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Developmental delay AND whole exome sequencing

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https://www.readbyqxmd.com/read/28086757/a-combination-of-genetic-and-biochemical-analyses-for-the-diagnosis-of-pi3k-akt-mtor-pathway-associated-megalencephaly
#1
Yutaka Negishi, Fuyuki Miya, Ayako Hattori, Yoshikazu Johmura, Motoo Nakagawa, Naoki Ando, Ikumi Hori, Takao Togawa, Kohei Aoyama, Kei Ohashi, Shinobu Fukumura, Seiji Mizuno, Ayako Umemura, Yoko Kishimoto, Nobuhiko Okamoto, Mitsuhiro Kato, Tatsuhiko Tsunoda, Mami Yamasaki, Yonehiro Kanemura, Kenjiro Kosaki, Makoto Nakanishi, Shinji Saitoh
BACKGROUND: Constitutive activation of the PI3K-AKT-mTOR pathway (mTOR pathway) underlies megalencephaly in many patients. Yet, prevalence of the involvement of the PI3K-AKT-mTOR pathway in patients with megalencephaly remains to be elucidated, and molecular diagnosis is challenging. Here, we have successfully established a combination of genetic and biochemical methods for diagnosis of mTOR pathway-associated megalencephaly, and have attempted to delineate the clinical characteristics of the disorder...
January 13, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28077841/pars2-and-nars2-mutations-in-infantile-onset-neurodegenerative-disorder
#2
Takeshi Mizuguchi, Mitsuko Nakashima, Mitsuhiro Kato, Keitaro Yamada, Tohru Okanishi, Nina Ekhilevitch, Hanna Mandel, Ayelet Eran, Miyuki Toyono, Yukio Sawaishi, Hirotaka Motoi, Masaaki Shiina, Kazuhiro Ogata, Satoko Miyatake, Noriko Miyake, Hirotomo Saitsu, Naomichi Matsumoto
Here we present four unrelated families with six individuals that have infantile-onset developmental delay/regression and epilepsy. Whole-exome sequencing revealed compound heterozygous mutations, c.[283G>A];[607G>A] in a gene encoding prolyl-tRNA synthetase (PARS2) in one family. Two pairs of compound heterozygous mutations, c.[151C>T];[1184T>G] and c.[707T>G];[594+1G>A], and a homozygous mutation, c.[500A>G];[500A>G], in a gene encoding asparaginyl-tRNA synthetase (NARS2) were also identified in the other three families...
January 12, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28017373/mutations-in-ebf3-disturb-transcriptional-profiles-and-cause-intellectual-disability-ataxia-and-facial-dysmorphism
#3
Frederike Leonie Harms, Katta M Girisha, Andrew A Hardigan, Fanny Kortüm, Anju Shukla, Malik Alawi, Ashwin Dalal, Lauren Brady, Mark Tarnopolsky, Lynne M Bird, Sophia Ceulemans, Martina Bebin, Kevin M Bowling, Susan M Hiatt, Edward J Lose, Michelle Primiano, Wendy K Chung, Jane Juusola, Zeynep C Akdemir, Matthew Bainbridge, Wu-Lin Charng, Margaret Drummond-Borg, Mohammad K Eldomery, Ayman W El-Hattab, Mohammed A M Saleh, Stéphane Bézieau, Benjamin Cogné, Bertrand Isidor, Sébastien Küry, James R Lupski, Richard M Myers, Gregory M Cooper, Kerstin Kutsche
From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic...
January 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27964749/truncating-de-novo-mutations-in-the-kr%C3%A3-ppel-type-zinc-finger-gene-znf148-in-patients-with-corpus-callosum-defects-developmental-delay-short-stature-and-dysmorphisms
#4
Servi J C Stevens, Anthonie J van Essen, Conny M A van Ravenswaaij, Abdallah F Elias, Jaclyn A Haven, Stefan H Lelieveld, Rolph Pfundt, Willy M Nillesen, Helger G Yntema, Kees van Roozendaal, Alexander P Stegmann, Christian Gilissen, Han G Brunner
BACKGROUND: Krüppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF genes encode proteins that recognize specific DNA motifs in gene promotors. They act as transcriptional co-activators or -repressors via interaction with chromatin remodeling proteins and other transcription factors. Only few ZNF genes are currently linked to human disorders and identification of ZNF gene-associated human diseases may help understand their function...
December 13, 2016: Genome Medicine
https://www.readbyqxmd.com/read/27928161/novel-kcnb1-mutation-associated-with-non-syndromic-intellectual-disability
#5
Xénia Latypova, Naomichi Matsumoto, Cécile Vinceslas-Muller, Stéphane Bézieau, Bertrand Isidor, Noriko Miyake
Potassium voltage-gated channel subfamily B member 1 (KCNB1) encodes Kv2.1 potassium channel of crucial role in hippocampal neuron excitation homeostasis. KCNB1 mutations are known to cause early-onset infantile epilepsy. To date, 10 KCNB1 mutations have been described in 11 patients. Using whole-exome sequencing, we identified a novel de novo missense (c.1132G>C, p.V378L) KCNB1 mutation in a patient with global developmental delay, intellectual disability, severe speech impairment, but no episode of epilepsy until the lastly examined age of 6 years old...
December 8, 2016: Journal of Human Genetics
https://www.readbyqxmd.com/read/27903293/personalized-medicine-approach-confirms-a-milder-case-of-abat-deficiency
#6
A Besse, A K Petersen, J V Hunter, V Appadurai, S R Lalani, P E Bonnen
ABAT deficiency (OMIM 613163) is a rare inborn error of metabolism caused by recessive variants in the gene 4-aminobutyric acid transaminase (ABAT), which is responsible for both the catalysis of GABA and maintenance of nucleoside pools in the mitochondria. To date, only a few patients have been reported worldwide. Their clinical presentation has been remarkably consistent with primary features of severe psychomotor retardation, encephalopathy, hypotonia, and infantile-onset refractory epilepsy. We report a new case of ABAT deficiency that marks an important departure from previous clinical findings...
December 1, 2016: Molecular Brain
https://www.readbyqxmd.com/read/27901041/bainbridge-ropers-syndrome-caused-by-loss-of-function-variants-in-asxl3-a-recognizable-condition
#7
Alma Kuechler, Johanna Christina Czeschik, Elisabeth Graf, Ute Grasshoff, Ulrike Hüffmeier, Tiffany Busa, Stefanie Beck-Woedl, Laurence Faivre, Jean-Baptiste Rivière, Ingrid Bader, Johannes Koch, André Reis, Ute Hehr, Olaf Rittinger, Wolfgang Sperl, Tobias B Haack, Thomas Wieland, Hartmut Engels, Holger Prokisch, Tim M Strom, Hermann-Josef Lüdecke, Dagmar Wieczorek
Truncating ASXL3 mutations were first identified in 2013 by Bainbridge et al. as a cause of syndromic intellectual disability in four children with similar phenotypes using whole-exome sequencing. The clinical features - postulated by Bainbridge et al. to be overlapping with Bohring-Opitz syndrome - were developmental delay, severe feeding difficulties, failure to thrive and neurological abnormalities. This condition was included in OMIM as 'Bainbridge-Ropers syndrome' (BRPS, #615485). To date, a total of nine individuals with BRPS have been published in the literature in four reports (Bainbridge et al...
November 30, 2016: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/27900362/de-novo-phip-predicted-deleterious-variants-are-associated-with-developmental-delay-intellectual-disability-obesity-and-dysmorphic-features
#8
Emily Webster, Megan T Cho, Nora Alexander, Sonal Desai, Sakkubai Naidu, Mir Reza Bekheirnia, Andrea Lewis, Kyle Retterer, Jane Juusola, Wendy K Chung
Using whole-exome sequencing, we have identified novel de novo heterozygous pleckstrin homology domain-interacting protein (PHIP) variants that are predicted to be deleterious, including a frameshift deletion, in two unrelated patients with common clinical features of developmental delay, intellectual disability, anxiety, hypotonia, poor balance, obesity, and dysmorphic features. A nonsense mutation in PHIP has previously been associated with similar clinical features. Patients with microdeletions of 6q14.1, including PHIP, have a similar phenotype of developmental delay, intellectual disability, hypotonia, and obesity, suggesting that the phenotype of our patients is a result of loss-of-function mutations...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900360/scn8a-mutation-in-a-child-presenting-with-seizures-and-developmental-delays
#9
Janet Malcolmson, Robert Kleyner, David Tegay, Whit Adams, Kenneth Ward, Justine Coppinger, Lesa Nelson, Miriam H Meisler, Kai Wang, Reid Robison, Gholson J Lyon
The SCN8A gene encodes the sodium voltage-gated channel alpha subunit 8. Mutations in this gene have been associated with early infantile epileptic encephalopathy type 13. With the use of whole-exome sequencing, a de novo missense mutation in SCN8A was identified in a 4-yr-old female who initially exhibited symptoms of epilepsy at the age of 5 mo that progressed to a severe condition with very little movement, including being unable to sit or walk on her own.
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27891590/bi-allelic-iars-mutations-in-a-child-with-intra-uterine-growth-retardation-neonatal-cholestasis-and-mild-developmental-delay
#10
Naama Orenstein, Karin Weiss, Stephanie N Oprescu, Rivka Shapira, Dvora Kidron, Lina Vanagaite-Basel, Anthony Antonellis, Maximilian Muenke
Recently, bi-allelic mutations in cytosolic isoleucyl-tRNA synthetase (IARS) have been described in three individuals with growth delay, hepatic dysfunction, and neurodevelopmental disabilities. Here we report an additional subject with this condition identified by whole-exome sequencing. Our findings support the association between this disorder and neonatal cholestasis with distinct liver pathology. Furthermore, we provide functional data on two novel missense substitutions and expand the phenotype to include mild developmental delay, skin hyper-elasticity, and hypervitaminosis D...
November 28, 2016: Clinical Genetics
https://www.readbyqxmd.com/read/27889060/autosomal-recessive-mutations-in-ap3b2-adaptor-related-protein-complex-3-beta-2-subunit-cause-an-early-onset-epileptic-encephalopathy-with-optic-atrophy
#11
Mirna Assoum, Christophe Philippe, Bertrand Isidor, Laurence Perrin, Periklis Makrythanasis, Neal Sondheimer, Caroline Paris, Jessica Douglas, Gaetan Lesca, Stylianos Antonarakis, Hanan Hamamy, Thibaud Jouan, Yannis Duffourd, Stéphane Auvin, Aline Saunier, Amber Begtrup, Catherine Nowak, Nicolas Chatron, Dorothée Ville, Kamiar Mireskandari, Paolo Milani, Philippe Jonveaux, Guylène Lemeur, Mathieu Milh, Masano Amamoto, Mitsuhiro Kato, Mitsuko Nakashima, Noriko Miyake, Naomichi Matsumoto, Amira Masri, Christel Thauvin-Robinet, Jean-Baptiste Rivière, Laurence Faivre, Julien Thevenon
Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of severe disorders characterized by seizures, interictal epileptiform activity with a disorganized electroencephalography background, developmental regression or retardation, and onset before 1 year of age. Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing...
December 1, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27878435/novel-phenotypes-and-loci-identified-through-clinical-genomics-approaches-to-pediatric-cataract
#12
Nisha Patel, Deepti Anand, Dorota Monies, Sateesh Maddirevula, Arif O Khan, Talal Algoufi, Mohammed Alowain, Eissa Faqeih, Muneera Alshammari, Ahmed Qudair, Hadeel Alsharif, Fatimah Aljubran, Hessa S Alsaif, Niema Ibrahim, Firdous M Abdulwahab, Mais Hashem, Haifa Alsedairy, Mohammed A Aldahmesh, Salil A Lachke, Fowzan S Alkuraya
Pediatric cataract is highly heterogeneous clinically and etiologically. While mostly isolated, cataract can be part of many multisystem disorders, further complicating the diagnostic process. In this study, we applied genomic tools in the form of a multi-gene panel as well as whole-exome sequencing on unselected cohort of pediatric cataract (166 patients from 74 families). Mutations in previously reported cataract genes were identified in 58% for a total of 43 mutations, including 15 that are novel. GEMIN4 was independently mutated in families with a syndrome of cataract, global developmental delay with or without renal involvement...
November 22, 2016: Human Genetics
https://www.readbyqxmd.com/read/27871432/a-novel-mutation-in-pgap2-gene-causes-developmental-delay-intellectual-disability-epilepsy-and-microcephaly-in-consanguineous-saudi-family
#13
Muhammad Imran Naseer, Mahmood Rasool, Mohammed M Jan, Adeel G Chaudhary, Peter Natesan Pushparaj, Adel M Abuzenadah, Mohammad H Al-Qahtani
PGAP2 (Post-GPI Attachment to Proteins 2) gene is involved in lipid remodeling steps of Glycosylphosphatidylinositol (GPI)-anchor maturation. At the surface of the cell this gene is required for proper expression of GPI-anchored proteins. Hyperphosphatasia with mental retardation syndrome-3 is an autosomal recessive disorder usually characterized by severe mental retardation. Mutations in the PGAP2 gene cause hyperphosphatasia mental retardation syndrome-3. We have identified a large consanguineous family from Saudi origin segregating developmental delay, intellectual disability, epilepsy and microcephaly...
December 15, 2016: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/27862890/de-novo-microdeletions-and-point-mutations-affecting-sox2-in-three-individuals-with-intellectual-disability-but-without-major-eye-malformations
#14
Nicola Dennert, Hartmut Engels, Kirsten Cremer, Jessica Becker, Eva Wohlleber, Beate Albrecht, Julia K Ehret, Hermann-Josef Lüdecke, Mohnish Suri, Giulia Carignani, Alessandra Renieri, Guido M Kukuk, Thomas Wieland, Joris Andrieux, Tim M Strom, Dagmar Wieczorek, Anne Dieux-Coëslier, Alexander M Zink
Loss-of-function mutations and deletions of the SOX2 gene are known to cause uni- and bilateral anophthalmia and microphthalmia as well as related disorders such as anophthalmia-esophageal-genital syndrome. Thus, anophthalmia/microphthalmia is the primary indication for targeted, "phenotype first" analyses of SOX2. However, SOX2 mutations are also associated with a wide range of non-ocular abnormalities, such as postnatal growth retardation, structural brain anomalies, hypogenitalism, and developmental delay...
February 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/27852057/novel-mutations-c-28g-t-p-ala10ser-and-c-189g-t-p-glu63asp-in-wdr62-associated-with-early-onset-acanthosis-and-hyperkeratosis-in-a-patient-with-autosomal-recessive-microcephaly-type-2
#15
Santasree Banerjee, Huishuang Chen, Hui Huang, Jing Wu, Zhiyun Yang, Weiping Deng, Dongna Chen, Jianlian Deng, Yan Su, Yang Li, Chao Wu, Ye Wang, Hao Zeng, Yiming Wang, Xunhua Li
Microcephaly (MCPH) is a developmental disorder characterized by reduced brain size and intellectual disability. A proportion of microcephaly is caused by defects in a single gene. Microcephaly 2 (MCPH2) is one of the most frequent subtypes of MCPH.WD repeat-containing protein 62 gene (WDR62) is the most frequently mutated gene in MCPH2 patients. Phenotypes involving dermatological changes in MCPH2 have not been reported. We have identified and investigated a 5-year-old Chinese girl with markedly reduced brain size (86% of normal size), intellectual disability and psychomotor developmental delay...
November 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27818011/human-grin2b-variants-in-neurodevelopmental-disorders
#16
REVIEW
Chun Hu, Wenjuan Chen, Scott J Myers, Hongjie Yuan, Stephen F Traynelis
The development of whole exome/genome sequencing technologies has given rise to an unprecedented volume of data linking patient genomic variability to brain disorder phenotypes. A surprising number of variants have been found in the N-methyl-d-aspartate receptor (NMDAR) gene family, with the GRIN2B gene encoding the GluN2B subunit being implicated in many cases of neurodevelopmental disorders, which are psychiatric conditions originating in childhood and include language, motor, and learning disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), developmental delay, epilepsy, and schizophrenia...
October 2016: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/27811305/ammecr1-a-single-point-mutation-causes-developmental-delay-midface-hypoplasia-and-elliptocytosis
#17
Gaia Andreoletti, Eleanor G Seaby, Jennifer M Dewing, Ita O'Kelly, Katherine Lachlan, Rodney D Gilbert, Sarah Ennis
BACKGROUND: Deletions in the Xq22.3-Xq23 region, inclusive of COL4A5, have been associated with a contiguous gene deletion syndrome characterised by Alport syndrome with intellectual disability (Mental retardation), Midface hypoplasia and Elliptocytosis (AMME). The extrarenal biological and clinical significance of neighbouring genes to the Alport locus has been largely speculative. We sought to discover a genetic cause for two half-brothers presenting with nephrocalcinosis, early speech and language delay and midface hypoplasia with submucous cleft palate and bifid uvula...
November 3, 2016: Journal of Medical Genetics
https://www.readbyqxmd.com/read/27804958/dominant-variants-in-the-splicing-factor-puf60-cause-a-recognizable-syndrome-with-intellectual-disability-heart-defects-and-short-stature
#18
Salima El Chehadeh, Wilhelmina S Kerstjens-Frederikse, Julien Thevenon, Paul Kuentz, Ange-Line Bruel, Christel Thauvin-Robinet, Candace Bensignor, Hélène Dollfus, Vincent Laugel, Jean-Baptiste Rivière, Yannis Duffourd, Caroline Bonnet, Matthieu P Robert, Rodica Isaiko, Morgane Straub, Catherine Creuzot-Garcher, Patrick Calvas, Nicolas Chassaing, Bart Loeys, Edwin Reyniers, Geert Vandeweyer, Frank Kooy, Miroslava Hančárová, Marketa Havlovicová, Darina Prchalová, Zdenek Sedláček, Christian Gilissen, Rolph Pfundt, Jolien S Klein Wassink-Ruiter, Laurence Faivre
Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype...
January 2016: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/27799064/mipep-recessive-variants-cause-a-syndrome-of-left-ventricular-non-compaction-hypotonia-and-infantile-death
#19
Mohammad K Eldomery, Zeynep C Akdemir, F-Nora Vögtle, Wu-Lin Charng, Patrycja Mulica, Jill A Rosenfeld, Tomasz Gambin, Shen Gu, Lindsay C Burrage, Aisha Al Shamsi, Samantha Penney, Shalini N Jhangiani, Holly H Zimmerman, Donna M Muzny, Xia Wang, Jia Tang, Ravi Medikonda, Prasanna V Ramachandran, Lee-Jun Wong, Eric Boerwinkle, Richard A Gibbs, Christine M Eng, Seema R Lalani, Jozef Hertecant, Richard J Rodenburg, Omar A Abdul-Rahman, Yaping Yang, Fan Xia, Meng C Wang, James R Lupski, Chris Meisinger, V Reid Sutton
BACKGROUND: Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease. METHODS: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia...
November 1, 2016: Genome Medicine
https://www.readbyqxmd.com/read/27789416/compound-heterozygous-variants-in-nbas-as-a-cause-of-atypical-osteogenesis-imperfecta
#20
M Balasubramanian, J Hurst, S Brown, N J Bishop, P Arundel, C DeVile, R C Pollitt, L Crooks, D Longman, J F Caceres, F Shackley, S Connolly, J H Payne, A C Offiah, D Hughes, M J Parker, W Hide, T M Skerry
BACKGROUND: Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit. REPORT: Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence)...
January 2017: Bone
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