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intellectual disease genetics

Aimé Lumaka, Valerie Race, Hilde Peeters, Anniek Corveleyn, Zeynep Coban-Akdemir, Shalini N Jhangiani, Xiaofei Song, Gerrye Mubungu, Jennifer Posey, James R Lupski, Joris R Vermeesch, Prosper Lukusa, Koenraad Devriendt
Pathogenic variants account for 4 to 41% of patients with intellectual disability (ID) or developmental delay (DD). In Sub-Saharan Africa, the prevalence of ID is thought to be higher, but data in Central Africa are limited to some case reports. In addition, clinical descriptions of some syndromes are not available for this population. This study aimed at providing an estimate for the fraction of ID/DD for which an underlying etiological genetic cause may be elucidated and provide insights into their clinical presentation in special institutions in a Central African country...
August 8, 2018: American Journal of Medical Genetics. Part A
Volkan Okur, Shannon Nees, Wendy K Chung, Usha Krishnan
Kleefstra Syndrome is a rare genetic disorder caused by mutations in EHMT1, Euchromatin Histone Methyl Transferase 1, or deletions encompassing EHMT1 on 9q34.3. Congenital heart defects are among the major findings in patients with 9q34.3 microdeletion/Kleefstra Syndrome along with recognizable facial appearance, developmental delay/intellectual disability including severely delayed or absent speech, hypotonia, seizures, behavioral and sleep abnormalities. Pulmonary hypertension (PH) is a rare condition associated with increased pulmonary artery and right heart pressures that can lead to right heart failure and death if untreated...
July 31, 2018: American Journal of Medical Genetics. Part A
Anne Gregor, Lynette G Sadleir, Reza Asadollahi, Silvia Azzarello-Burri, Agatino Battaglia, Lilian Bomme Ousager, Paranchai Boonsawat, Ange-Line Bruel, Rebecca Buchert, Eduardo Calpena, Benjamin Cogné, Bruno Dallapiccola, Felix Distelmaier, Frances Elmslie, Laurence Faivre, Tobias B Haack, Victoria Harrison, Alex Henderson, David Hunt, Bertrand Isidor, Pascal Joset, Satoko Kumada, Augusta M A Lachmeijer, Melissa Lees, Sally Ann Lynch, Francisco Martinez, Naomichi Matsumoto, Carey McDougall, Heather C Mefford, Noriko Miyake, Candace T Myers, Sébastien Moutton, Addie Nesbitt, Antonio Novelli, Carmen Orellana, Anita Rauch, Monica Rosello, Ken Saida, Avni B Santani, Ajoy Sarkar, Ingrid E Scheffer, Marwan Shinawi, Katharina Steindl, Joseph D Symonds, Elaine H Zackai, André Reis, Heinrich Sticht, Christiane Zweier
Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies...
August 2, 2018: American Journal of Human Genetics
A Jeremy Willsey, Montana T Morris, Sheng Wang, Helen R Willsey, Nawei Sun, Nia Teerikorpi, Tierney B Baum, Gerard Cagney, Kevin J Bender, Tejal A Desai, Deepak Srivastava, Graeme W Davis, Jennifer Doudna, Edward Chang, Vikaas Sohal, Daniel H Lowenstein, Hao Li, David Agard, Michael J Keiser, Brian Shoichet, Mark von Zastrow, Lennart Mucke, Steven Finkbeiner, Li Gan, Nenad Sestan, Michael E Ward, Ruth Huttenhain, Tomasz J Nowakowski, Hugo J Bellen, Loren M Frank, Mustafa K Khokha, Richard P Lifton, Martin Kampmann, Trey Ideker, Matthew W State, Nevan J Krogan
Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic...
July 26, 2018: Cell
Curtis R Coughlin, Michael A Swanson, Elaine Spector, Naomi J L Meeks, Kathryn E Kronquist, Mezhgan Aslamy, Michael F Wempe, Clara D M van Karnebeek, Sidney M Gospe, Verena G Aziz, Becky P Tsai, Hanlin Gao, Peter L Nagy, Keith Hyland, Silvy J M van Dooren, Gajja S Salomons, Johan L K Van Hove
Pyridoxine dependent epilepsy (PDE) is a treatable epileptic encephalopathy characterized by a positive response to pharmacologic doses of pyridoxine. Despite seizure control, at least 75% of individuals have intellectual disability and developmental delay. Current treatment paradigms have resulted in improved cognitive outcomes emphasizing the importance of an early diagnosis. As genetic testing is increasingly accepted as first tier testing for epileptic encephalopathies, we aimed to provide a comprehensive overview of ALDH7A1 mutations that cause PDE...
July 24, 2018: Journal of Inherited Metabolic Disease
Laksshman Sundaram, Hong Gao, Samskruthi Reddy Padigepati, Jeremy F McRae, Yanjun Li, Jack A Kosmicki, Nondas Fritzilas, Jörg Hakenberg, Anindita Dutta, John Shon, Jinbo Xu, Serafim Batzloglou, Xiaolin Li, Kyle Kai-How Farh
Millions of human genomes and exomes have been sequenced, but their clinical applications remain limited due to the difficulty of distinguishing disease-causing mutations from benign genetic variation. Here we demonstrate that common missense variants in other primate species are largely clinically benign in human, enabling pathogenic mutations to be systematically identified by the process of elimination. Using hundreds of thousands of common variants from population sequencing of six non-human primate species, we train a deep neural network that identifies pathogenic mutations in rare disease patients with 88% accuracy and enables the discovery of 14 new candidate genes in intellectual disability at genome-wide significance...
August 2018: Nature Genetics
Birgit M Repp, Elisa Mastantuono, Charlotte L Alston, Manuel Schiff, Tobias B Haack, Agnes Rötig, Anna Ardissone, Anne Lombès, Claudia B Catarino, Daria Diodato, Gudrun Schottmann, Joanna Poulton, Alberto Burlina, An Jonckheere, Arnold Munnich, Boris Rolinski, Daniele Ghezzi, Dariusz Rokicki, Diana Wellesley, Diego Martinelli, Ding Wenhong, Eleonora Lamantea, Elsebet Ostergaard, Ewa Pronicka, Germaine Pierre, Hubert J M Smeets, Ilka Wittig, Ingrid Scurr, Irenaeus F M de Coo, Isabella Moroni, Joél Smet, Johannes A Mayr, Lifang Dai, Linda de Meirleir, Markus Schuelke, Massimo Zeviani, Raphael J Morscher, Robert McFarland, Sara Seneca, Thomas Klopstock, Thomas Meitinger, Thomas Wieland, Tim M Strom, Ulrike Herberg, Uwe Ahting, Wolfgang Sperl, Marie-Cecile Nassogne, Han Ling, Fang Fang, Peter Freisinger, Rudy Van Coster, Valentina Strecker, Robert W Taylor, Johannes Häberle, Jerry Vockley, Holger Prokisch, Saskia Wortmann
BACKGROUND: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9...
July 19, 2018: Orphanet Journal of Rare Diseases
Swati Chaudhary, Mahima Kaushik, Saami Ahmed, Ritushree Kukreti, Shrikant Kukreti
A gradual dementia, which leads to the loss of memory and intellectual abilities, is the main characteristics of Alzheimer's disease. Amyloid-β (Aβ) plaques are the main components that accumulate and form clumps in the brains of people suffering from Alzheimer's disease. Apolipoprotein E ( APOE ), an amyloid-binding protein is considered as one of the main genetic risk factor of the late-onset Alzheimer's disease. Different isoforms of APOE gene named APOE2, APOE3, and APOE4 are known to exist, which differ from each other at certain positions involving single-nucleotide polymorphisms (SNPs)...
March 31, 2018: ACS Omega
Elisenda Cortès-Saladelafont, Noa Lipstein, Àngels García-Cazorla
The aim of this report is to present a tentative clinical and pathophysiological approach to diseases affecting the neuronal presynaptic terminal, with a major focus on synaptic vesicles (SVs). Diseases are classified depending on which step of the neurobiology of the SV is predominantly affected: (1) biogenesis of vesicle precursors in the neuronal soma; (2) transport along the axon; (3) vesicle cycle at the presynaptic terminal (exocytosis-endocytosis cycle, with the main purpose of neurotransmitter release)...
July 18, 2018: Journal of Inherited Metabolic Disease
Preetika Gupta, Ogul E Uner, Soumyashant Nayak, Gregory R Grant, Robert G Kalb
Synapse associated protein of 97KDa (SAP97) belongs to a family of scaffolding proteins, the membrane-associated guanylate kinases (MAGUKs), that are highly enriched in the postsynaptic density of synapses and play an important role in organizing protein complexes necessary for synaptic development and plasticity. The Dlg-MAGUK family of proteins are structurally very similar, and an effort has been made to parse apart the unique function of each Dlg-MAGUK protein by characterization of knockout mice. Knockout mice have been generated and characterized for PSD-95, PSD-93, and SAP102, however SAP97 knockout mice have been impossible to study because the SAP97 null mice die soon after birth due to a craniofacial defect...
2018: PloS One
Arnaud Fernandez, Emmanuelle Dor, Thomas Maurin, Gaelle Laure, Marie-Line Menard, Małgorzata Drozd, Francois Poinso, Barbara Bardoni, Florence Askenazy, Susanne Thümmler
INTRODUCTION: Early-onset schizophrenia (EOS) is a rare and severe condition. A higher rate of neurodevelopmental abnormalities, such as intellectual or communication impairments as well as attention deficit hyperactivity disorder, is observed in EOS compared with adult-onset schizophrenia. Early signs of autism spectrum disorders (ASD) are present in about 30% of patients. Genetic abnormalities, including copy number variations, are frequent in neurodevelopmental disorders and have been associated to ASD physiopathology...
July 5, 2018: BMJ Open
Oili Sauna-Aho, Nina Bjelogrlic-Laakso, Auli Siren, Maria Arvio
BACKGROUND: Intellectual disability (ID) and dementia reflect disturbed cortical function during and after developmental age, respectively. Due to the wide heterogeneity of ID population the decline in cognitive and adaptive skills may be different in distinct genetic subgroups. METHODS: Using the British Present Psychiatric State-learning Disabilities assessment (PPS-LD) questionnaire the dementia signs were screened in 62, 22 and 44 individuals (> 35 year of age) with Down (DS, OMIM number 190685), Williams (WS, OMIM number, 194050), and Fragile X syndrome (FXS, OMIM number 309550), respectively...
July 3, 2018: Molecular Genetics & Genomic Medicine
Samra Sardar, Katrine Kanne, Åsa Andersson
The Mediator complex subunit 13-like (MED13L) protein is part of the multi-protein mediator complex and plays an important role in gene transcription. Polymorphisms in the MED13L gene have been linked to congenital heart anomalies and intellectual disabilities. Despite recent evidence of indirect links of MED13L to cytokine release and inflammation, impact of genetic variations in MED13L on immune cells remains unexplored. The B10.RIII and RIIIS/J mouse strains vary in susceptibility to induced experimental autoimmune disease models...
June 27, 2018: Archivum Immunologiae et Therapiae Experimentalis
Annabel Folch, Luis Salvador-Carulla, Paloma Vicens, Maria José Cortés, Marcia Irazábal, Silvia Muñoz, Lluís Rovira, Carmen Orejuela, Juan A González, Rafael Martínez-Leal
BACKGROUND: The aim of this paper was to summarize the main results of the POMONA-ESP project, the first study to explore health status in a large representative, randomized and stratified sample of people with intellectual developmental disorders in Spain. METHODS: The POMONA-ESP project collected information about the health of 953 individuals with intellectual developmental disorders. RESULTS: Diseases such as urinary incontinence, oral problems, epilepsy, constipation or obesity were highly prevalent among the participants; with gender-differentiated prevalences for certain conditions, and age and intellectual disability level as risk factors for disease...
June 27, 2018: Journal of Applied Research in Intellectual Disabilities: JARID
Henrike O Heyne, Tarjinder Singh, Hannah Stamberger, Rami Abou Jamra, Hande Caglayan, Dana Craiu, Peter De Jonghe, Renzo Guerrini, Katherine L Helbig, Bobby P C Koeleman, Jack A Kosmicki, Tarja Linnankivi, Patrick May, Hiltrud Muhle, Rikke S Møller, Bernd A Neubauer, Aarno Palotie, Manuela Pendziwiat, Pasquale Striano, Sha Tang, Sitao Wu, Annapurna Poduri, Yvonne G Weber, Sarah Weckhuysen, Sanjay M Sisodiya, Mark J Daly, Ingo Helbig, Dennis Lal, Johannes R Lemke
Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene...
July 2018: Nature Genetics
N Morchiladze, B Tkeshelashvili, T Gagua, D Gagua
The isolated hypothyroxinemia of pregnancy (IHP) has gained specific attention in the specialized literature during the recent years as the possible factor impeding the intellectual development of fetus and increasing the risk of complications related with pregnancy, delivery and perinatal period. Aim of the study was to define the importance of isolated hypothyroxinemia in the development of obstetric and somatic pathologies in outpatient population of pregnant females. The study of prospective design was performed at the base of "David Gagua Clinic" Ltd...
May 2018: Georgian Medical News
Victor Faundez, Ilario De Toma, Barbara Bardoni, Renata Bartesaghi, Dean Nizetic, Rafael de la Torre, Roi Cohen Kadosh, Yann Herault, Mara Dierssen, Marie-Claude Potier
Ongoing treatments for genetic developmental disorders of the central nervous system are mostly symptomatic and do not correct the genetic cause. Recent identification of common mechanisms between diseases has suggested that new therapeutic targets could be applied across intellectual disabilities with potential disease-modifying properties. The European Down syndrome and other genetic developmental disorders (DSG2D) network joined basic and clinical scientists to foster this research and carry out clinical trials...
June 2018: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
H Hengel, R Keimer, W Deigendesch, A Rieß, H Marzouqa, J Zaidan, P Bauer, L Schöls
Various genetic defects can cause intellectual and developmental disabilities (IDDs). Often IDD is a symptom of a more complex neurodevelopmental or neurodegenerative syndrome. Identifying syndromic patterns is substantive for diagnostics and for understanding the pathomechanism of a disease. Recessive glutamate pyruvate transaminase (GPT2) mutations have recently been associated with IDD in 4 families. Here, we report a novel recessive GPT2 stop mutation p.Gln24* causing a complex IDD phenotype in a homozygous state in 5 patients from 2 consanguineous Arab families...
June 7, 2018: Clinical Genetics
Yuxia Tan, Mei Hou, Shaochun Ma, Peipei Liu, Shungang Xia, Yu Wang, Liping Chen, Zongbo Chen
BACKGROUND: The link between the protocadherin-19 (PCDH19) gene and epilepsy suggests that an unusual form of X-linked inheritance affects females but is transmitted through asymptomatic males. Individuals with epilepsy associated with mutations in the PCDH19 gene display generalized or focal seizures with or without fever sensitivity. The clinical manifestation of the condition ranges from mild to severe, resulting in intellectual disability and behavioural disturbance. In the present study, we assessed mutations in the PCDH19 gene and the clinical features of a group of Chinese patients with early infantile epileptic encephalopathy and aimed to provide further insight into the understanding of epilepsy and mental retardation limited to females (EFMR; MIM 300088)...
June 4, 2018: BMC Medical Genetics
Alison M Elliott, Christèle du Souich, Shelin Adam, Nick Dragojlovic, Clara van Karnebeek, Tanya N Nelson, Anna Lehman, Larry D Lynd, Jan M Friedman
BACKGROUND: Access to clinical diagnostic genome-wide sequencing (GWS; exome or whole genome sequencing) is limited in British Columbia. The establishment of a translational research initiative (CAUSES) to provide diagnostic genome-wide sequencing for 500 children necessitated the development of a genomic consultation service, a clinical service established to provide consultation for physicians considering GWS for their pediatric patients throughout British Columbia. The Genomic Consultation Service provides patient-specific genomic advice that may include: GWS, multi-gene panel, single gene test, referral to medical genetics for clinical evaluation, or no genetic testing...
May 30, 2018: Molecular Genetics & Genomic Medicine
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