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Journal of Medical Genetics

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https://read.qxmd.com/read/30894412/genetic-linkage-analysis-of-a-large-family-identifies-fign-as-a-candidate-modulator-of-reduced-penetrance-in-heritable-pulmonary-arterial-hypertension
#1
Pau Puigdevall, Lucilla Piccari, Isabel Blanco, Joan Albert Barberà, Dan Geiger, Celia Badenas, Montserrat Milà, Robert Castelo, Irene Madrigal
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 ( BMPR2 ) 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 BMPR2 mutation c...
March 20, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30890586/alternative-splicing-and-acmg-amp-2015-based-classification-of-palb2-genetic-variants-an-enigma-report
#2
Irene Lopez-Perolio, Raphaël Leman, Raquel Behar, Vanessa Lattimore, John F Pearson, Laurent Castéra, Alexandra Martins, Dominique Vaur, Nicolas Goardon, Grégoire Davy, Pilar Garre, Vanesa García-Barberán, Patricia Llovet, Pedro Pérez-Segura, Eduardo Díaz-Rubio, Trinidad Caldés, Kathleen S Hruska, Vickie Hsuan, Sitao Wu, Tina Pesaran, Rachid Karam, Johan Vallon-Christersson, Ake Borg, kConFab Investigators, Alberto Valenzuela-Palomo, Eladio Andrés Velasco, Melissa Southey, Maaike P G Vreeswijk, Peter Devilee, Anders Kvist, Amanda B Spurdle, Logan C Walker, Sophie Krieger, Miguel de la Hoya
BACKGROUND: PALB2 monoallelic loss-of-function germ-line variants confer a breast cancer risk comparable to the average BRCA2 pathogenic variant. Recommendations for risk reduction strategies in carriers are similar. Elaborating robust criteria to identify loss-of-function variants in PALB2- without incurring overprediction-is thus of paramount clinical relevance. Towards this aim, we have performed a comprehensive characterisation of alternative splicing in PALB2 , analysing its relevance for the classification of truncating and splice site variants according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines...
March 19, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30877238/mutations-in-nlrp2-and-nlrp5-cause-female-infertility-characterised-by-early-embryonic-arrest
#3
Jian Mu, Wenjing Wang, Biaobang Chen, Ling Wu, Bin Li, Xiaoyan Mao, Zhihua Zhang, Jing Fu, Yanping Kuang, Xiaoxi Sun, Qiaoli Li, Li Jin, Lin He, Qing Sang, Lei Wang
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. OBJECTIVE: We aim to identify genetic causes of infertile patients characterised by early embryonic arrest...
March 15, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30877237/clinical-characteristics-of-patients-with-colorectal-cancer-with-double-somatic-mismatch-repair-mutations-compared-with-lynch-syndrome
#4
Rachel Pearlman, Sigurdis Haraldsdottir, Albert de la Chapelle, Jon G Jonasson, Sandya Liyanarachchi, Wendy L Frankel, Thorunn Rafnar, Kari Stefansson, Colin C Pritchard, Heather Hampel
BACKGROUND: Patients with colorectal cancer (CRC) with mismatch repair-deficient (dMMR) tumours without MLH1 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. METHODS: We included patients with CRC from Ohio 2013-2016 and Iceland 2000-2009...
March 15, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30877236/evidence-for-heightened-genetic-instability-in-precancerous-spasmolytic-polypeptide-expressing-gastric-glands
#5
Jiangrong Chen, Chunchao Zhu, Chaojie Wang, Chuansheng Hu, Daniel M Czajkowsky, Yan Guo, Bingya Liu, Zhifeng Shao
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 Helicobacter felis (H. felis) -infected mice and human clinical samples...
March 15, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30877235/review-of-the-scientific-evolution-of-gene-therapy-for-the-treatment-of-homozygous-familial-hypercholesterolaemia-past-present-and-future-perspectives
#6
Ricardo Rodriguez-Calvo, Luis Masana
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 ( LDLR ) 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...
March 15, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30877234/targeted-next-generation-sequencing-detects-rare-genetic-events-in-pheochromocytoma-and-paraganglioma
#7
Laurène Ben Aim, Pascal Pigny, Luis Jaime Castro-Vega, Alexandre Buffet, Laurence Amar, Jérôme Bertherat, Delphine Drui, Isabelle Guilhem, Eric Baudin, Charlotte Lussey-Lepoutre, Carole Corsini, Gérard Chabrier, Claire Briet, Laurence Faivre, Catherine Cardot-Bauters, Judith Favier, Anne-Paule Gimenez-Roqueplo, Nelly Burnichon
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. The NGS assay was first validated in a retrospective cohort of 201 frozen tumour DNAs and then applied prospectively to 623 DNAs extracted from leucocytes, frozen or paraffin-embedded PPGL tumours...
March 15, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30858171/homozygosity-for-chek2-p-gly167arg-leads-to-a-unique-cancer-syndrome-with-multiple-complex-chromosomal-translocations-in-peripheral-blood-karyotype
#8
Tamar Paperna, Nitzan Sharon-Shwartzman, Alina Kurolap, Yael Goldberg, Nivin Moustafa, Yariv Carasso, Miora Feinstien, Adi Mory, Gili Reznick-Levi, Claudia Gonzaga-Jauregui, Alan R Shuldiner, Lina Basel-Salmon, Yishai Ofran, Elizabeth E Half, Hagit Baris Feldman
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...
March 11, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30852527/promising-member-of-the-short-interspersed-nuclear-elements-alu-elements-mechanisms-and-clinical-applications-in-human-cancers
#9
Yun Jiang, Wei Zong, Shaoqing Ju, Rongrong Jing, Ming Cui
Alu elements are one of most ubiquitous repetitive sequences in human genome, which were considered as the junk DNA in the past. Alu 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, Alu elements are widely used as target molecule of liquid biopsy. Alu -based cell-free DNA shows feasible application value in tumour diagnosis, postoperative monitoring and adjuvant therapy...
March 9, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30842225/-naa10-polyadenylation-signal-variants-cause-syndromic-microphthalmia
#10
Jennifer J Johnston, Kathleen A Williamson, Christopher M Chou, Julie C Sapp, Morad Ansari, Heather M Chapman, David N Cooper, Tabib Dabir, Jeffrey N Dudley, Richard J Holt, Nicola K Ragge, Alejandro A Schäffer, Shurjo K Sen, Anne M Slavotinek, David R FitzPatrick, Thomas M Glaser, Fiona Stewart, Graeme Cm Black, Leslie G Biesecker
BACKGROUND: A single variant in NAA10 (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. METHODS: Three families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in NAA10 were evaluated using quantitative PCR and RNAseq...
March 6, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30842224/genetic-landscape-of-rett-syndrome-like-phenotypes-revealed-by-whole-exome-sequencing
#11
Kazuhiro Iwama, Takeshi Mizuguchi, Eri Takeshita, Eiji Nakagawa, Tetsuya Okazaki, Yoshiko Nomura, Yoshitaka Iijima, Ichiro Kajiura, Kenji Sugai, Takashi Saito, Masayuki Sasaki, Kotaro Yuge, Tomoko Saikusa, Nobuhiko Okamoto, Satoru Takahashi, Masano Amamoto, Ichiro Tomita, Satoko Kumada, Yuki Anzai, Kyoko Hoshino, Aviva Fattal-Valevski, Naohide Shiroma, Masaharu Ohfu, Masaharu Moroto, Koichi Tanda, Tomoko Nakagawa, Takafumi Sakakibara, Shin Nabatame, Muneaki Matsuo, Akiko Yamamoto, Shoko Yukishita, Ken Inoue, Chikako Waga, Yoko Nakamura, Shoko Watanabe, Chihiro Ohba, Toru Sengoku, Atsushi Fujita, Satomi Mitsuhashi, Satoko Miyatake, Atsushi Takata, Noriko Miyake, Kazuhiro Ogata, Shuichi Ito, Hirotomo Saitsu, Toyojiro Matsuishi, Yu-Ichi Goto, Naomichi Matsumoto
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 ( MECP2 ). Our objective to investigate the genetic landscape of MECP2 -negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES). METHODS: We performed WES on 77 MECP2 -negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria...
March 6, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30842223/advances-in-identification-of-genes-involved-in-autosomal-recessive-intellectual-disability-a-brief-review
#12
Yaser Rafiq Mir, Raja Amir Hassan Kuchay
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. Autosomal dominant genes have recently been the focus of several large-scale studies. The total number of autosomal recessive ID (ARID) genes is estimated to be very high, and most are still unknown. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause ARID has lagged behind, predominantly due to non-availability of sizeable families...
March 6, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30819809/genotype-phenotype-correlations-in-ataxia-telangiectasia-patients-with-atm-c-3576g-a-and-c-8147t-c-mutations
#13
Nienke J H van Os, Luciana Chessa, Corry M R Weemaes, Marcel van Deuren, Alice Fiévet, Judith van Gaalen, Nizar Mahlaoui, Nel Roeleveld, Christoph Schrader, Detlev Schindler, Alexander M R Taylor, Bart P C Van de Warrenburg, Thilo Dörk, Michèl A A P Willemsen
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 ATM mutations that appeared to be associated with prolonged survival and decided to study patients carrying one of these mutations. METHODS: Data were retrospectively collected from the Dutch, Italian, German and French A-T cohorts...
February 28, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30814270/parkinson-s-disease-gwas-linked-park16-carriers-show-greater-motor-progression
#14
Xiao Deng, Bin Xiao, John Carson Allen, Ebonne Ng, Jia Nee Foo, Yew-Long Lo, Louis C S Tan, Eng-King Tan
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...
February 27, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30808802/genome-wide-meta-analysis-identifies-genetic-locus-on-chromosome-9-associated-with-modic-changes
#15
Maxim Freidin, Minna Kraatari, Sini Skarp, Juhani Määttä, Johannes Kettunen, Jaakko Niinimäki, Jaro Karppinen, Frances Williams, Minna Männikkö
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. It is strongly associated with LBP and has heritability around 30%. Our objective was to identify genetic loci associated with MC using a genome-wide meta-analysis. METHODS: Presence of MC was evaluated in lumbar MRI in the Northern Finland Birth Cohort 1966 (n=1182) and TwinsUK (n=647)...
February 26, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30803986/distal-chromosome-16p11-2-duplications-containing-sh2b1-in-patients-with-scoliosis
#16
Brooke Sadler, Gabe Haller, Lilian Antunes, Xavier Bledsoe, Jose Morcuende, Philip Giampietro, Cathleen Raggio, Nancy Miller, Yared Kidane, Carol A Wise, Ina Amarillo, Nephi Walton, Mark Seeley, Darren Johnson, Conner Jenkins, Troy Jenkins, Matthew Oetjens, R Spencer Tong, Todd E Druley, Matthew B Dobbs, Christina A Gurnett
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. CNV calls were filtered to include only highly confident CNVs with >10 average reads per region and mean log-ratio of coverage consistent with single-copy duplication or deletion...
February 25, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30745424/natural-history-of-renal-tumours-in-von-hippel-lindau-disease-a-large-retrospective-study-of-chinese-patients
#17
Xiang Peng, Jinchao Chen, Jiangyi Wang, Shuanghe Peng, Shengjie Liu, Kaifang Ma, Jingcheng Zhou, Baoan Hong, Bowen Zhou, Jiufeng Zhang, Lin Cai, Kan Gong
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. METHODS: In this retrospective study, we included 196 renal tumours from 150 patients with VHL disease...
February 11, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30745423/contribution-of-spurious-transcription-to-intellectual-disability-disorders
#18
Marilyn Scandaglia, Angel Barco
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...
February 11, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30745422/associations-of-cdh1-germline-variant-location-and-cancer-phenotype-in-families-with-hereditary-diffuse-gastric-cancer-hdgc
#19
Winifred Lo, Bin Zhu, Arvind Sabesan, Ho-Hsiang Wu, Astin Powers, Rebecca A Sorber, Sarangan Ravichandran, Ina Chen, Lucas A McDuffie, Humair S Quadri, Joal D Beane, Kathleen Calzone, Markku M Miettinen, Stephen M Hewitt, Christopher Koh, Theo Heller, Sholom Wacholder, Udo Rudloff
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. METHODS: One hundred and fifty-two HDGC families, including six previously unreported families, were identified...
February 11, 2019: Journal of Medical Genetics
https://read.qxmd.com/read/30728173/genetic-diagnosis-of-subfertility-the-impact-of-meiosis-and-maternal-effects
#20
Alexander Gheldof, Deborah J G Mackay, Ying Cheong, Willem Verpoest
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. Idiopathic infertility patients with a suspicion of an underlying genetic cause can be expected to have mutations in genes that do not readily affect general health but are only essential in certain processes connected to fertility...
February 6, 2019: Journal of Medical Genetics
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