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European Journal of Medical Genetics

Eugenio Zapata-Aldana, David Dongkyung Kim, Salma Remtulla, Chitra Prasad, Cam-Tu Nguyen, Craig Campbell
Deleterious homozygous or compound heterozygous mutations in the TBCK (TBC1-domain-containing kinase) gene (implicated in the MTOR pathway) produce profound hypotonia, global developmental delay, facial dysmorphic features, and brain abnormalities. The disorder has been named "infantile hypotonia with psychomotor retardation and characteristic facies-3" (IHPRF3). Here we present two sisters with a novel mutation in TBCK (NM_001163435.2: c.753dup; p.(Lys252*)) who have this ultrarare disorder. We have reviewed the literature on the 33 previously reported cases to provide a characterization of this emerging phenotype...
August 10, 2018: European Journal of Medical Genetics
Maella Severino-Freire, Aude Maza, Paul Kuentz, Yannis Duffourd, Laurence Fiavre, Edith Brazet, Nicolas Chassaing, Eliane Mery-Lemarche, Pierre Vabres, Juliette Mazereeuw-Hautier
Proteus Syndrome is a rare complex overgrowth syndrome. We report a young female patient with Proteus Syndrome due to AKT1 mutation c.49G > A (p.Glu17Lys), presenting with a severe gynaecological involvement which necessitated a complete hysterectomy and a left adnexectomy. Cases of gynecological involvements in Proteus Syndrome are rare, not well known by physicians while they can be potentially severe.
August 10, 2018: European Journal of Medical Genetics
Lara El Bazzal, Alexandre Atkinson, Anne-Celine Guillard, Valerie Delague, André Mégarbané
We report a consanguineous family where 2 boys presented with developmental delay, hypotonia, microcephaly, seizures, gastro-intestinal abnormalities, osteopenia, and neurological regression. Whole exome sequencing performed in one of the boys revealed the presence of a novel homozygous missense variant in the EXT2 gene: c.11C > T (p.Ser4Leu). Segregation analysis by Sanger sequencing confirmed homozygous by Descent autosomal recessive transmission of this mutation. Another family was previously reported with homozygous mutations in this gene in four siblings affected with a nearly similar clinical condition (Farhan et al...
July 31, 2018: European Journal of Medical Genetics
Avi Saskin, Ahmed Alfares, Chantal Bernard, Miriam Blumenkrantz, Nancy Braverman, Indra Gupta, K Bridget Brosnihan, Corinne Antignac, Marie Claire Gubler, Vincent Morinière, Isabelle De Bie, Martin Bitzan
Renal tubular dysgenesis (RTD) is a developmental abnormality of the nephron characterized by fetal anuria, oligohydramnios, and severe postnatal hypotension. Genetic forms have an autosomal recessive inheritance and are caused by mutations in genes encoding key components of the renin-angiotensin pathway. We report three patients from two unrelated families with RTD due to pathogenic variants of the angiotensin-converting enzyme (ACE) gene, in whom RTD was associated with microcolon. We also detail key variations of the renin-angiotensin system in one of these infants...
July 31, 2018: European Journal of Medical Genetics
Thangaraj Abiramalatha, Gautham Arunachal, Karthik Muthusamy, Niranjan Thomas
Congenital disorders of glycosylation (CDG) are a rapidly expanding group of inborn errors of metabolism with around 100 types described so far. Because of the limited number of reported cases in each type except PMM2-CDG, the complete clinical picture of other types is not known. RFT1-CDG is a rare type, with ten cases reported in the literature. Our patient presented as a floppy neonate with severe respiratory insufficiency and ventilator dependence in the newborn period. He had fetal growth restriction, facial dysmorphism, high arched palate, bilateral cryptorchidism, hypoplastic pons and cerebellum and probable hearing impairment...
July 30, 2018: European Journal of Medical Genetics
Grazia M S Mancini
No abstract text is available yet for this article.
July 24, 2018: European Journal of Medical Genetics
Natalya Karp, Donald Lee, Salma Shickh, Mary E Jenkins
Alexander disease (AD) is a rare form of leukodystrophy caused by pathogenic variants in the GFAP gene. In young children the condition is fatal, while adults have variable neurological symptoms and prognosis. On magnetic resonance imaging, a pattern of atrophy of the medulla oblongata and cervical spinal cord with a 'tadpole' appearance is highly suggestive of adult-onset Alexander disease (AOAD). GFAP gene sequencing is used to confirm the diagnosis. Pre-mRNA of this gene undergoes alternative splicing resulting in formation of at least 8 different protein isoforms...
July 23, 2018: European Journal of Medical Genetics
Mahmoud Aarabi, Elena Kessler, Suneeta Madan-Khetarpal, Urvashi Surti, Daniel Bellissimo, Aleksandar Rajkovic, Svetlana A Yatsenko
Proper function of GABAergic synapses depends upon the postsynaptic compartment anchoring of neurotransmitter receptors to the membrane by gephyrin and collybistin (Cb). In humans, Cb is encoded by ARHGEF9 on Xq11.1. ARHGEF9 alterations, some inherited from unaffected mothers, have been reported in males with autism, seizures and severe neurodevelopmental abnormalities. In females, a spectrum of mild to moderate phenotype has been detected. We report two unrelated females with autism and mild intellectual disability...
July 23, 2018: European Journal of Medical Genetics
Schaida Schirwani, Antonio Novelli, Maria Cristina Digilio, David Bourn, Valerie Wilson, Catherine Roberts, Dallapiccola Bruno, Emma Hobson
GPC3 and GPC4 are the only two genes in which mutations are known to cause Simpson-Golabi-Behmel syndrome type 1 (SGBS1). The majority of SGBS1 patients have point mutations or deletions in GPC3. Only one SGBS1 family has been reported with duplication of both GPC3 and GPC4. Although clinical presentation of SGBS1 in affected males is well defined, the phenotype in female carriers is less clear. In total, six female carriers with clinical expression of SGBS1 have been reported to date. In this study, we provide description of two families with rare duplications in both GPC3 and GPC4...
July 23, 2018: European Journal of Medical Genetics
Amélie Chaussade, Gaël Millot, Constance Wells, Hervé Brisse, Marick Laé, Alexia Savignoni, Laurence Desjardins, Rémi Dendale, François Doz, Isabelle Aerts, Irène Jimenez, Nathalie Cassoux, Dominique Stoppa Lyonnet, Marion Gauthier Villars, Claude Houdayer
Retinoblastoma (Rb) results from biallelic inactivation of the RB1 gene. Hereditary Rb patients i. e germline carriers of a RB1 mutation also have a risk of developing subsequent malignant neoplasms (SMN) such as osteosarcomas. This SMN risk is maximized by external beam radiotherapy treatments (EBRT), which is why these treatments are now avoided. Nevertheless, EBRT is still a matter of great concern, as EBRT-treated patients are in their adulthood and SMNs remain the major cause of death for patients. To decipher the relationship between RB1 genotype and SMN development in EBRT treated patients, we conducted a retrospective study in a cohort of 160 irradiated hereditary Rbs with fully resolved RB1 mutational status...
July 18, 2018: European Journal of Medical Genetics
Anna L Burgemeister, Eva Daumiller, Gabriele du Bois, Luitgard M Graul-Neumann, Birgit Köhler, Susanne Knecht, Stefan Burgemeister, Sarah Gronwald, Martin H Maurer, Birgit Zirn
49,XXXXY syndrome is a rare sex chromosome aneuploidy syndrome. Cognitive impairment with expressive language deficits in combination with developmental and speech dyspraxia are cardinal symptoms. Testicular insufficiency becomes apparent during adolescence. Neurological, musculoskeletal, genital, orthodontic and immunological anomalies are common and a higher incidence of congenital malformations has been described. Here we show the evolving clinical and facial phenotype of eight boys and men with 49,XXXXY, demonstrating an increasingly perceptible distinct facial gestalt over time...
July 18, 2018: European Journal of Medical Genetics
Maryam Al Shehhi, Eva B Forman, Jacqueline E Fitzgerald, Veronica McInerney, Janusz Krawczyk, Sanbing Shen, David R Betts, Linda Mc Ardle, Kathleen M Gorman, Mary D King, Andrew Green, Louise Gallagher, Sally A Lynch
The spectrum of phenotypes associated with heterozygous deletions of neurexin-1 (NRXN1) is diverse and includes: autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability, seizures, schizophrenia, mood disorders and congenital malformations. Reduced penetrance and variable expressivity of deletions in this gene remain a challenge for genetic counselling. We clinically reviewed 67 NRXN1 deletions from 34 families to document the phenotype and determine odds ratio. Thirty-four probands (5 adults, 29 children (<16 years)) were initially identified from a cohort clinically referred for arrayCGH...
July 18, 2018: European Journal of Medical Genetics
Valtter B Virtanen, Perttu P Salo, Jia Cao, Anna Löf-Granström, Lili Milani, Andres Metspalu, Risto J Rintala, Outi Saarenpää-Heikkilä, Tiina Paunio, Tomas Wester, Agneta Nordenskjöld, Markus Perola, Mikko P Pakarinen
The pathogenesis of Hirschsprung disease is complex. Although the RET proto-oncogene is the most frequently affected gene in Hirschsprung disease, rare coding sequence variants explain only a small part of Hirschsprung disease cases. We aimed to assess the genetic background of Hirschsprung disease using a genome-wide association analysis combined with sequencing all RET exons in samples from 105 Hirschsprung disease cases (30 familial and 75 sporadic) and 386 controls. As expected, variants in or near RET showed the strongest overall association with Hirschsprung disease and the most statistically significant association was observed when using a recessive genetic model (rs2435357, NC_000010...
July 18, 2018: European Journal of Medical Genetics
Miki Kawai, Makiko Tsutsumi, Fumihiko Suzuki, Kiyoko Sameshima, Yuri Dowa, Takuji Kyoya, Hidehito Inagaki, Hiroki Kurahashi
Jacobsen syndrome refers to a congenital anomaly caused by deletion at 11q23.3-qter. We here describe two siblings with the same 11q23.3-qter deletion. Both parents were healthy with a normal karyotype. Cytogenetic microarray analysis revealed no mosaicism in either parent but the mother showed uniparental disomy encompassing the deleted region found in the two siblings. The pattern of X chromosome inactivation was almost completely skewed in the mother. These data suggested that the mother was a carrier of the 11q23...
July 18, 2018: European Journal of Medical Genetics
Andrea Accogli, Marcello Scala, Annalisa Calcagno, Flavia Napoli, Natascia Di Iorgi, Serena Arrigo, Maria Margherita Mancardi, Giulia Prato, Livia Pisciotta, Mato Nagel, Mariasavina Severino, Valeria Capra
Magnesium (Mg2+ ) plays a crucial role in many biological processes especially in the brain, heart and skeletal muscle. Mg2+ homeostasis is regulated by intestinal absorption and renal reabsorption, involving a combination of different epithelial transport pathways. Mutations in any of these transporters result in hypomagnesemia with variable clinical presentations. Among these, CNNM2 is found along the basolateral membrane of distal tubular segments where it is involved in Mg2+ reabsorption. To date, heterozygous mutations in CNNM2 have been associated with a variable phenotype, ranging from isolated hypomagnesemia to intellectual disability and epilepsy...
July 17, 2018: European Journal of Medical Genetics
Romina Romaniello, Filippo Arrigoni, Andrew E Fry, Maria T Bassi, Mark I Rees, Renato Borgatti, Daniela T Pilz, Thomas D Cushion
A large number of genes encoding for tubulin proteins are expressed in the developing brain. Each is subject to specific spatial and temporal expression patterns. However, most are highly expressed in post-mitotic neurons during stages of neuronal migration and differentiation. The major tubulin subclasses (alpha- and beta-tubulin) share high sequence and structural homology. These globular proteins form heterodimers and subsequently co-assemble into microtubules. Microtubules are dynamic, cytoskeletal polymers which play key roles in cellular processes crucial for cortical development, including neuronal proliferation, migration and cortical laminar organisation...
July 17, 2018: European Journal of Medical Genetics
Oliver De la Torre-García, Roberto Mar-Aldama, Ramón Salgado-Sangri, Noe Diaz-Gomez, Luis Bonilla-Arcaute, Juan Diaz-Ponce-Medrano, Roberto Guevara-Yañez, Emilio J Córdova, Tulia Monge-Cazares, Lorena Orozco, Angélica Martínez-Hernández
Mosaic variegated aneuploidy syndrome (MVA) is a rare autosomal recessive disorder characterized by random chromosome gains and losses. Mutations in BUB1B and CEP57 genes have been involved in MVA. Here we report on a male child with MVA due to c.915_925dupCAATGTTCAGC mutation in the CEP57 gene. Our patient was homozygous for this mutation and he is the first case with rhizomelic shortening of both the upper and lower limbs and mild respiratory insufficiency due to a narrow thorax. It is also the second MVA Mexican family reported with this mutation that lives in the northwestern region of Mexico, suggesting a "local founding effect"...
July 16, 2018: European Journal of Medical Genetics
Shiroh Miura, Kengo Kosaka, Ryuta Fujioka, Yusuke Uchiyama, Tomofumi Shimojo, Takuya Morikawa, Azusa Irie, Takayuki Taniwaki, Hiroki Shibata
Spinocerebellar ataxia 27 (SCA27) is an autosomal dominant SCA caused by variants in the fibroblast growth factor 14 (FGF14) gene. We examined a Japanese SCA patient whose deceased father also suffered from SCA. The patient was a 63-year-old male. He graduated from junior high school but received no further education. The predominant complaint was slowly progressive dysarthria and gait disturbance, which appeared at age 47. He showed pathological saccadic dysmetria, saccadic intrusions into smooth pursuit eye movements, dysarthria, and limb and truncal ataxia...
July 11, 2018: European Journal of Medical Genetics
Marion Imbert-Bouteille, Frédéric Tran Mau Them, Julien Thevenon, Thomas Guignard, Vincent Gatinois, Jean-Baptiste Riviere, Anne Boland, Vincent Meyer, Jean-François Deleuze, Elodie Sanchez, Florence Apparailly, David Geneviève, Marjolaine Willems
Alazami syndrome (AS) (MIM# 615071) is an autosomal recessive microcephalic primordial dwarfism (PD) with recognizable facial features and severe intellectual disability due to depletion or loss of function variants in LARP7. To date, 15 patients with AS have been reported. Here we describe two consanguineous Algerian sisters with Alazami PD due to LARP7 homozygous pathogenic variants detected by whole exome sequencing. By comparing these two additional cases with those previously reported, we strengthen the key features of AS: severe growth restriction, severe intellectual disability and some distinguishing facial features such as broad nose, malar hypoplasia, wide mouth, full lips and abnormally set teeth...
July 10, 2018: European Journal of Medical Genetics
Zhangyang Wang, Jie Lin, Kai Qiao, Shuang Cai, Victor W Zhang, Chongbo Zhao, Jiahong Lu
Autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) is a rare form of hereditary neuropathy. Mutations in HINT1 gene have been identified to be the cause of this disorder. We report two unrelated patients who presented gait impairment, progressive distal muscle weakness and atrophy, neuromyotonia and foot deformities. Electrophysiological studies showed axonal motor neuropathy and neuromyotonic discharges. Using Next-generation sequencing, we identified two homozygous mutations, NM_005340.6: c...
July 10, 2018: European Journal of Medical Genetics
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