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neurodevelopmental delay genetics

Masayuki Itoh, Hongmei Dai, Shin-Ichi Horike, John Gonzalez, Yoshikazu Kitami, Makiko Meguro-Horike, Ichiro Kuki, Shuichi Shimakawa, Harumi Yoshinaga, Yoko Ota, Tetsuya Okazaki, Yoshihiro Maegaki, Shin Nabatame, Shin Okazaki, Hisashi Kawawaki, Naoto Ueno, Yu-Ichi Goto, Yoichi Kato
The leukodystrophies cause severe neurodevelopmental defects from birth and follow an incurable and progressive course that often leads to premature death. It has recently been reported that abnormalities in aminoacyl t-RNA synthetase (ARS) genes are linked to various unique leukodystrophies and leukoencephalopathies. Aminoacyl t-RNA synthetase proteins are fundamentally known as the first enzymes of translation, catalysing the conjugation of amino acids to cognate tRNAs for protein synthesis. It is known that certain aminoacyl t-RNA synthetase have multiple non-canonical roles in both transcription and translation, and their disruption results in varied and complicated phenotypes...
February 3, 2019: Brain: a Journal of Neurology
Liang Huo, Ziteng Teng, Hua Wang, Xueyan Liu
BACKGROUND: Pettigrew syndrome (PGS) is a rare X-linked mental retardation that caused by AP1S2 mutation. The pathogenesis of AP1S2 deficiency has remained elusive. The purpose of this study is to give a comprehensive overview of the phenotypic and genetic spectrum of AP1S2 mutations. METHODS: This study systematically analyzed clinical features and genetic information of a Chinese family with AP1S2 variation, and reviewed previously reported literatures with the same gene variation...
February 4, 2019: Brain and Behavior
Melinda Zombor, Tibor Kalmár, Nikoletta Nagy, Marianne Berényi, Borbála Telcs, Zoltán Maróti, Oliver Brandau, László Sztriha
Autosomal recessive primary microcephaly (MCPH) is a group of rare neurodevelopmental diseases with severe microcephaly at birth. One type of the disorder, MCPH2, is caused by biallelic mutations in the WDR62 gene, which encodes the WD repeat-containing protein 62. Patients with WDR62 mutation may have a wide range of malformations of cortical development in addition to congenital microcephaly. We describe two patients, a boy and a girl, with severe congenital microcephaly, global developmental delay, epilepsy, and failure to thrive...
February 1, 2019: Journal of Applied Genetics
Mitsuko Nakashima, Yutaka Negishi, Ikumi Hori, Ayako Hattori, Shinji Saitoh, Hirotomo Saitsu
TBC1D24-related disorders are rare neurodevelopmental disorders that show a broad range of neuropsychiatric deficits and are mostly inherited in an autosomal recessive manner. Here we describe a case with early-onset epileptic encephalopathy, in whom exome sequencing detected a novel pathogenic homozygous c.442G>A, p.(Glu148Lys) variant in TBC1D24. She showed severe developmental delay, congenital sensorineural hearing loss and seizures, but the combination of a high dose phenobarbital and potassium bromide was very effective for the seizures...
January 24, 2019: American Journal of Medical Genetics. Part A
Heba Yasin, William T Gibson, Sylvie Langlois, Robert M Stowe, Erica S Tsang, Leora Lee, Jenny Poon, Grant Tran, Christine Tyson, Chi Kin Wong, Marco A Marra, Jan M Friedman, Farah R Zahir
A decade ago, we described novel de novo submicroscopic deletions of chromosome 14q11.2 in three children with developmental delay, cognitive impairment, and similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip, and auricular anomalies. We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H. The three patients in our original cohort were between 2 years and 3 years of age at the time...
January 22, 2019: Journal of Human Genetics
Catarina Catela, Edgar Correa, Kailong Wen, Jihad Aburas, Laura Croci, G Giacomo Consalez, Paschalis Kratsios
BACKGROUND: Mammalian motor circuits display remarkable cellular diversity with hundreds of motor neuron (MN) subtypes innervating hundreds of different muscles. Extensive research on limb muscle-innervating MNs has begun to elucidate the genetic programs that control animal locomotion. In striking contrast, the molecular mechanisms underlying the development of axial muscle-innervating MNs, which control breathing and spinal alignment, are poorly studied. METHODS: Our previous studies indicated that the function of the Collier/Olf/Ebf (COE) family of transcription factors (TFs) in axial MN development may be conserved from nematodes to simple chordates...
January 18, 2019: Neural Development
David C Gershlick, Morié Ishida, Julie R Jones, Allison Bellomo, Juan S Bonifacino, David B Everman
GARP and EARP are related heterotetrameric protein complexes that associate with the cytosolic face of the trans-Golgi network and recycling endosomes, respectively. At these locations, GARP and EARP function to promote the fusion of endosome-derived transport carriers with their corresponding compartments. GARP and EARP share three subunits, VPS51, VPS52 and VPS53, and each has an additional complex-specific subunit, VPS54 or VPS50, respectively. The role of these complexes in human physiology, however, remains poorly understood...
January 8, 2019: Human Molecular Genetics
Qingming Wang, Xiaoling Huang, Yanhui Liu, Qian Peng, Yuqiong Zhang, Jianxin Liu, Haiming Yuan
Xia-Gibbs syndrome is a rare genetic condition characterized by intellectual disability, growth retardation, delayed psychomotor development with absent or poor expressive language, distinctive facial features, hypotonia, laryngomalacia and obstructive sleep apnea. At present, Xia-Gibbs syndrome has been reported to be mainly caused by truncating mutations in AHDC1 gene located on chromosome 1p36.11. However, the evidence supporting AHDC1 deletion as a cause of this syndrome is still limited. Here we report an 8-year-old boy carrying a de novo 575 Kb microdeletion at 1p36...
January 4, 2019: European Journal of Medical Genetics
Karen J Woodward, Julie Stampalia, Hannah Vanyai, Hashika Rijhumal, Kim Potts, Fiona Taylor, Joanne Peverall, Tanya Grumball, Soruba Sivamoorthy, Hamid Alinejad-Rokny, John Wray, Andrew Whitehouse, Lakshmi Nagarajan, Jacqueline Scurlock, Sabine Afchani, Matthew Edwards, Ashleigh Murch, John Beilby, Gareth Baynam, Cathy Kiraly-Borri, Fiona McKenzie, Julian I T Heng
BACKGROUND: Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. METHODS: We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11...
January 4, 2019: Molecular Genetics & Genomic Medicine
Daniela Prayer, Dario Paladini, Jan Deprest
A ventricular diameter of 10 mm correlates with more than two standard deviations of the normal, hence is qualified as ventriculomegaly. The relevance of it is dependent on whether there are associated infectious, genetic or structural problems. The chance for neurodevelopmental delay in isolated ventriculomegaly less than 15mm is 7.9% (4.7-11.1), and less if it is unilateral. It can be further divided in mild (10-12) or moderate (13-15), though this is not widely accepted. As part of the work-up, structural assessment today may include ultrasound or magnetic resonance imaging, or both...
January 6, 2019: Prenatal Diagnosis
Berihun Assefa Dachew, James G Scott, Abdullah Mamun, Rosa Alati
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent heterogeneous neurodevelopmental syndrome associated with various environmental factors. This study examined the association between maternal pre-eclampsia and offspring ADHD at 7- and 10-years. The study cohort consisted of more than 7200 children who participated in Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study. ADHD was diagnosed using parent reported Development and Wellbeing Assessment (DAWBA). Log-binomial regression and Generalized Estimating Equation (GEE) models were used...
December 25, 2018: Psychiatry Research
Thomas Arbogast, Parisa Razaz, Jacob Ellegood, Spencer McKinstry, Serkan Erdin, Benjamin Currall, Tanya Aneichyk, Jason P Lerch, Lily R Qiu, Ramona M Rodriguiz, R Mark Henkelman, Michael E Talkowski, William C Wetsel, Christelle Golzio, Nicholas Katsanis
The 16p11.2 BP4-BP5 deletion and duplication syndromes are associated with a complex spectrum of neurodevelopmental phenotypes that includes developmental delay and autism spectrum disorder, with a reciprocal effect on head circumference, brain structure and body mass index. Mouse models of the 16p11.2 copy number variant have recapitulated some of the patient phenotypes, while studies in flies and zebrafish have uncovered several candidate contributory genes within the region, as well as complex genetic interactions...
December 26, 2018: Human Molecular Genetics
Maureen Handoko, Lisa T Emrick, Jill A Rosenfeld, Xia Wang, Alyssa A Tran, Alicia Turner, John W Belmont, Brendan H Lee, Carlos A Bacino, Hsiao-Tuan Chao
Genetic alterations leading to overactivation of mammalian target of rapamycin (mTOR) signaling result in brain overgrowth syndromes such as focal cortical dysplasia (FCD) and megalencephaly. Megalencephaly with cutis tri-color of the Blaschko-linear type pigmentary mosaicism and intellectual disability is a rare neurodevelopmental disorder attributed to the recurrent mosaic c.5930C > T (p.Thr1977Ile) MTOR variant. This variant was previously reported at low to intermediate levels of mosaicism in the peripheral blood of three unrelated individuals with consistent clinical findings...
December 19, 2018: American Journal of Medical Genetics. Part A
Taichi Imaizumi, Akira Kumakura, Keiko Yamamoto-Shimojima, Yumko Ondo, Toshiyuki Yamamoto
Because biallelic SZT2 variants have been reported in patients with neurodevelopmental disorders associated with various degrees of developmental delay, intractable seizures, and distinctive features; this condition is recognized as an autosomal recessive disorder. Previously, eleven patients have been reported and most of them have compound heterozygous SZT2 variants, leading to premature termination. In these patients, all reported variants were unique and there were no common pathogenic variants identified...
November 2018: Intractable & Rare Diseases Research
Brooke McKenna, Tanner Koomar, Kevin Vervier, Jamie Kremsreiter, Jacob J Michaelson
Over the past decade, a focus on de novo mutations has rapidly accelerated gene discovery in autism spectrum disorder (ASD), intellectual disability (ID), and other neurodevelopmental disorders (NDDs). However, recent studies suggest that only a minority of cases are attributable to de novo mutations, and instead these disorders often result from an accumulation of various forms of genetic risk. Consequently, we adopted an inclusive approach to investigate the genetic risk contributing to a case of male monozygotic twins with ASD and ID...
December 2018: Cold Spring Harbor Molecular Case Studies
Xiujuan Du, Xueren Gao, Xin Liu, Lixiao Shen, Kai Wang, Yanjie Fan, Yu Sun, Xiaomei Luo, Huili Liu, Lili Wang, Yu Wang, Zhuwen Gong, Jianguo Wang, Yongguo Yu, Fei Li
Autism spectrum disorder (ASD) is a group of clinically and genetically heterogeneous neurodevelopmental disorders. Recent tremendous advances in the whole exome sequencing (WES) enable rapid identification of variants associated with ASD including single nucleotide variations (SNVs) and indels. To further explore genetic etiology of ASD in Chinese children with negative findings of copy number variants (CNVs), we applied WES in 80 simplex families with a single affected offspring with ASD or suspected ASD, and validated variations predicted to be damaging by Sanger sequencing...
2018: Frontiers in Genetics
Florian Studer, Emel Laghouati, Guillaume Jarre, Olivier David, Benoît Pouyatos, Antoine Depaulis
KEY POINTS: Absence epilepsy is characterized by the occurrence of spike-and-wave discharges concomitant with an alteration of consciousness and associated with cognitive comorbidities. In a genetic model of absence epilepsy in the rat, the GAERS, we showed that spike-and-wave discharges are initiated in the barrel field primary somatosensory cortex that codes whisker-related information therefore playing an essential role in rodents' interactions with their environment. Sensory-information processing is impaired in the epileptic barrel field primary somatosensory cortex of GAERS with a delayed sensory-evoked potential and a duplicated neuronal response to whisker-stimulation in in vivo extracellular recordings...
December 13, 2018: Journal of Physiology
Vincent Strehlow, Henrike O Heyne, Danique R M Vlaskamp, Katie F M Marwick, Gabrielle Rudolf, Julitta de Bellescize, Saskia Biskup, Eva H Brilstra, Oebele F Brouwer, Petra M C Callenbach, Julia Hentschel, Edouard Hirsch, Peter C Kind, Cyril Mignot, Konrad Platzer, Patrick Rump, Paul A Skehel, David J A Wyllie, Giles E Hardingham, Conny M A van Ravenswaaij-Arts, Gaetan Lesca, Johannes R Lemke
Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals...
December 12, 2018: Brain: a Journal of Neurology
Nancy Vegas, Mara Cavallin, Camille Maillard, Nathalie Boddaert, Joseph Toulouse, Elise Schaefer, Tally Lerman-Sagie, Dorit Lev, Barth Magalie, Sébastien Moutton, Eric Haan, Bertrand Isidor, Delphine Heron, Mathieu Milh, Stéphane Rondeau, Caroline Michot, Stephanie Valence, Sabrina Wagner, Marie Hully, Cyril Mignot, Alice Masurel, Alexandre Datta, Sylvie Odent, Mathilde Nizon, Leila Lazaro, Marie Vincent, Benjamin Cogné, Anne Marie Guerrot, Stéphanie Arpin, Jean Michel Pedespan, Isabelle Caubel, Benedicte Pontier, Baptiste Troude, Francois Rivier, Christophe Philippe, Thierry Bienvenu, Marie-Aude Spitz, Amandine Bery, Nadia Bahi-Buisson
Objective: To provide new insights into the FOXG1- related clinical and imaging phenotypes and refine the phenotype-genotype correlation in FOXG1 syndrome. Methods: We analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic FOXG1 variant and performed phenotype-genotype correlations. Results: A total of 37 FOXG1 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures...
December 2018: Neurology. Genetics
Teresa H Wen, Jonathan W Lovelace, Iryna M Ethell, Devin K Binder, Khaleel A Razak
Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. Sensory-processing deficits are common in humans with FXS and an animal model, the Fmr1 knockout (KO) mouse, manifesting in the auditory system as debilitating hypersensitivity and abnormal electroencephalographic (EEG) and event-related potential (ERP) phenotypes. FXS is a neurodevelopmental disorder, but how EEG/ERP phenotypes change during development is unclear. Therefore, we characterized baseline and stimulus-evoked EEG in auditory and frontal cortex of developing (postnatal day (P) 21 and P30) and adult (P60) wildtype (WT) and Fmr1 KO mice with the FVB genetic background...
December 5, 2018: Neuroscience
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