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Journal of Medical Genetics

Ian M Frayling, Victor-Felix Mautner, Rick van Minkelen, Roope A Kallionpaa, Safiye Aktaş, Diana Baralle, Shay Ben-Shachar, Alison Callaway, Harriet Cox, Diana M Eccles, Salah Ferkal, Holly LaDuca, Conxi Lázaro, Mark T Rogers, Aaron J Stuenkel, Pia Summerour, Ali Varan, Yoon Sim Yap, Ouidad Zehou, Juha Peltonen, Gareth D Evans, Pierre Wolkenstein, Meena Upadhyaya
BACKGROUND: Neurofibromatosis type 1 (NF1) predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described. METHODS: Constitutional NF1 mutations in 78 patients with NF1 with BC (NF1-BC) were compared with the NF1 Leiden Open Variation Database (n=3432). RESULTS: No cases were observed with whole or partial gene deletions (HR 0.10; 95% CI 0.006 to 1.63; p=0.014, Fisher's exact test). There were no gross relationships with mutation position...
December 10, 2018: Journal of Medical Genetics
Liam Aspit, Aviva Levitas, Sharon Etzion, Hanna Krymko, Leonel Slanovic, Raz Zarivach, Yoram Etzion, Ruti Parvari
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. METHODS AND RESULTS: Using exome sequencing and searching for rare homozygous variations, we identified a nucleotide change in the donor splice consensus sequence of exon 7 in CAP2 as the causative mutation...
December 5, 2018: Journal of Medical Genetics
Yu-Gang Wang, Dong-Hui Zheng, Min Shi, Xi-Ming Xu
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). METHODS: RNA sequencing was performed to compare the transcriptome of CD8 +T cells isolated from healthy donors' blood, tumour tissues of patients with HCC and chronic HBV infected HCC patients' paracancerous tissues...
December 5, 2018: Journal of Medical Genetics
Jun-Yu Ma, Li-Ying Yan, Zhen-Bo Wang, Shi-Ming Luo, William S B Yeung, Xiang-Hong Ou, Qing-Yuan Sun, Jie Qiao
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. OBJECTIVE: To assess meiotic chromatid recombination and segregation in human oocytes...
December 4, 2018: Journal of Medical Genetics
Margaret P Adam, Siddharth Banka, Hans T Bjornsson, Olaf Bodamer, Albert E Chudley, Jaqueline Harris, Hiroshi Kawame, Brendan C Lanpher, Andrew W Lindsley, Giuseppe Merla, Noriko Miyake, Nobuhiko Okamoto, Constanze T Stumpel, Norio Niikawa
BACKGROUND: Kabuki syndrome (KS) is a clinically recognisable syndrome in which 70% of patients have a pathogenic variant in KMT2D or KDM6A . 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. METHODS: An international group of experts created consensus diagnostic criteria for KS. Systematic PubMed searches returned 70 peer-reviewed publications in which at least one individual with molecularly confirmed KS was reported...
December 4, 2018: Journal of Medical Genetics
Noomi Mueller, Takayuki Sassa, Susanne Morales-Gonzalez, Joanna Schneider, Daniel J Salchow, Dominik Seelow, Ellen Knierim, Werner Stenzel, Akio Kihara, Markus Schuelke
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 ELOVL1 mutation. Independently, Kutkowska-Kaźmierczak et al. had investigated the same patients and found the same mutation. We extended our study towards additional biochemical, functional, and therapeutic aspects. METHODS: We did mutation screening by whole exome sequencing...
November 28, 2018: Journal of Medical Genetics
Abolfazl Rad, Umut Altunoglu, Rebecca Miller, Reza Maroofian, Kiely N James, Ahmet Okay Çağlayan, Maryam Najafi, Valentina Stanley, Rose-Mary Boustany, Gözde Yeşil, Afsaneh Sahebzamani, Gülhan Ercan-Sencicek, Kolsoum Saeidi, Kaman Wu, Peter Bauer, Zeineb Bakey, Joseph G Gleeson, Natalie Hauser, Murat Gunel, Hulya Kayserili, Miriam Schmidts
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 MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism...
November 28, 2018: Journal of Medical Genetics
Samin A Sajan, Jaya Ganesh, Deepali N Shinde, Zöe Powis, Maria I Scarano, Jennifer Stone, Susan Winter, Sha Tang
BACKGROUND: During mouse embryonic development the protein kinase domain containing, cytoplasmic ( Pkdcc ) gene, also known as Vlk, is expressed in several tissues including the ventral midbrain, with particularly strong expression in branchial arches and limb buds. Homozygous Pkdcc knockout mice have dysmorphic features and shortened long bones as the most obvious morphological abnormalities. The human PKDCC gene has currently not been associated with any disorders. OBJECTIVE: To use clinical diagnostic exome sequencing (DES) for providing genetic diagnoses to two apparently unrelated patients with similar skeletal abnormalities comprising rhizomelic shortening of limbs and dysmorphic features...
November 26, 2018: Journal of Medical Genetics
Gemma Montalban, Sandra Bonache, Alejandro Moles-Fernández, Alexandra Gisbert-Beamud, Anna Tenés, Vanessa Bach, Estela Carrasco, Adrià López-Fernández, Neda Stjepanovic, Judith Balmaña, Orland Diez, Sara Gutiérrez-Enríquez
BACKGROUND: Genetic analysis of BRCA1 and BRCA2 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 BRCA1/2 deep intronic regions to identify potential spliceogenic variants that could explain part of the missing HBOC susceptibility. METHODS: We analysed BRCA1/2 deep intronic regions by targeted gene sequencing in 192 high-risk HBOC families testing negative for BRCA1/2 during conventional analysis...
November 24, 2018: Journal of Medical Genetics
(no author information available yet)
No abstract text is available yet for this article.
November 22, 2018: Journal of Medical Genetics
Daniel Halperin, Rotem Kadir, Yonatan Perez, Max Drabkin, Yuval Yogev, Ohad Wormser, Erez M Berman, Ekaterina Eremenko, Barak Rotblat, Zamir Shorer, Libe Gradstein, Ilan Shelef, Ruth Birk, Uri Abdu, Hagit Flusser, Ohad S Birk
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. We aimed at elucidating the molecular basis of this disease...
November 21, 2018: Journal of Medical Genetics
An-Liang Xia, Yong Xu, Xiao-Jie Lu
No abstract text is available yet for this article.
November 21, 2018: Journal of Medical Genetics
Antonio Martinez-Monseny, Daniel Cuadras, Mercè Bolasell, Jordi Muchart, César Arjona, Mar Borregan, Adi Algrabli, Raquel Montero, Rafael Artuch, Ramón Velázquez-Fragua, Alfons Macaya, Celia Pérez-Cerdá, Belén Pérez-Dueñas, Belén Pérez, Mercedes Serrano
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. METHODS: Paediatric PMM2-CDG patients were evaluated and compared with controls...
November 21, 2018: Journal of Medical Genetics
Holger Langhof, Johannes Schwietering, Daniel Strech
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. In order to fully meet its goal, every governance solution needs to be implemented, evaluated and, if necessary, adapted and improved in practice...
November 21, 2018: Journal of Medical Genetics
Xiaojin He, Weiyu Li, Huan Wu, Mingrong Lv, Wangjie Liu, Chunyu Liu, Fuxi Zhu, Caihua Li, Youyan Fang, Chenyu Yang, Huiru Cheng, Junqiang Zhang, Jing Tan, Tingting Chen, Dongdong Tang, Bing Song, Xue Wang, Xiaomin Zha, Hongyan Wang, Zhaolian Wei, Shenmin Yang, Hexige Saiyin, Ping Zhou, Li Jin, Jian Wang, Zhiguo Zhang, Feng Zhang, Yunxia Cao
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. Previous studies on MMAF reported that genetic defects in cilia-related genes (eg, AKAP4 , DNAH1 , CFAP43 , CFAP44 and CFAP69 ) are the major cause of MMAF...
November 10, 2018: Journal of Medical Genetics
Vincenzo Lupo, Marina Frasquet, Ana Sánchez-Monteagudo, Ana Lara Pelayo-Negro, Tania García-Sobrino, María José Sedano, Julio Pardo, Mercedes Misiego, Jorge García-García, María Jesús Sobrido, María Dolores Martínez-Rubio, María José Chumillas, Juan Jesús Vílchez, Juan Francisco Vázquez-Costa, Carmen Espinós, Teresa Sevilla
BACKGROUND: Mutations in the metalloendopeptidase ( MME ) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME 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 MME . METHODS: We screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes...
November 10, 2018: Journal of Medical Genetics
Jee-Soo Lee, Sohee Oh, Sue Kyung Park, Min-Hyuk Lee, Jong Won Lee, Sung-Won Kim, Byung Ho Son, Dong-Young Noh, Jeong Eon Lee, Hai-Lin Park, Man Jin Kim, Sung Im Cho, Young Kyung Lee, Sung Sup Park, Moon-Woo Seong
BACKGROUND: BRCA1 and BRCA2 ( BRCA1/2 ) 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 BRCA1/2 -targeted agents is uncertain. To minimise the proportion of VUS in BRCA1/2 , we performed the multifactorial likelihood analysis and validated this method using an independent cohort of patients with breast cancer...
November 10, 2018: Journal of Medical Genetics
Manon Suerink, Tim Ripperger, Ludwine Messiaen, Fred H Menko, Franck Bourdeaut, Chrystelle Colas, Marjolijn Jongmans, Yael Goldberg, Maartje Nielsen, Martine Muleris, Mariëtte van Kouwen, Irene Slavc, Christian Kratz, Hans F Vasen, Laurence Brugiѐres, Eric Legius, Katharina Wimmer
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 NF1 / SPRED1 germline mutation...
November 10, 2018: Journal of Medical Genetics
Angelo M Taveira-DaSilva, Thomas C Markello, David E Kleiner, Amanda M Jones, Catherine Groden, Ellen Macnamara, Tadafumi Yokoyama, William A Gahl, Bernadette R Gochuico, Joel Moss
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.698 G>A, p.Arg233His) in COPA was identified in four members of a three-generation kindred with lung, autoimmune and malignant disease of unknown aetiology...
November 1, 2018: Journal of Medical Genetics
Iris M de Lange, Marco J Koudijs, Ruben van 't Slot, Anja C M Sonsma, Flip Mulder, Ellen C Carbo, Marjan J A van Kempen, Isaac J Nijman, Robert F Ernst, Sanne M C Savelberg, Nine V A M Knoers, Eva H Brilstra, Bobby P C Koeleman
BACKGROUND: Dravet syndrome is a severe genetic encephalopathy, caused by pathogenic variants in SCN1A. 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 SCN1A variants in a cohort of 90 families and assess the feasibility of this technique...
October 27, 2018: Journal of Medical Genetics
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