Patients with Fabry disease (FD) and amenable mutations can be treated with the chaperone migalastat to restore endogenous α-galactosidase A (AGAL) activity. However, certain amenable mutations do not respond biochemically in vivo as expected. Here, we aimed to establish a patient-specific and mutation-specific cell model to evaluate the amenability to chaperone therapy in FD. Read More

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http://dx.doi.org/10.1136/jmedgenet-2019-106005DOI Listing

Deciphering the complexity of the 4q and 10q subtelomeres by molecular combing in healthy individuals and patients with facioscapulohumeral dystrophy.

J Med Genet 2019 Apr 22. Epub 2019 Apr 22.

Aix Marseille Univ, INSERM, MMG, Marseille Medical Genetics U1251, Marseille, France

Background: Subtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy (FSHD). In most cases, this disease involves shortening of an array of D4Z4 macrosatellite elements at the 4q35 locus. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105949DOI Listing

A novel mutation in the gene expands the phenotype of Alexander disease.

J Med Genet 2019 Apr 19. Epub 2019 Apr 19.

Neurometabolic Diseases Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Catalonia, Spain

Background: Alexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in . Although mostly diagnosed in children, associated with severe leukoencephalopathy, milder adult forms also exist.

Methods: A family affected by adult-onset spastic paraplegia underwent neurological examination and cerebral MRI. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105959
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http://dx.doi.org/10.1136/jmedgenet-2018-105959DOI Listing
April 2019
1 Read
6.335 Impact Factor

Multivariate genome-wide association study of rapid automatised naming and rapid alternating stimulus in Hispanic American and African-American youth.

J Med Genet 2019 Apr 17. Epub 2019 Apr 17.

Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA

Background: Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105874
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http://dx.doi.org/10.1136/jmedgenet-2018-105874DOI Listing
April 2019
1 Read

Resectable lung lesions malignancy assessment and cancer detection by ultra-deep sequencing of targeted gene mutations in plasma cell-free DNA.

J Med Genet 2019 Apr 13. Epub 2019 Apr 13.

Department of Medical Oncology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.

Background: Early detection of lung cancer to allow curative treatment remains challenging. Cell-free circulating tumour (ct) DNA (ctDNA) analysis may aid in malignancy assessment and early cancer diagnosis of lung nodules found in screening imagery.

Methods: The multicentre clinical study enrolled 192 patients with operable occupying lung diseases. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105825DOI Listing
April 2019
1 Read

Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883).

J Med Genet 2019 Apr 12. Epub 2019 Apr 12.

Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte Evangelische Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany.

Background: For individuals with ovarian cancer (OC), therapy options mainly depend on germline status. What is the prevalence of deleterious somatic variants, that is, does genetic tumour testing identify subgroups of individuals who also might benefit from targeted therapy?

Methods: Paired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (, , , , and ) and the and genes in individuals with OC (AGO-TR1 study, NCT02222883). Results were complemented by , and promoter methylation analyses and stratified by histological subtype; 473 individuals were included. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105930DOI Listing
April 2019
1 Read

Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report.

J Med Genet 2019 Apr 8. Epub 2019 Apr 8.

Faculty of Medicine, University of Southampton, Southampton, UK.

The vocabulary currently used to describe genetic variants and their consequences reflects many years of studying and discovering monogenic disease with high penetrance. With the recent rapid expansion of genetic testing brought about by wide availability of high-throughput massively parallel sequencing platforms, accurate variant interpretation has become a major issue. The vocabulary used to describe single genetic variants in silico, in vitro, in vivo and as a contributor to human disease uses terms in common, but the meaning is not necessarily shared across all these contexts. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105872DOI Listing
April 2019
1 Read

Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders.

J Med Genet 2019 Mar 28. Epub 2019 Mar 28.

Service de Génétique, Hospices Civils de Lyon, Bron, France.

Background: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies.

Methods: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105778DOI Listing
March 2019
3 Reads

Allele frequency analysis of variants reported to cause autosomal dominant inherited retinal diseases question the involvement of 19% of genes and 10% of reported pathogenic variants.

J Med Genet 2019 Mar 25. Epub 2019 Mar 25.

Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Background: Next generation sequencing (NGS) generates a large amount of genetic data that can be used to better characterise disease-causing variants. Our aim was to examine allele frequencies of sequence variants reported to cause autosomal dominant inherited retinal diseases (AD-IRDs).

Methods: Genetic information was collected from various databases, including PubMed, the Human Genome Mutation Database, RETNET and gnomAD. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105971DOI Listing

Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation.

J Med Genet 2019 Mar 25. Epub 2019 Mar 25.

Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.

Background: Spinocerebellar ataxia type 28 (SCA28) is a dominantly inherited neurodegenerative disease caused by pathogenic variants in The AFG3L2 protein is a subunit of mitochondrial -AAA complexes involved in protein quality control. Objective of this study was to determine the molecular mechanisms of SCA28, which has eluded characterisation to date.

Methods: We derived SCA28 patient fibroblasts carrying different pathogenic variants in the AFG3L2 proteolytic domain (missense: the newly identified p. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105766DOI Listing

Genetic linkage analysis of a large family identifies as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension.

J Med Genet 2019 Mar 20. Epub 2019 Mar 20.

Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Background: Mapping the genetic component of molecular mechanisms responsible for the reduced penetrance (RP) of rare disorders constitutes one of the most challenging problems in human genetics. Heritable pulmonary arterial hypertension (PAH) is one such disorder characterised by rare mutations mostly occurring in the bone morphogenetic protein receptor type 2 () gene and a wide heterogeneity of penetrance modifier mechanisms. Here, we analyse 32 genotyped individuals from a large Iberian family of 65 members, including 22 carriers of the pathogenic mutation c. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105669DOI Listing

Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report.

J Med Genet 2019 Mar 19. Epub 2019 Mar 19.

Molecular Oncology Laboratory CIBERONC, Hospital Clínico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.

Background: monoallelic germ-line variants confer a breast cancer risk comparable to the average pathogenic variant. Recommendations for risk reduction strategies in carriers are similar. Elaborating robust criteria to identify variants in without incurring overprediction-is thus of paramount clinical relevance. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105834DOI Listing
March 2019
5 Reads

Mutations in and cause female infertility characterised by early embryonic arrest.

J Med Genet 2019 Mar 15. Epub 2019 Mar 15.

State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Zhongshan Hospital, School of Life Sciences, Fudan University, Shanghai, China.

Background: Successful human reproduction requires normal spermatogenesis, oogenesis, fertilisation and early embryonic development, and abnormalities in any of these processes will result in infertility. Early embryonic arrest is commonly observed in infertile patients with recurrent failure of assisted reproductive technology (ART). However, the genetic basis for early embryonic arrest is largely unknown. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105936DOI Listing
March 2019
2 Reads

Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome.

J Med Genet 2019 Mar 15. Epub 2019 Mar 15.

Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Background: Patients with colorectal cancer (CRC) with mismatch repair-deficient (dMMR) tumours without methylation or germline MMR pathogenic variants (PV) were previously thought to have Lynch syndrome (LS). It is now appreciated that they can have double somatic (DS) MMR PVs. We explored the clinical characteristics between patients with DS tumours and LS in two population-based cohorts. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105698DOI Listing
March 2019
6.335 Impact Factor

Evidence for heightened genetic instability in precancerous spasmolytic polypeptide expressing gastric glands.

J Med Genet 2019 Mar 15. Epub 2019 Mar 15.

Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.

Background: Spasmolytic polypeptide-expressing metaplasia (SPEM) is present in more than 90% of resected gastric cancer tissues. However, although widely regarded as a pre-cancerous tissue, its genetic characteristics have not been well studied.

Methods: Immunohistochemistry using Trefoil factor 2 (TFF2) antibodies was used to identify TFF2-positive SPEM cells within SPEM glands in the stomach of -infected mice and human clinical samples. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105752DOI Listing
March 2019
1 Read

Review of the scientific evolution of gene therapy for the treatment of homozygous familial hypercholesterolaemia: past, present and future perspectives.

J Med Genet 2019 Mar 15. Epub 2019 Mar 15.

Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, 'Sant Joan' University Hospital, Universitat Rovira i Virgili, Institut de Investigació Sanitaria Pere Virgili (IISPV), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Reus, Spain.

Familial hypercholesterolaemia (FH) is a devastating genetic disease that leads to extremely high cholesterol levels and severe cardiovascular disease, mainly caused by mutations in any of the main genes involved in low-density lipoprotein cholesterol (LDL-C) uptake. Among these genes, mutations in the LDL receptor () are responsible for 80%-90% of the FH cases. The severe homozygous variety (HoFH) is not successfully treated with standard cholesterol-lowering therapies, and more aggressive strategies must be considered to mitigate the effects of this disease, such as weekly/biweekly LDL apheresis. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105713DOI Listing
March 2019
5 Reads

Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma.

J Med Genet 2019 Mar 15. Epub 2019 Mar 15.

Genetics department, Assistance Publique-Hôpitaux de Paris, Hôpitaleuropéen Georges Pompidou, F-75015, Paris, France.

Background: Knowing the genetic status of patients affected by paragangliomas and pheochromocytomas (PPGL) is important for the guidance of their management and their relatives. Our objective was to improve the diagnostic performances of PPGL genetic testing by next-generation sequencing (NGS).

Methods: We developed a custom multigene panel, which includes 17 PPGL genes and is compatible with both germline and tumour DNA screening. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105714DOI Listing
March 2019
1 Read
6.335 Impact Factor

Homozygosity for CHEK2 p.Gly167Arg leads to a unique cancer syndrome with multiple complex chromosomal translocations in peripheral blood karyotype.

J Med Genet 2019 Mar 11. Epub 2019 Mar 11.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

Background: Chromosomal instability, as reflected by structural or copy-number changes, is a known cancer characteristic but are rarely observed in healthy tissue. Mutations in DNA repair genes disrupt the maintenance of DNA integrity and predispose to hereditary cancer syndromes.

Objective: To clinically characterise and genetically diagnose two reportedly unrelated patients with unique cancer syndromes, including multiorgan tumourogenesis (patient 1) and early-onset acute myeloid leukaemia (patient 2), both displaying unique peripheral blood karyotypes. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105824DOI Listing
March 2019
1 Read

Promising member of the short interspersed nuclear elements ( elements): mechanisms and clinical applications in human cancers.

J Med Genet 2019 Mar 9. Epub 2019 Mar 9.

Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.

elements are one of most ubiquitous repetitive sequences in human genome, which were considered as the junk DNA in the past. elements have been found to be associated with human diseases including cancers via events such as amplification, insertion, recombination or RNA editing, which provide a new perspective of oncogenesis at both DNA and RNA levels. Due to the prevalent distribution, elements are widely used as target molecule of liquid biopsy. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105761DOI Listing

polyadenylation signal variants cause syndromic microphthalmia.

J Med Genet 2019 Mar 6. Epub 2019 Mar 6.

National Institutes of Health, National Human Genome Research Institute, Bethesda, Maryland, USA.

Background: A single variant in (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105836DOI Listing

Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing.

J Med Genet 2019 Mar 6. Epub 2019 Mar 6.

Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

Background: Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (). Our objective to investigate the genetic landscape of -negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES). Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105775
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http://dx.doi.org/10.1136/jmedgenet-2018-105775DOI Listing
March 2019
8 Reads

Advances in identification of genes involved in autosomal recessive intellectual disability: a brief review.

J Med Genet 2019 Mar 6. Epub 2019 Mar 6.

Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, India.

Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1%-3% of the general population. The number of ID-causing genes is high. Many X-linked genes have been implicated in ID. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105821DOI Listing
March 2019
1 Read

Genotype-phenotype correlations in ataxia telangiectasia patients with c.3576G>A and c.8147T>C mutations.

J Med Genet 2019 Feb 28. Epub 2019 Feb 28.

Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: Ataxia telangiectasia (A-T) is a neurodegenerative disorder. While patients with classic A-T generally die in their 20s, some patients with variant A-T, who have residual ataxia-telangiectasia mutated (ATM) kinase activity, have a milder phenotype. We noticed two commonly occurring mutations that appeared to be associated with prolonged survival and decided to study patients carrying one of these mutations. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105635DOI Listing
February 2019
1 Read

Parkinson's disease GWAS-linked Park16 carriers show greater motor progression.

J Med Genet 2019 Feb 27. Epub 2019 Feb 27.

Department of Neurology, National Neuroscience Institute, Singapore general hospital campus, Singapore, Singapore.

Background: Data on the long-term motor outcomes of genome-wide association study (GWAS)-linked Parkinson disease (PD) carriers are useful for clinical management.

Objectives: To characterise the association between GWAS-linked PARK16 gene variant and disease progression in PD over a 9-year time frame.

Methods: Over a 9-year period, carriers of PARK16 rs11240572 variant and non-carriers were followed up and evaluated using the modified Hoehn and Yahr (H&Y) staging scale and Unified Parkinson's Disease Rating Scale (UPDRS) part III. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105661DOI Listing
February 2019

Genome-wide meta-analysis identifies genetic locus on chromosome 9 associated with Modic changes.

J Med Genet 2019 Feb 26. Epub 2019 Feb 26.

Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland.

Background: Low back pain (LBP) is a common disabling condition. Lumbar disc degeneration (LDD) may be a contributing factor for LBP. Modic change (MC), a distinct phenotype of LDD, is presented as a pathological bone marrow signal change adjacent to vertebral endplate on MRI. Read More

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http://dx.doi.org/10.1136/jmedgenet-2018-105726DOI Listing
February 2019

Distal chromosome 16p11.2 duplications containing in patients with scoliosis.

J Med Genet 2019 Feb 25. Epub 2019 Feb 25.

Department of Neurology, Division of Pediatric Neurology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.

Introduction: Adolescent idiopathic scoliosis (AIS) is a common musculoskeletal disorder with strong evidence for a genetic contribution. CNVs play an important role in congenital scoliosis, but their role in idiopathic scoliosis has been largely unexplored.

Methods: Exome sequence data from 1197 AIS cases and 1664 in-house controls was analysed using coverage data to identify rare CNVs. Read More

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http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105877
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http://dx.doi.org/10.1136/jmedgenet-2018-105877DOI Listing
February 2019
7 Reads

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, 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
2 Reads

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
2 Reads

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
7 Reads

promoter deletion causes endoactivation and Liebenberg syndrome.

J Med Genet 2019 Apr 2;56(4):246-251. 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

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
6 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
1 Read

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

J Med Genet 2019 Mar 25;56(3):123-130. 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
March 2019
5 Reads

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

J Med Genet 2019 Apr 19;56(4):252-260. 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
April 2019
14 Reads

Clinical spectrum and pleiotropic nature of germline mutations.

J Med Genet 2019 Apr 19;56(4):199-208. 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
April 2019
7 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
5 Reads
6.335 Impact Factor

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
2 Reads

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
3 Reads

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
9 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
2 Reads

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
2 Reads

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

J Med Genet 2019 Mar 19;56(3):186-194. 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
March 2019
4 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 2019 Apr 10;56(4):209-219. 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
April 2019
6 Reads
6.335 Impact Factor

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

J Med Genet 2019 Apr 5;56(4):228-235. 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
April 2019
5 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
2 Reads

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

J Med Genet 2019 Mar 4;56(3):156-163. 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
March 2019
1 Read

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
7 Reads

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

J Med Genet 2019 Mar 28;56(3):164-175. 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
March 2019
7 Reads

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
4 Reads
6.335 Impact Factor