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European Journal of Medical Genetics

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https://www.readbyqxmd.com/read/28645800/high-throughput-sequencing-of-the-entire-genomic-regions-of-ccm1-krit1-ccm2-and-ccm3-pdcd10-to-search-for-pathogenic-deep-intronic-splice-mutations-in-cerebral-cavernous-malformations
#1
Matthias Rath, Sönke E Jenssen, Konrad Schwefel, Stefanie Spiegler, Dana Kleimeier, Christian Sperling, Lars Kaderali, Ute Felbor
Cerebral cavernous malformations (CCM) are vascular lesions of the central nervous system that can cause headaches, seizures and hemorrhagic stroke. Disease-associated mutations have been identified in three genes: CCM1/KRIT1, CCM2 and CCM3/PDCD10. The precise proportion of deep-intronic variants in these genes and their clinical relevance is yet unknown. Here, a long-range PCR (LR-PCR) approach for target enrichment of the entire genomic regions of the three genes was combined with next generation sequencing (NGS) to screen for coding and non-coding variants...
June 20, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28645799/genotype-phenotype-evaluation-of-med13l-defects-in-the-light-of-a-novel-truncating-and-a-recurrent-missense-mutation
#2
Reza Asadollahi, Markus Zweier, Laura Gogoll, Raphael Schiffmann, Heinrich Sticht, Katharina Steindl, Anita Rauch
A decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextro-looped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation...
June 20, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28642162/ngs-panel-analysis-in-24-ectopia-lentis-patients-a-clinically-relevant-test-with-a-high-diagnostic-yield
#3
E Overwater, K Floor, D van Beek, K de Boer, T van Dijk, Y Hilhorst-Hofstee, A J M Hoogeboom, K J van Kaam, J M van de Kamp, M Kempers, I P C Krapels, H Y Kroes, B Loeys, S Salemink, C T R M Stumpel, V J M Verhoeven, E Wijnands-van den Berg, J M Cobben, J P van Tintelen, M M Weiss, A C Houweling, A Maugeri
BACKGROUND: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. OBJECTIVE: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients...
June 19, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28642161/digenic-inheritance-of-mutations-in-the-cardiac-troponin-tnnt2-and-cardiac-beta-myosin-heavy-chain-myh7-as-the-cause-of-severe-dilated-cardiomyopathy
#4
Evmorfia Petropoulou, Mohammadhossein Soltani, Ali Dehghani Firoozabadi, Seyedeh Mahdieh Namayandeh, Jade Crockford, Reza Maroofian, Yalda Jamshidi
Familial dilated cardiomyopathy (DCM) is characterized by ventricular dilation and depressed myocardial performance. It is a genetically heterogeneous disorder associated with mutations in over 60 genes. We carried out whole exome sequencing in combination with cardiomyopathy-related gene-filtering on two affected family members to identify the possible causative mutation in a consanguineous Iranian family with DCM. Two novel variants in cardiomyopathy-related genes were identified: c.247 A > C; p.N83H in the Troponin T Type 2 gene (TNNT2) and c...
June 19, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28642160/a-novel-missense-variant-gln220arg-of-gnb4-encoding-guanine-nucleotide-binding-protein-subunit-beta-4-in-a-japanese-family-with-autosomal-dominant-motor-and-sensory-neuropathy
#5
Shiroh Miura, Takuya Morikawa, Ryuta Fujioka, Kazuhito Noda, Kengo Kosaka, Takayuki Taniwaki, Hiroki Shibata
Dominant intermediate Charcot-Marie-Tooth disease F (CMTDIF) is an autosomal dominant hereditary form of Charcot-Marie-Tooth disease (CMT) caused by variations in the guanine nucleotide-binding protein, subunit beta-4 gene (GNB4). We examined two Japanese familial cases with CMT. Case 1 was a 49-year-old male whose chief complaint was slowly progressive gait disturbance and limb dysesthesia that appeared at the age of 47. On neurological examination, he showed hyporeflexia or areflexia, distal limb muscle weakness, and distal sensory impairment with lower dominancy...
June 19, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28602933/familial-epilepsy-with-anterior-polymicrogyria-as-a-presentation-of-col18a1-mutations
#6
Mark A Corbett, Samantha J Turner, Alison Gardner, Jeremy Silver, Jim Stankovich, Richard J Leventer, Christopher P Derry, Renée Carroll, Thuong Ha, Ingrid E Scheffer, Melanie Bahlo, Graeme D Jackson, David A Mackey, Samuel F Berkovic, Jozef Gecz
Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1. Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made...
June 8, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28602932/postzygotic-telomere-capture-causes-segmental-upd-duplication-and-deletion-of-chromosome-8p-in-a-patient-with-intellectual-disability-and-obesity
#7
Jeroen Knijnenburg, Madiek E W Uytdewilligen, Daniella A C M van Hassel, Rianne Oostenbrink, Bert H J Eussen, Annelies de Klein, Alice S Brooks, Laura J C M van Zutven
Using SNP array and FISH analysis, a patient with moderate intellectual disability and obesity was found to harbour an atypical 1.6 Mb inverted duplication on 8p23.1, directly flanked by a distally located interstitial deletion of 2.3 Mb and a terminal segmental uniparental disomy. The duplicated and deleted regions lie exactly between the two segmental duplication regions. These segmental duplications on chromosome 8p23.1 are known to be involved in chromosomal rearrangements because of mutual homology and homology to other genomic regions...
June 8, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28602931/pachydermoperiostosis-of-the-complete-type-a-novel-missense-mutation-c-101t%C3%A2-%C3%A2-c-in-the-slco2a1-gene
#8
Wenbin Ma, Shuqin Guo, Yan Li, Zhihong Li
We report on a rare case of pachydermoperiostosis (PDP) in a 25-year-old male who was admitted to our hospital because of enlargement of fingers and toes. Through examination, we found some typical features on the patient including finger clubbing, periostosis, pachydermia, and cutis verticis gyrata (CVG). But laboratory tests were almost within normal ranges, which ruled out rheumatic arthritis, osteopulmonary arthropathy, thyroid acropathy, and acromegaly. Then, we diagnosed this case as PDP, which was confirmed by gene sequencing...
June 8, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28576691/recurrent-elevated-liver-transaminases-and-acute-liver-failure-in-two-siblings-with-novel-bi-allelic-mutations-of-nbas
#9
Frederico S Regateiro, Serkan Belkaya, Nélson Neves, Sandra Ferreira, Paula Silvestre, Sónia Lemos, Margarida Venâncio, Jean-Laurent Casanova, Isabel Gonçalves, Emmanuelle Jouanguy, Luísa Diogo
BACKGROUND: Acute liver failure (ALF) in children can be life-threatening. Although many causes are known, ALF remains unexplained in about half of the cases. Recently, bi-allelic mutations in NBAS were reported to underlie recurrent episodes of elevated liver transaminases (ELT) and ALF in the context of diverse extrahepatic phenotypes. RESULTS: We here describe two sisters, born to non-consanguineous Portuguese parents, who had short stature and presented with recurrent episodes of severe ELT triggered by febrile respiratory viral infections from early childhood...
May 30, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28559208/novel-splice-mutation-in-lrp4-causes-severe-type-of-cenani-lenz-syndactyly-syndrome-with-oro-facial-and-skeletal-symptoms
#10
Muhammad Afzal, Qamar Zaman, Uwe Kornak, Stefan Mundlos, Sajid Malik, Ricarda Flöttmann
Cenani-Lenz syndactyly syndrome (CLSS; MIM-212780) is a rare autosomal recessive limb malformation characterized by complete osseous fusion of all fingers and toes, disorganization of phalangeal elements and severe shortening of the radius and ulna. It is occasionally associated with renal hypoplasia, oro-facial defects, scoliosis of the thoracic spine, hearing loss, and genital anomalies. Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly and disorganization of fingers, oligo-syndactyly of toes, shortening of limbs, frontal bossing, and hypoplasia/agenesis of left kidney...
May 27, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28554868/a-novel-deletion-of-snurf-snrpn-exon-1-in-a-patient-with-prader-willi-like-phenotype
#11
Yang Cao, Susan S AlHumaidi, Eissa A Faqeih, Beth A Pitel, Patrick Lundquist, Umut Aypar
Here we report the smallest deletion involving SNURF/SNRPN that causes major symptoms of Prader-Willi syndrome (PWS), including hypotonia, dysmorphic features, intellectual disability, and obesity. A female patient with the aforementioned and additional features was referred to the Mayo Clinic Cytogenetics laboratory for genetic testing. Chromosomal microarray analysis and subsequent Sanger sequencing identified a de novo 6.4 kb deletion at 15q11.2, containing exon 1 of the SNURF gene and exon 1 of the shortest isoform of the SNRPN gene...
May 26, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28528193/novel-missense-loss-of-function-mutations-of-wnt1-in-an-autosomal-recessive-osteogenesis-imperfecta-patient
#12
Joon Yeon Won, Woo Young Jang, Hye-Ran Lee, Seon Young Park, Woo-Young Kim, Jong Hoon Park, Yonghwan Kim, Tae-Joon Cho
Osteogenesis imperfecta (OI) is a heritable skeletal disorder characterized by bone fragility and low bone mass. Recently, loss-of-function mutations of WNT1 have been reported to be causative in OI or osteoporosis. We report an OI patient with novel compound heterozygous WNT1 missense mutations, p.Glu123Asp and p.Cys153Gly. Both mutations are found in the exon 3, and the p.Glu123Asp is the most proximal N-terminus missense mutation among the reported WNT1 missense mutations in OI patients. In vitro functional analysis reveals that while expression of wildtype WNT1 stimulates canonical WNT1-mediated β-catenin signaling, that of individual WNT1 mutant fails to do so, indicative of the pathogenic nature of the WNT1 variants...
May 17, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28501562/a-joint-venture-model-of-recontacting-in-clinical-genomics-challenges-for-responsible-implementation
#13
Sandi Dheensa, Daniele Carrieri, Susan Kelly, Angus Clarke, Shane Doheny, Peter Turnpenny, Anneke Lucassen
Advances in genomics often lead healthcare professionals (HCPs) to learn new information, e.g., about reinterpreted variants that could have clinical significance for patients seen previously. A question arises of whether HCPs should recontact these former patients. We present some findings interrogating the views of patients (or parents of patients) with a rare or undiagnosed condition about how such recontacting might be organised ethically and practically. Forty-one interviews were analysed thematically...
May 10, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28473268/the-congenital-great-toe-malformation-of-fibrodysplasia-ossificans-progressiva-a-close-call
#14
O Will Towler, Eileen M Shore, Meiqi Xu, Abbey Bamford, Ilse Anderson, Robert J Pignolo, Frederick S Kaplan
BACKGROUND: Congenital bilateral hallux valgus with associated absence or fusion of the interphalangeal joint is a classic diagnostic feature of fibrodysplasia ossificans progressiva (FOP), a human genetic disease of extra-skeletal bone formation caused in nearly all cases by a gain-of-function mutation in Activin A Receptor I/Activin-like Kinase 2 (ACVR1/ALK2), which encodes a bone morphogenetic protein (BMP) Type 1 receptor. This toe malformation prompts the suspicion of FOP even before the appearance of extra-skeletal bone...
May 1, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28455154/fetal-costello-syndrome-with-neuromuscular-spindles-excess-and-p-gly12val-hras-mutation
#15
LETTER
Chloé Quélin, Philippe Loget, Céline Rozel, Dominique D'Hervé, Mélanie Fradin, Florence Demurger, Sylvie Odent, Laurent Pasquier, Hélène Cavé, Pascale Marcorelles
Costello syndrome (CS) is a rare multiple congenital disorder caused by activating germline mutations in HRAS gene and is characterized by coarse facial features, severe feeding difficulties, failure to thrive, mild to severe intellectual disability, severe postnatal growth retardation, cardiac abnormalities or cancer predisposition. Phenotypic spectrum associated with HRAS mutations is broad, ranging from attenuated CS phenotype to neonatal and lethal forms with limited genotype-phenotype correlations. Congenital myopathy with neuromuscular spindle excess has been rarely described in the literature...
April 25, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28442439/marshall-smith-syndrome-novel-pathogenic-variant-and-previously-unreported-associations-with-precocious-puberty-and-aortic-root-dilatation
#16
Anjali Aggarwal, Joanne Nguyen, Michelle Rivera-Davila, David Rodriguez-Buritica
Marshall-Smith Syndrome (MRSHSS) is a very rare genetic disorder characterized by failure to thrive and characteristic dysmorphic features associated with accelerated osseous maturation. We present a nine-year-old girl who was diagnosed with MRSHSS based on characteristic clinical features supported by the identification of a novel de novo pathogenic variant in the NFIX gene. The patient also presented with precocious puberty diagnosed at five years of age and had an abnormal GnRH stimulation test indicative of central precocious puberty...
April 24, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28434922/association-of-autoimmune-thyroiditis-and-celiac-disease-with-juvenile-polyposis-due-to-10q23-1q23-31-deletion-potential-role-of-pi3k-akt-pathway-dysregulation
#17
Federica Guaraldi, Giovanni Di Nardo, Luigi Tarani, Luca Bertelli, Francesco Claudio Susca, Rosanna Bagnulo, Nicoletta Resta
Juvenile Polyposis (JP) is a rare hereditary condition characterized by diffuse hamartomatous gastrointestinal polyposis, associated with a significantly increased risk of neoplastic transformation. Most of the cases are caused by SMAD and BMPR1A mutations, while 10q23 microdeletions, encompassing both PTEN and BMPR1A oncogenes, are extremely rare, typically associated with more aggressive JP, and extraintestinal features overlapping with PTEN Hamartoma Tumor Syndrome. We present the first case of a young female with multiple autoimmune disorders (i...
April 18, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28434921/identification-of-a-novel-and-functional-mutation-in-the-tbx5-gene-in-a-patient-by-screening-from-354-patients-with-isolated-ventricular-septal-defect
#18
Huan-Xin Chen, Xi Zhang, Hai-Tao Hou, Jun Wang, Qin Yang, Xiu-Li Wang, Guo-Wei He
Ventricular septal defect (VSD) is the most frequently occurring congenital heart disease in newborns. A number of genetic studies have linked TBX5 mutations to cardiac abnormalities. We aimed to identify potential pathogenic mutations in TBX5 and to provide insights into the etiology of sporadic and isolated VSD. Case-control mutational and functional analyses were performed in 354 sporadic patients with isolated VSD and 341 controls. All the coding exons and intron-exon boundaries of TBX5 were first sequenced in a group of VSD patients and controls...
April 18, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28419882/novel-homozygous-fancl-mutation-and-somatic-heterozygous-setbp1-mutation-in-a-chinese-girl-with-fanconi-anemia
#19
Weiqing Wu, Yang Liu, Qinghua Zhou, Qin Wang, Fuwei Luo, Zhiyong Xu, Qian Geng, Peining Li, Hui Z Zhang, Jiansheng Xie
Fanconi Anemia (FA) is a rare genetically heterogeneous disorder with 17 known complement groups caused by mutations in different genes. FA complementation group L (FA-L, OMIM #608111) occurred in 0.2% of all FA and only eight mutant variants in the FANCL gene were documented. Phenotype and genotype correlation in FANCL associated FA is still obscure. Here we describe a Chinese girl with FA-L caused by a novel homozygous mutation c.822_823insCTTTCAGG (p.Asp275LeufsX13) in the FANCL gene. The patient's clinical course was typical for FA with progression to bone marrow failure, and death from acute myelomonocytic leukemia (AML-M4) at 9 years of age...
April 15, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28414188/a-case-of-splenomegaly-in-cbl-syndrome
#20
Rachel R Coe, Margaret L McKinnon, Maja Tarailo-Graovac, Colin J Ross, Wyeth W Wasserman, Jan M Friedman, Paul C Rogers, Clara D M van Karnebeek
INTRODUCTION: We present a child with unexplained splenomegaly to highlight this feature as a presenting sign of the RASopathy CBL syndrome and to draw attention to the power and utility of next generation genomic sequencing for providing rapid diagnosis and critical information to guide care in the pediatric clinical setting. CLINICAL REPORT: A 7-year-old boy presented with unexplained splenomegaly, attention deficit hyperactivity disorder, mild learning difficulties, easy bruising, mild thrombocytopenia, and subtle dysmorphic features...
April 13, 2017: European Journal of Medical Genetics
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