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Gene intellectual disability

Magalie S Leduc, Marianne Mcguire, Suneeta Madan-Khetarpal, Damara Ortiz, Susan Hayflick, Kory Keller, Christine M Eng, Yaping Yang, Weimin Bi
PRR12 encodes a proline-rich protein nuclear factor suspected to be involved in neural development. Its nuclear expression in fetal brains and in the vision system supports its role in brain and eye development more specifically. However, its function and potential role in human disease has not been determined. Recently, a de novo t(10;19) (q22.3;q13.33) translocation disrupting the PRR12 gene was detected in a girl with intellectual disability and neuropsychiatric alterations. Here we report on three unrelated patients with heterozygous de novo apparent loss-of-function mutations in PRR12 detected by clinical whole exome sequencing: c...
March 19, 2018: Human Genetics
Sato Suzuki-Muromoto, Keisuke Wakusawa, Takuya Miyabayashi, Ryo Sato, Yukimune Okubo, Wakaba Endo, Takehiko Inui, Noriko Togashi, Atsuko Kato, Hiroshi Oba, Mitsuko Nakashima, Hirotomo Saitsu, Naomichi Matsumoto, Kazuhiro Haginoya
Here we report a Japanese patient with new compound heterozygous truncating variants in the PCDH12 gene. As compared to the previously reported families who had congenital microcephaly, intrauterine growth retardation, intracranial calcification, and neonatal seizure associated with dysplasia of the midbrain-hypothalamus-optic tract, the present patient showed no midbrain-hypothalamus dysplasia or congenital/postnatal microcephaly, but dyskinetic cerebral palsy and severe intellectual disability as well as multifocal epilepsy...
March 19, 2018: Journal of Human Genetics
Marta Zamarbide, Adam W Oaks, Heather L Pond, Julia S Adelman, M Chiara Manzini
Hundreds of genes are mutated in non-syndromic intellectual disability (ID) and autism spectrum disorder (ASD), with each gene often involved in only a handful of cases. Such heterogeneity can be daunting, but rare recessive loss of function (LOF) mutations can be a good starting point to provide insight into the mechanisms of neurodevelopmental disease. Biallelic LOF mutations in the signaling scaffold CC2D1A cause a rare form of autosomal recessive ID, sometimes associated with ASD and seizures. In parallel, we recently reported that Cc2d1a -deficient mice present with cognitive and social deficits, hyperactivity and anxiety...
2018: Frontiers in Genetics
Gözde Yeşil, Ayşe Aralaşmak, Enes Akyüz, Dilara İçağasıoğlu, Türkan Uygur Şahin, Yavuz Bayram
BACKGROUND: The KCNMA1 gene encodes the α-subunit of the large conductance, voltage and calcium-sensitive potassium channel (BK channels) which plays an important role in neuronal excitability. Heterozygous mutations in KCNMA1 were firstly described in a large family with generalized epilepsy and paroxysmal nonkinesigenic dyskinesia. Recently, homozygous KCNMA1 mutations were reported to cause a phenotype of cerebellar atrophy, developmental delay and seizures. CASE REPORT: Herein; we report a patient with a novel homozygous truncating mutation in KCNMA1 (p...
March 16, 2018: Balkan Medical Journal
Huihui Sun, Naijun Wan, Xinli Wang, Liang Chang, Dazhi Cheng
18p deletion syndrome is a rare chromosomal disease caused by deletion of the short arm of chromosome 18. By using cytogenetic and SNP array analysis, we identified a girl with 18p deletion syndrome exhibiting craniofacial anomalies, intellectual disability, and short stature. G-banding analysis of metaphase cells revealed an abnormal karyotype 46,XX,del(18)(p10). Further, SNP array detected a 15.3-Mb deletion at 18p11.21p11.32 (chr18:12842-15375878) including 61 OMIM genes. Genotype-phenotype correlation analysis showed that clinical manifestations of the patient were correlated with LAMA1, TWSG1, and GNAL deletions...
March 16, 2018: Cytogenetic and Genome Research
Saud Alsahli, Muhammad Talal Alrifai, Saeed Al Tala, Fuad Al Mutairi, Majid Alfadhel
Background: Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) is a heterogeneous group of genetic disorders that have been grouped by shared clinical features; all of these features are transmitted via an autosomal recessive mechanism. Four variants of this syndrome have been identified so far, and each one differs in terms of both clinical and genotypical features. CAMRQ4 is a rare genetic disorder characterized by mental retardation, ataxia or an inability to walk, dysarthria and, in some patients, quadrupedal gait...
2018: Journal of Central Nervous System Disease
Tae-Yong Choi, Seung-Hyun Lee, Yoon-Jung Kim, Jae Ryul Bae, Kwang Min Lee, Youhwa Jo, Soo-Jeong Kim, A-Ram Lee, Sekyu Choi, La-Mee Choi, Sunhoe Bang, Mi-Ryoung Song, Jongkyeong Chung, Kyung Jin Lee, Sung Hyun Kim, Chul-Seung Park, Se-Young Choi
Mutations in the cereblon ( CRBN ) gene cause human intellectual disability, one of the most common cognitive disorders. However, the molecular mechanisms of CRBN -related intellectual disability remain poorly understood. We investigated the role of CRBN in synaptic function and animal behavior using male mouse and Drosophila models. Crbn knockout (KO) mice showed normal brain and spine morphology as well as intact synaptic plasticity; however, they also exhibited decreases in synaptic transmission and presynaptic release probability exclusively in excitatory synapses...
March 12, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Davide Caputo, Marina Trivisano, Federico Vigevano, Lucia Fusco
CHD2 gene has been described in association with different types of childhood myoclonic epilepsy and is emerging as a gene involved in photosensitivity alone or combined with epilepsy. Recent studies suggest that CHD2 could be responsible for a proper phenotype characterized by infantile-onset generalized epilepsy, intellectual disability, and photosensitivity and in particular with self-induced seizures. We report the case of a child with CHD2 mutation and mild developmental impairment that since the age of 3 years started with myoclonic seizures apparently well responding to antiepileptic drugs and that subsequently developed intractable self-induced seizures...
March 3, 2018: Seizure: the Journal of the British Epilepsy Association
Katherine E Manning, Roger Tait, John Suckling, Anthony J Holland
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder of genomic imprinting, presenting with a characteristic overeating disorder, mild to moderate intellectual disability, and a variable range of social and behavioral difficulties. Consequently, widespread alterations in neural structure and developmental and maturational trajectory would be expected. To date, there have been few quantitative and systematic studies of brain morphology in PWS, although alterations of volume and of cortical organisation have been reported...
2018: NeuroImage: Clinical
Yonatan Perez, Shay Menascu, Idan Cohen, Rotem Kadir, Omer Basha, Zamir Shorer, Hila Romi, Gal Meiri, Tatiana Rabinski, Rivka Ofir, Esti Yeger-Lotem, Ohad S Birk
RSRC1, whose polymorphism is associated with altered brain function in schizophrenia, is a member of the serine and arginine rich-related protein family. Through homozygosity mapping and whole exome sequencing we show that RSRC1 mutation causes an autosomal recessive syndrome of intellectual disability, aberrant behaviour, hypotonia and mild facial dysmorphism with normal brain MRI. Further, we show that RSRC1 is ubiquitously expressed, and that the RSRC1 mutation triggers nonsense-mediated mRNA decay of the RSRC1 transcript in patients' fibroblasts...
March 7, 2018: Brain: a Journal of Neurology
Jonathan R I Coleman, Julien Bryois, Héléna A Gaspar, Philip R Jansen, Jeanne E Savage, Nathan Skene, Robert Plomin, Ana B Muñoz-Manchado, Sten Linnarsson, Greg Crawford, Jens Hjerling-Leffler, Patrick F Sullivan, Danielle Posthuma, Gerome Breen
Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta-analyzed with a study comparing 1247 individuals with mean IQ ~170 to 8185 controls...
March 8, 2018: Molecular Psychiatry
A Özge Sungur, Lea Stemmler, Markus Wöhr, Marco B Rust
Autism spectrum disorder (ASD), schizophrenia (SCZ) and intellectual disability (ID) show a remarkable overlap in symptoms, including impairments in cognition, social behavior and communication. Human genetic studies revealed an enrichment of mutations in actin-related genes for these disorders, and some of the strongest candidate genes control actin dynamics. These findings led to the hypotheses: (i) that ASD, SCZ and ID share common disease mechanisms; and (ii) that, at least in a subgroup of affected individuals, defects in the actin cytoskeleton cause or contribute to their pathologies...
2018: Frontiers in Behavioral Neuroscience
K J Low, K Stals, R Caswell, M Wakeling, J Clayton-Smith, A Donaldson, N Foulds, A Norman, M Splitt, K Urankar, K Vijayakumar, A Majumdar, Ddd Study, S Ellard, S F Smithson
CHN is genetically heterogeneous and its genetic basis is difficult to determine on features alone. CNTNAP1 encodes CASPR, integral in the paranodal junction high molecular mass complex. Nineteen individuals with biallelic variants have been described in association with severe congenital hypomyelinating neuropathy, respiratory compromise, profound intellectual disability and death within the first year. We report 7 additional patients ascertained through exome sequencing. We identified 9 novel CNTNAP1 variants in 6 families: three missense variants, four nonsense variants, one frameshift variant and one splice site variant...
March 6, 2018: European Journal of Human Genetics: EJHG
Stéphanie Moortgat, Damien Lederer, Marie Deprez, Marga Buzatu, Philippe Clapuyt, Sébastien Boulanger, Valérie Benoit, Sandrine Mary, Agnès Guichet, Alban Ziegler, Estelle Colin, Dominique Bonneau, Isabelle Maystadt
Mutations in the oligophrenin 1 gene (OPHN1) have been identified in patients with X-linked intellectual disability (XLID) associated with cerebellar hypoplasia and ventriculomegaly, suggesting it could be a recognizable syndromic intellectual disability (ID). Affected individuals share additional clinical features including speech delay, seizures, strabismus, behavioral difficulties, and slight facial dysmorphism. OPHN1 is located in Xq12 and encodes a Rho-GTPase-activating protein involved in the regulation of the G-protein cycle...
March 3, 2018: European Journal of Medical Genetics
J Lévy, D Haye, N Marziliano, G Casu, F Guimiot, C Dupont, N Teissier, B Benzacken, P Gressens, E Pipiras, A Verloes, A-C Tabet
Ephrin B2, one of the ligand of the EphB receptors, is involved in a complex signaling pathway regulating the development of the nervous system, neuronal migration, erythropoiesis and vasculogenesis. We report a patient with a de novo variant in EFNB2 and a family in which segregates a 610-kb deletion at chromosome 13q33 encompassing only ARGLU1 and EFNB2 genes. The de novo variant was observed in a patient with anal stenosis, hypoplastic left ventricle and mild developmental delay. The deletion was identified in 2 sibs with congenital heart defect and mild developmental delay...
March 6, 2018: Clinical Genetics
María López, Alberto García-Oguiza, Judith Armstrong, Inmaculada García-Cobaleda, Sixto García-Miñaur, Fernando Santos-Simarro, Verónica Seidel, Elena Domínguez-Garrido
BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder characterized by broad thumbs and halluces. RSTS is caused by mutations in CREBBP and in EP300 genes in 50-60% and 8%, respectively. Up to now, 76 RSTS-EP300 patients have been described. We present the clinical and molecular characterization of a cohort of RSTS patients carrying EP300 mutations. METHODS: Patients were selected from a cohort of 72 individuals suspected of RSTS after being negative in CREBBP study...
March 5, 2018: BMC Medical Genetics
Elisa Tassano, Sara Uccella, Thea Giacomini, Mariasavina Severino, Laura Siri, Marcella Gherzi, Maria Elena Celle, Simona Porta, Giorgio Gimelli, Patrizia Ronchetto
Heterogeneous clinical and neuropsychological features, such as intellectual disability, developmental and language delay, hypotonia, and, to a lesser extent, microcephaly that is present in about the half of the reported patients, characterize the 3q29 microduplication syndrome with usually a milder phenotype compared with the corresponding 3q29 microdeletion syndrome. The duplications described so far range from 2.3 Mb to 1.6 Mb, spanning from TFRC to BDH1 genes. Here we report on two patients with overlapping interstitial duplications of the 3q29 region differing in size...
March 1, 2018: European Journal of Medical Genetics
John M McCarthy, Bonnie M McCann-Crosby, Megan E Rech, Jiani Yin, Chun-An Chen, May A Ali, HaiThuy N Nguyen, Jennifer L Miller, Christian P Schaaf
BACKGROUND: Nonsense and frameshift mutations in the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13, have been reported to cause Schaaf-Yang syndrome (SYS), a genetic disorder that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties and autism spectrum disorder. Prader-Willi syndrome (PWS) is a genetic disorder characterised by severe infantile hypotonia, hypogonadotrophic hypogonadism, early childhood onset obesity/hyperphagia, developmental delay/intellectual disability and short stature...
March 1, 2018: Journal of Medical Genetics
Georgios Kellaris, Kamal Khan, Shahid M Baig, I-Chun Tsai, Francisca Millan Zamora, Paul Ruggieri, Marvin R Natowicz, Nicholas Katsanis
BACKGROUND: Intellectual disability (ID) is a common condition with a population prevalence frequency of 1-3% and an enrichment for males, driven in part by the contribution of mutant alleles on the X-chromosome. Among the more than 500 genes associated with ID, DDX3X represents an outlier in sex specificity. Nearly all reported pathogenic variants of DDX3X are de novo, affect mostly females, and appear to be loss of function variants, consistent with the hypothesis that haploinsufficiency at this locus on the X-chromosome is likely to be lethal in males...
March 1, 2018: Human Genomics
Sumaira Zamurrad, Hayden A M Hatch, Coralie Drelon, Helen M Belalcazar, Julie Secombe
Mutations in KDM5 family histone demethylases cause intellectual disability in humans. However, the molecular mechanisms linking KDM5-regulated transcription and cognition remain unknown. Here, we establish Drosophila as a model to understand this connection by generating a fly strain harboring an allele analogous to a disease-causing missense mutation in human KDM5C (kdm5A512P ). Transcriptome analysis of kdm5A512P flies revealed a striking downregulation of genes required for ribosomal assembly and function and a concomitant reduction in translation...
February 27, 2018: Cell Reports
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