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neurodevelopmental delay genetics

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 4, 2018: Neuroscience
Joshi Stephen, Sateesh Maddirevula, Sheela Nampoothiri, John D Burke, Matthew Herzog, Anju Shukla, Katharina Steindl, Ascia Eskin, Siddaramappa J Patil, Pascal Joset, Hane Lee, Lisa J Garrett, Tadafumi Yokoyama, Nicholas Balanda, Steven P Bodine, Nathanial J Tolman, Patricia M Zerfas, Allison Zheng, Georgia Ramantani, Katta M Girisha, Cecilia Rivas, Pujar V Suresh, Abdel Elkahloun, Hessa S Alsaif, Salma M Wakil, Laila Mahmoud, Rehab Ali, Michaela Prochazkova, Ashok B Kulkarni, Tawfeg Ben-Omran, Dilek Colak, H Douglas Morris, Anita Rauch, Julian A Martinez-Agosto, Stanley F Nelson, Fowzan S Alkuraya, William A Gahl, May Christine V Malicdan
Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals...
December 6, 2018: American Journal of Human Genetics
Yanyan Qian, Bingbing Wu, Yulan Lu, Xinran Dong, Qian Qin, Wenhao Zhou, Huijun Wang
Epileptic encephalopathies are severe seizure disorders accompanied by intellectual disability. Whole-exome sequencing technology has enabled the discovery of genetic mutations responsible for a wide range of diseases, and severe epilepsy and neurodevelopmental diseases are often associated with rare de novo mutations. We identified a novel de novo frameshift mutation in the PPP3CA gene encoding calcium-dependent protein phosphatase (calcineurin) catalytic subunit A (c.1255_1256del, p.Ser419Cysfs*31) in an 11...
November 19, 2018: Cold Spring Harbor Molecular Case Studies
Bitten Schönewolf-Greulich, Anne-Marie Bisgaard, Morten Dunø, Cathrine Jespersgaard, Mette Rokkjaer, Lars K Hansen, Eirini Tsoutsou, Christalena Sofokleous, Meral Topcu, Simran Kaur, Nicole J Van Bergen, Karen Brøndum-Nielsen, Martin J Larsen, Kristina P Sørensen, John Christodoulou, Christina R Fagerberg, Zeynep Tümer
Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa)...
November 11, 2018: Clinical Genetics
Gerarda Cappuccio, Annalaura Torella, Mario Mastrangelo, Claudia Carducci, Vincenzo Nigro, Nicola Brunetti-Pierri, Vincenzo Leuzzi
In 2012 Acta Paediatrica published our paper, which reported a possible new form of cerebral folate deficiency, with microcephaly, growth delay, severe intellectual disability and compulsive self-harm behaviour (1). Our patient has now been included in the Telethon Undiagnosed Diseases Program, which aims at providing diagnoses for paediatric patients with an unnamed genetic disease. This article is protected by copyright. All rights reserved.
November 1, 2018: Acta Paediatrica
C Peters, A S P van Trotsenburg, N Schoenmakers
Congenital hypothyroidism (CH) may be primary, due to a defect affecting the thyroid gland itself, or central, due to impaired thyroid-stimulating hormone (TSH)-mediated stimulation of the thyroid gland as a result of hypothalamic or pituitary pathology. Primary CH is the most common neonatal endocrine disorder, traditionally subdivided into thyroid dysgenesis (TD), referring to a spectrum of thyroid developmental abnormalities, and dyshormonogenesis, where a defective molecular pathway for thyroid hormonogenesis results in failure of hormone production by a structurally intact gland...
September 24, 2018: European Journal of Endocrinology
Elana F Pinchefsky, Andrea Accogli, Michael I Shevell, Christine Saint-Martin, Myriam Srour
AIM: Neurodevelopmental outcomes in children with congenital cerebellar malformations (CCMs) remain poorly defined. We aimed to assess whether specific neuroimaging features in CCM patients correlate with neurodevelopmental outcomes. METHOD: Hospital records and neuroimaging of 67 children with CCMs were systematically reviewed. Logistic regression analyses were used to assess associations between specific imaging features and neurodevelopmental outcomes. RESULTS: CCM categories were distributed as follows: 28 percent isolated vermis hypoplasia (n=19), 28 percent global cerebellar hypoplasia (n=19), 15 percent Dandy-Walker malformation (n=10), 13 percent pontocerebellar hypoplasia (PCH, n=9), 9 percent molar tooth malformation (n=6), 3 percent rhombencephalosynapsis (n=2), and 3 percent unilateral cerebellar malformation (n=2)...
October 15, 2018: Developmental Medicine and Child Neurology
Katherine Nelson, Christopher Jackman, Jennifer Bell, Chie-Schin Shih, Katelyn Payne, Stephen Dlouhy, Laurence Walsh
Mutations in the STE20-related kinase adaptor α ( STRADA) gene have been reported to cause an autosomal recessive neurodevelopmental disorder characterized by infantile-onset epilepsy, developmental delay, and craniofacial dysmorphisms. To date, there have been 17 reported individuals diagnosed with STRADA mutations, 16 of which are from a single Old Order Mennonite cohort and share a deletion of exons 9-13. The remaining individual is of consanguineous Indian descent and has a homozygous single-base pair duplication...
December 2018: Journal of Child Neurology
Niu Li, Yirou Wang, Yu Yang, Pengpeng Wang, Hui Huang, Shiyi Xiong, Luming Sun, Min Cheng, Cui Song, Xinran Cheng, Yu Ding, Guoying Chang, Yao Chen, Yufei Xu, Tingting Yu, Ru-En Yao, Yiping Shen, Xiumin Wang, Jian Wang
BACKGROUND: Wiedemann-Steiner syndrome (WDSTS) is a rare genetic disorder characterized by facial gestalt, neurodevelopmental delay, skeletal anomalies and growth retardation, which is caused by variation of KMT2A gene. To date, only 2 Chinese WDSTS patients have been reported. Here, we report the phenotypes and KMT2A gene variations in 14 unrelated Chinese WDSTS patients and investigate the phenotypic differences between the Chinese and French cohorts. METHODS: Next generation sequencing was performed for each patient, and the variants in the KMT2A gene were validated by Sanger sequencing...
October 11, 2018: Orphanet Journal of Rare Diseases
John McCarthy, Philip J Lupo, Erin Kovar, Megan Rech, Bret Bostwick, Daryl Scott, Katerina Kraft, Tony Roscioli, Joel Charrow, Samantha A Schrier Vergano, Edward Lose, Robert Smiegel, Yves Lacassie, Christian P Schaaf
Schaaf-Yang Syndrome (SYS) is a genetic disorder caused by truncating pathogenic variants in the paternal allele of the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13. SYS is a neurodevelopmental disorder that has clinical overlap with Prader-Willi Syndrome in the initial stages of life but becomes increasingly distinct throughout childhood and adolescence. Here, we describe the phenotype of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2...
October 10, 2018: American Journal of Medical Genetics. Part A
Linh Huynh, Fereydoun Hormozdiari
Early prediction of complex disorders (e.g., autism and other neurodevelopmental disorders) is one of the fundamental goals of precision medicine and personalized genomics. An early prediction of complex disorders can improve the prognosis, increase the effectiveness of interventions and treatments, and enhance the life quality of affected patients. Considering the genetic heritability of neurodevelopmental disorders, we are proposing a novel framework for utilizing rare coding variation for early prediction of these disorders in subset of affected samples...
October 8, 2018: Genetics
E Salzano, S E Raible, M Kaur, A Wilkens, G Sperti, R K Tilton, L R Bettini, A Rocca, G Cocchi, A Selicorni, L K Conlin, D McEldrew, R Gupta, S Thakur, K Izumi, I D Krantz
Pallister-Killian syndrome (PKS) is a tissue limited mosaic disorder, characterized by variable degrees of neurodevelopmental delay and intellectual disability, typical craniofacial findings, skin pigmentation anomalies and multiple congenital malformations. The wide phenotypic spectrum of PKS in conjunction with the mosaic distribution of the i(12p) makes PKS an underdiagnosed disorder. Recognition of prenatal findings that should raise a suspicion of PKS is complicated by the fragmentation of data currently available in the literature and challenges in diagnosing a mosaic diagnosis on prenatal testing...
October 5, 2018: American Journal of Medical Genetics. Part A
Naomi Tsuchida, Keisuke Hamada, Masaaki Shiina, Mitsuhiro Kato, Yu Kobayashi, Jun Tohyama, Kazue Kimura, Kyoko Hoshino, Vigneswari Ganesan, Keng Wee Teik, Mitsuko Nakashima, Satomi Mitsuhashi, Takeshi Mizuguchi, Atsushi Takata, Noriko Miyake, Hirotomo Saitsu, Kazuhiro Ogata, Satoko Miyatake, Naomichi Matsumoto
N-methyl-D-aspartate (NMDA) receptors are glutamate-activated ion channels that are widely distributed in the central nervous system and essential for brain development and function. Dysfunction of NMDA receptors has been associated with various neurodevelopmental disorders. Recently, a de novo recurrent GRIN2D missense variant was found in two unrelated patients with developmental and epileptic encephalopathy. In this study, we identified by whole exome sequencing novel heterozygous GRIN2D missense variants in three unrelated patients with severe developmental delay and intractable epilepsy...
October 3, 2018: Clinical Genetics
Lucas L Baltussen, Priscilla D Negraes, Margaux Silvestre, Suzanne Claxton, Max Moeskops, Evangelos Christodoulou, Helen R Flynn, Ambrosius P Snijders, Alysson R Muotri, Sila K Ultanir
Loss-of-function mutations in CDKL5 kinase cause severe neurodevelopmental delay and early-onset seizures. Identification of CDKL5 substrates is key to understanding its function. Using chemical genetics, we found that CDKL5 phosphorylates three microtubule-associated proteins: MAP1S, EB2 and ARHGEF2, and determined the phosphorylation sites. Substrate phosphorylations are greatly reduced in CDKL5 knockout mice, verifying these as physiological substrates. In CDKL5 knockout mouse neurons, dendritic microtubules have longer EB3-labelled plus-end growth duration and these altered dynamics are rescued by reduction of MAP1S levels through shRNA expression, indicating that CDKL5 regulates microtubule dynamics via phosphorylation of MAP1S...
September 28, 2018: EMBO Journal
Mari E K Niemi, Hilary C Martin, Daniel L Rice, Giuseppe Gallone, Scott Gordon, Martin Kelemen, Kerrie McAloney, Jeremy McRae, Elizabeth J Radford, Sui Yu, Jozef Gecz, Nicholas G Martin, Caroline F Wright, David R Fitzpatrick, Helen V Firth, Matthew E Hurles, Jeffrey C Barrett
There are thousands of rare human disorders that are caused by single deleterious, protein-coding genetic variants1 . However, patients with the same genetic defect can have different clinical presentations2-4 , and some individuals who carry known disease-causing variants can appear unaffected5 . Here, to understand what explains these differences, we study a cohort of 6,987 children assessed by clinical geneticists to have severe neurodevelopmental disorders such as global developmental delay and autism, often in combination with abnormalities of other organ systems...
October 2018: Nature
Francesca Scionti, Maria Teresa Di Martino, Licia Pensabene, Valentina Bruni, Daniela Concolino
Submicroscopic chromosomal copy number variations (CNVs), such as deletions and duplications, account for about 15⁻20% of patients affected with developmental delay, intellectual disability, multiple congenital anomalies, and autism spectrum disorder. Most of CNVs are de novo or inherited rearrangements with clinical relevance, but there are also rare inherited imbalances with unknown significance that make difficult the clinical management and genetic counselling. Chromosomal microarrays analysis (CMA) are recognized as the first-line test for CNV detection and are now routinely used in the clinical diagnostic laboratory...
September 14, 2018: High-throughput
Ana Carolina P Cruz, Adriano Ferrasa, Alysson R Muotri, Roberto H Herai
Mitochondria are small cytosolic organelles and the main source of energy production for the cells, especially in the brain. This organelle has its own genome, the mitochondrial DNA (mtDNA), and genetic variants in this molecule can alter the normal energy metabolism in the brain, contributing to the development of a wide assortment of Neurological Disorders (ND), including neurodevelopmental syndromes, neurodegenerative diseases and neuropsychiatric disorders. These ND are comprised by a heterogeneous group of syndromes and diseases that encompass different cognitive phenotypes and behavioral disorders, such as autism, Asperger's syndrome, pervasive developmental disorder, attention deficit hyperactivity disorder, Huntington disease, Leigh Syndrome and bipolar disorder...
September 12, 2018: Mitochondrion
Mona Entezam, Masoumeh Razipour, Saeed Talebi, Mehran Beiraghi Toosi, Mohammad Keramatipour
Microcephaly is a rare neurological disorder, occurs in both isolated and syndromic forms. This classification could be confusing in rare disorders with variable phenotypic characteristics. However, identification of the causative gene through genetic study would allow determining the definite diagnosis. Here we reported a novel missense variant c.1133A>C (p.Lys378Thr) on the 13th exon of PNKP gene identified by whole exome sequencing (WES) in an Iranian multi-affected family with microcephaly, seizures and developmental delay (MCSZ) disorder...
September 5, 2018: Brain & Development
Lidia V Gabis, Shahar Shefer, Noah Gruber, Ravit Raviv, Yoram Cohen, Michal Berkenstadt, Liat Ries-Levavi, Orit Pinhas-Hamiel, Shai Elizur
At the end of the last century Fragile X syndrome was identified, and the main syndrome characteristics were discovered. The syndrome is caused from a flaw in the number of nucleotide repeats that encodes for a regulatory protein which is critical for neural connectivity and normal brain development. The syndrome is characterized by neurodevelopmental and intellectual disabilities, autism spectrum features and other clinical features associated with the same gene aberration. The number of trinucleotide repeats have a direct effect on the outcome and the need for genetic counseling...
August 2018: Harefuah
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