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European Journal of Medical Genetics

Shiroh Miura, Kengo Kosaka, Takuo Nomura, Shuji Nagata, Tomofumi Shimojo, Takuya Morikawa, Ryuta Fujioka, Masaya Harada, Takayuki Taniwaki, Hiroki Shibata
Distal hereditary motor neuropathies (dHMNs) comprise a group of clinically and genetically heterogeneous inherited lower motor neuron syndromes mainly characterized by a distal-predominant pattern of progressive muscle atrophy, weakness and hyporeflexia, without sensory dysfunction. Although at least 21 causative genes for dHMN have been reported, mutational scanning of these genes often fails to identify the causative variants in dHMN cohorts, suggesting that additional causative genes remain to be identified...
November 29, 2018: European Journal of Medical Genetics
M J Szego, M S Meyn, C Shuman, R Zlotnik Shaul, J A Anderson, S Bowdin, N Monfared, R Z Hayeems
Whole genome sequencing (WGS) is a transformative technology which promises improved diagnostic rates compared to conventional genetic testing strategies and tailored approaches to patient care. Due to the practical and ethical complexities associated with using WGS, particularly in the paediatric context, input from a broad spectrum of healthcare providers can guide implementation strategies. We recruited healthcare providers from the largest paediatric academic health science centre in Canada and conducted semi-structured qualitative interviews, exploring experiences with and perceptions of the opportunities and challenges associated with WGS...
November 29, 2018: European Journal of Medical Genetics
Sandi Dheensa, Anneke Lucassen, Angela Fenwick
In this paper, we present findings from a project involving 20 patients with rare diseases, or parents thereof, participating in the 100,000 genomes project (100 kG P) about their experiences of, and views about, the project, including why they took part, and their hopes and concerns about the future of genomic medicine. Patients who attended genetic clinics for testing were offered the opportunity to undergo the more extensive whole genome sequencing (WGS) if they agreed to take part in the 100 kG P...
November 29, 2018: European Journal of Medical Genetics
Mario Mastrangelo, Stefano Sartori, Alessandro Simonati, Mario Brinciotti, Francesca Moro, Margherita Nosadini, Francesco Pezzini, Stefano Doccini, Filippo Maria Santorelli, Vincenzo Leuzzi
BACKGROUND: Mutations in the KCTD7 gene have been associated with progressive myoclonus epilepsy and, in a single patient, with the so-called "Neuronal Ceroid Lipofuscinosis 14" (characterised by myoclonic seizures, cognitive regression, optic atrophy leading to visual loss, and progressive cortical and cerebellar atrophy). CLINICAL REPORTS: We describe two new patients carrying two novel pathogenic mutations in the KCTD7 gene. Patient 1 (NM_153033.4: c...
November 27, 2018: European Journal of Medical Genetics
Naz Guleray, Pelin Ozlem Simsek Kiper, Gulen Eda Utine, Koray Boduroglu, Mehmet Alikasifoglu
Spondyloocular syndrome is characterized by generalized osteoporosis, multiple fractures and severe ocular findings. The causative XYLT2 mutations have recently been identified with the use of whole exome sequencing. We report on two siblings with spondyloocular syndrome who presented with varying clinical severity. A novel XYLT2 missense mutation was detected in a region evolutionary conserved across the species. This report along with the previous reports demonstrates that variable expressivity may be possible even within the same family...
November 26, 2018: European Journal of Medical Genetics
Peter E Grant, Maria Pampaka, Katherine Payne, Angus Clarke, Marion McAllister
The Genetic Counselling Outcome Scale (GCOS-24) is a 24-item patient reported outcome measure for use in evaluations of genetic counselling and testing services. The aim of this study was to develop a short form of GCOS-24. The study comprised three phases. Phase I: Cognitive interviews were used to explore interpretability of GCOS-24 items and which GCOS-24 items were most valued by the target population. Phase II: The Graded Response Model was used to analyse an existing set of GCOS-24 responses (n = 395) to examine item discrimination...
November 26, 2018: European Journal of Medical Genetics
María José Borrero Corte, Fátima Jara Rubio, María José Morán Jiménez, Silvia Díaz Díaz, Francisco Javier Castelbón Fernandez, Inmaculada García Pastor, Rafael Enríquez de Salamanca, Manuel Méndez
Porphyrias are rare diseases caused by alterations in the heme biosynthetic pathway. Depending on the afected enzyme, porphyrin precursors or porphyrins are overproduced, causing acute neurovisceral attacks or dermal photosensitivity, respectively. Hereditary Coproporphyria (HCP) and Variegate Porphyria (VP) are mixed porphyrias since they can present acute and/or cutaneous symptoms. These diseases are caused by a deficiency of coproporphyrinogen oxidase (CPOX) in HCP, and protoporphyrinogen oxidase (PPOX) in VP...
November 23, 2018: European Journal of Medical Genetics
Anna Middleton, Richard Milne, Adrian Thorogood, Erika Kleiderman, Emilia Niemiec, Barbara Prainsack, Lauren Farley, Paul Bevan, Claire Steed, James Smith, Danya Vears, Jerome Atutornu, Heidi C Howard, Katherine I Morley
With the use of genetic technology, researchers have the potential to inform medical diagnoses and treatment in actionable ways. Accurate variant interpretation is a necessary condition for the utility of genetic technology to unfold. This relies on the ability to access large genomic datasets so that comparisons can be made between variants of interest. This can only be successful if DNA and medical data are donated by large numbers of people to 'research', including clinical, non-profit and for-profit research initiatives, in order to be accessed by scientists and clinicians worldwide...
November 23, 2018: European Journal of Medical Genetics
Ahmed H Al-Amri, Abeer Al Saegh, Watfa Al-Mamari, Mohammed E El-Asrag, Mohammed N Al-Kindi, Mazin Al Khabouri, Nadia Al Wardy, Khalsa Al Lamki, Ahlam Gabr, Ahmed Idris, Chris F Inglehearn, Steven J Clapcote, Manir Ali
Hearing loss is a debilitating disorder that impairs language acquisition, resulting in disability in children and potential isolation in adulthood. Its onset can have a genetic basis, though environmental factors, which are often preventable, can also cause the condition. The genetic forms are highly heterogeneous, and early detection is necessary to arrange appropriate patient support. Here we report the molecular basis of hereditary hearing loss in a consanguineous family with multiple affected members from Oman...
November 23, 2018: European Journal of Medical Genetics
I Esteban, A Lopez-Fernandez, J Balmaña
Massively parallel sequencing is being implemented in clinical practice through the use of multigene panel testing, whole exome sequencing and whole genome sequencing. In this manuscript we explore how the use of massively parallel sequencing, and in particular multigene cancer panel testing, is potentially changing the process of genetic counselling and how patients cope with the pre-test genetic counselling and with results. We found that the main challenges are around uncertainty, hopes and expectations and the amount and complexity of information that needs to be discussed...
November 23, 2018: European Journal of Medical Genetics
Elizabeth J Bhoj, Damien Haye, Annick Toutain, Dominique Bonneau, Irene Kibæk Nielsen, Ida Bay Lund, Pauline Bogaard, Stine Leenskjold, Kadri Karaer, Katherine T Wild, Katheryn L Grand, Mirena C Astiazaran, Luis A Gonzalez-Nieto, Ana Carvalho, Daphné Lehalle, Shivarajan M Amudhavalli, Elena Repnikova, Carol Saunders, Isabelle Thiffault, Irfan Saadi, Dong Li, Hakon Hakonarson, Yoann Vial, Elaine Zackai, Patrick Callier, Séverine Drunat, Alain Verloes
The SPECC1L protein plays a role in adherens junctions involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. It modulates PI3K-AKT signaling and controls cranial neural crest cell delamination during facial morphogenesis. SPECC1L causative variants were first identified in individuals with oblique facial clefts. Recently, causative variants in SPECC1L were reported in a pedigree reported in 1988 as atypical Opitz GBBB syndrome. Six families with SPECC1L variants have been reported thus far...
November 22, 2018: European Journal of Medical Genetics
D Abdin, A Rump, A Tzschach, K Sarnow, E Schröck, K Hackmann, N Di Donato
Expression of the fusion genes is considered to be an important mechanism of tumorigenesis. However it is hardly ever discussed in relation to the neurodevelopmental disorders. Here we report on an 18-years-old female patient with 13.1 kb deletion of 8q24.3 fusing the 5'-portion of SCRIB with the 3'-portion of PUF60 and presenting with borderline intellectual disability, eye coloboma, short stature, scoliosis, heart defects and interestingly postnatal megalencephaly, in contrast to microcephaly, which is usually associated with 8q24...
November 22, 2018: European Journal of Medical Genetics
Holger Hengel, Yvonne Schelling, Reinhard Keimer, Werner Deigendesch, Peter Bauer, Ludger Schöls
Based on a homozygous missense variant p.Pro311Ala found in three siblings of a consanguineous family, mutations in the STYXL1 gene were suggested to cause moderate intellectual disability, epilepsy and complex behavioural abnormalities. We have detected this variant via whole exome sequencing in a homozygous stage in two families. Segregation analyses in our families and thorough validation in international genetic databases provides evidence that this variant is most likely benign. This is important information for genetic counselling...
November 22, 2018: European Journal of Medical Genetics
Mohammed Mohammed, Nadia Al-Hashmi, Samiya Al-Rashdi, Nashat Al-Sukaiti, Kawther Al-Adawi, Marwa Al-Riyami, Almundher Al-Maawali
Several types of Hermansky-Pudlak syndromes (HPS) represent a group of immunodeficiency syndromes that feature both leukocyte defects with partial albinism of hair, skin, and eyes. These conditions share defects in genes that encode proteins involved in the biogenesis, function, and trafficking of secretory lysosomes. Mutations in AP3D1 which encode the main subunit AP-3(δ) were recently reported on one individual and led to Hermansky-Pudlak Syndrome type 10 (HPS10; OMIM 617050). HPS10 is a severe condition that manifests with symptoms of oculocutaneous albinism, neurodevelopmental delays, platelet dysfunction, and immunodeficiency...
November 22, 2018: European Journal of Medical Genetics
Maryam Hassanzad, Poopak Farnia, Jalaledin Ghanavi, Farshid Parvini, Shima Saif, Ali Akbar Velayati
Identification of modifier genes influencing phenotype of cystic fibrosis (CF) patients has become a challenge in CF pathophysiology, prognostic estimations and development of new therapeutic strategies. The aim of this study was to explore the association between four genetic polymorphisms of three modifier genes with CF, by comparing their alleles, genotypes and haplotype frequencies in patients and controls. In this favor, two regulatory polymorphic loci in TNFα promoter (-857C/T, rs1799724 and -238A/G, rs361525) and two functional polymorphic loci in TNFR1 (+36A/G, rs767455) and TNFR2 (+587T/G, rs1061622) were genotyped in 70 patients and 79 controls, using PCR-RFLP...
November 22, 2018: European Journal of Medical Genetics
Mathilde Pacault, Mathilde Nizon, Olivier Pichon, Marie Vincent, Cédric Le Caignec, Bertrand Isidor
Autism spectrum disorders are complex neurodevelopmental syndromes characterized by phenotypic and genetic heterogeneity. Further identification of causal genes may help in better understanding the underlying mechanisms of the disorder, thus improving the patients' management. To date, abnormal synaptogenesis is thought to be one of the major underlying causes of autism spectrum disorders. Here, using oligoarray-based comparative genomic hybridization, we identified a de novo deletion at 2q37.2 locus spanning 1 Mb and encompassing AGAP1 and SH3BP4, in a boy with autism and intellectual disability...
November 22, 2018: European Journal of Medical Genetics
Cecilia Mancini, Andrea Zonta, Giovanni Botta, Andrea Breda Klobus, Stefano Valbonesi, Barbara Pasini, Elisa Giorgio, Elsa Viora, Alfredo Brusco, Alessandro Brussino
Microphthalmia with limb anomalies (MLA, OMIM, 206920) is a rare autosomal-recessive disease caused by biallelic pathogenic variants in the SMOC1 gene. It is characterized by ocular disorders (microphtalmia or anophtalmia) and limb anomalies (oligodactyly, syndactyly, and synostosis of the 4th and 5th metacarpals), variably associated with long bone hypoplasia, horseshoe kidney, venous anomalies, vertebral anomalies, developmental delay, and intellectual disability. Here, we report the case of a woman who interrupted her pregnancy after ultrasound scans revealed a depression of the frontal bone, posterior fossa anomalies, cerebral ventricular enlargement, cleft spine involving the sacral and lower-lumbar vertebrae, and bilateral microphthalmia...
November 13, 2018: European Journal of Medical Genetics
Sylvia A Metcalfe, Chriselle Hickerton, Jacqueline Savard, Elaine Stackpoole, Rigan Tytherleigh, Erin Tutty, Bronwyn Terrill, Erin Turbitt, Kathleen Gray, Anna Middleton, Brenda Wilson, Ainsley J Newson, Clara Gaff
Personal genomic testing using direct-to-consumer and consumer-directed models, with or without involvement of healthcare providers, is increasing internationally, including in Australia. This study forms a sub-set of the Genioz study - Genomics: National Insights of Australians. We aimed to explore Australians' experiences with these types of tests, especially online DNA tests, and their views regarding whom they would seek support from around understanding test results. The study used a mixed methods approach, employing an exploratory quantitative online survey and follow-up qualitative semi-structured interviews...
November 13, 2018: European Journal of Medical Genetics
Cui Song, Niu Li, Xuyun Hu, Yu Shi, Lili Chen, Ting Zhou, Xuejiao Xu, Jun Shen, Min Zhu
Metaphyseal anadysplasia 1 (MIM# 602111) belongs to a heterogeneous group of skeletal diseases characterized by an autosomal dominant form of growth defects due to metaphyseal changes with epiphyseal involvement similar to other metaphyseal disorders. Matrix metalloproteinase 13 encoded by MMP13 presumably plays important roles in bone formation and growth, and pathogenic variants in MMP13 have been identified to cause metaphyseal anadysplasia 1. Only six pathogenic variants in MMP13 have been previously reported worldwide...
November 12, 2018: European Journal of Medical Genetics
Brent A Penque, Leila Su, Jianghai Wang, Weizhen Ji, Allen Bale, Frank Luh, Robert K Fulbright, Uzair Sarmast, Annalisa G Sega, Monica Konstantino, Michele Spencer-Manzon, Richard Pierce, Yun Yen, Saquib A Lakhani
RRM2B encodes the crucial p53-inducible ribonucleotide reductase small subunit 2 homolog (p53R2), which is required for DNA synthesis throughout the cell cycle. Mutations in this gene have been associated with a lethal mitochondrial depletion syndrome. Here we present the case of an infant with a novel homozygous p.Asn221Ser mutation in RRM2B who developed hypotonia, failure to thrive, sensorineural hearing loss, and severe metabolic lactic acidosis, ultimately progressing to death at 3 months of age. Through molecular modeling using the X-ray crystal structure of p53R2, we demonstrate that this mutation likely causes disruption of a highly conserved helix region of the protein by altering intramolecular interactions...
November 12, 2018: European Journal of Medical Genetics
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