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Developmental delay AND whole exome sequencing

Nadia A Akawi, Salma Ben-Salem, Jozef Hertecant, Anne John, Thachillath Pramathan, Praseetha Kizhakkedath, Bassam R Ali, Lihadh Al-Gazali
BACKGROUND: The group of ELAC2-related encephalomyopathies is a recent addition to the rapidly growing heterogeneous mitochondrial disorders. RESULTS: We describe a highly inbred consanguineous Pakistani family with multiple affected children in 2 branches exhibiting moderately severe global developmental delay. Using homozygosity mapping, we mapped the phenotype in this family to a single locus on chromosome 17. In addition, whole-exome sequencing identified a homozygous splicing mutation (c...
October 21, 2016: Orphanet Journal of Rare Diseases
Tomokazu Kimizu, Yukitoshi Takahashi, Taikan Oboshi, Asako Horino, Takayoshi Koike, Shinsaku Yoshitomi, Tatsuo Mori, Tokito Yamaguchi, Hiroko Ikeda, Nobuhiko Okamoto, Mitsuko Nakashima, Hirotomo Saitsu, Mitsuhiro Kato, Naomichi Matsumoto, Katsumi Imai
INTRODUCTION: Mutations of SLC35A2 that encodes Golgi-localized Uridine diphosphate (UDP)-galactose transporter at Xp11.23 lead to congenital disorders of glycosylation (CDG). Although patients with CDG generally have diverse systemic symptoms, patients with a SLC35A2 mutation manifest predominantly disorders of the central nervous system (CNS). CASE REPORT: A female infant aged 12months was referred to our center because of intractable seizures. The patient was born with birth weight of 3228g after 40weeks of unremarkable gestation...
October 12, 2016: Brain & Development
Vandana Shashi, Loren D M Pena, Katherine Kim, Barbara Burton, Maja Hempel, Kelly Schoch, Magdalena Walkiewicz, Heather M McLaughlin, Megan Cho, Nicholas Stong, Scott E Hickey, Christine M Shuss, Michael S Freemark, Jane S Bellet, Martha Ann Keels, Melanie J Bonner, Maysantoine El-Dairi, Megan Butler, Peter G Kranz, Constance T R M Stumpel, Sylvia Klinkenberg, Karin Oberndorff, Malik Alawi, Rene Santer, Slavé Petrovski, Outi Kuismin, Satu Korpi-Heikkilä, Olli Pietilainen, Palotie Aarno, Mitja I Kurki, Alexander Hoischen, Anna C Need, David B Goldstein, Fanny Kortüm
The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder...
October 6, 2016: American Journal of Human Genetics
Fabio Acquaviva, Maria Elena Sana, Matteo Della Monica, Michele Pinelli, Diana Postorivo, Paolo Fontana, Maria Teresa Falco, Anna Maria Nardone, Fortunato Lonardo, Maria Iascone, Gioacchino Scarano
Smith-Magenis syndrome (SMS) is a complex genetic disorder caused by interstitial 17p11.2 deletions encompassing multiple genes, including the retinoic acid induced 1 gene-RAI1-or mutations in RAI1 itself. The clinical spectrum includes developmental delay, cognitive impairment, and behavioral abnormalities, with distinctive physical features that become more evident with age. No patients have been reported to have had offspring. We here describe a girl with developmental delay, mainly compromising the speech area, and her mother with mild intellectual disabilities and minor dysmorphic features...
September 28, 2016: American Journal of Medical Genetics. Part A
Lijiang Ma, Yavuz Bayram, Heather M McLaughlin, Megan T Cho, Alyson Krokosky, Clesson E Turner, Kristin Lindstrom, Caleb P Bupp, Katey Mayberry, Weiyi Mu, Joann Bodurtha, Veronique Weinstein, Neda Zadeh, Wendy Alcaraz, Zöe Powis, Yunru Shao, Daryl A Scott, Andrea M Lewis, Janson J White, Shalani N Jhangiani, Elif Yilmaz Gulec, Seema R Lalani, James R Lupski, Kyle Retterer, Rhonda E Schnur, Ingrid M Wentzensen, Sherri Bale, Wendy K Chung
Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta (PPP1CB) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins...
December 2016: Human Genetics
Fatma Mujgan Sonmez, Eyyup Uctepe, Mehmet Gunduz, Zeliha Gormez, Seval Erpolat, Murat Oznur, Mahmut Samil Sagiroglu, Huseyin Demirci, Esra Gunduz
Coffin-Siris syndrome (CSS) (MIM 135900) is characterized by developmental delay, severe speech impairment, distinctive facial features, hypertrichosis, aplasia or hypoplasia of the distal phalanx or nail of the fifth digit and agenesis of the corpus callosum. Recently, it was shown that mutations in the ARID1B gene are the main cause of CSS, accounting for 76% of identified mutations. Here, we report a 15 year-old female patient who was admitted to our clinic with seizures, speech problems, dysmorphic features, bilaterally big, large thumb, café-au-lait (CAL) spots, obesity and hyperinsulinism...
August 2016: Intractable & Rare Diseases Research
Mari Matsuo, Akemi Yamauchi, Yasushi Ito, Masako Sakauchi, Toshiyuki Yamamoto, Nobuhiko Okamoto, Yoshinori Tsurusaki, Noriko Miyake, Naomichi Matsumoto, Kayoko Saito
We report a case of mandibulofacial dysostosis with microcephaly presenting with seizures. The proband, a 6-year-old Korean boy, had microcephaly, malar and mandibular hypoplasia, and deafness. He showed developmental delay and had suffered recurrent seizures beginning at 21months of age. Electroencephalography revealed occasional spike discharges from the right frontal area. Head magnetic resonance imaging revealed dilatation of the lateral ventricles and a small frontal lobe volume. Whole exome sequencing revealed a de novo frame shift mutation, c...
September 23, 2016: Brain & Development
Karen Low, Tazeen Ashraf, Natalie Canham, Jill Clayton-Smith, Charu Deshpande, Alan Donaldson, Richard Fisher, Frances Flinter, Nicola Foulds, Alan Fryer, Kate Gibson, Ian Hayes, Alison Hills, Susan Holder, Melita Irving, Shelagh Joss, Emma Kivuva, Kathryn Lachlan, Alex Magee, Vivienne McConnell, Meriel McEntagart, Kay Metcalfe, Tara Montgomery, Ruth Newbury-Ecob, Fiona Stewart, Peter Turnpenny, Julie Vogt, David Fitzpatrick, Maggie Williams, Sarah Smithson
KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. We describe 32 KBG patients aged 2-47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent...
November 2016: American Journal of Medical Genetics. Part A
Aneek Das Bhowmik, Neerja Gupta, Ashwin Dalal, Madhulika Kabra
In the present study we report on genetic analysis in a patient with developmental delay, truncal obesity and vision problem, to find the causative mutation. Whole exome sequencing was performed on genomic DNA extracted from whole blood of the patient which revealed a homozygous nonsense variant (c.2816T>A) in exon 8 of ALMS1 gene that results in a stop codon and premature truncation at codon 939 (p.L939Ter) of the protein. The mutation was confirmed by Sanger sequencing. Exome sequencing was helpful in establishing diagnosis of Alstrom syndrome in this patient...
September 21, 2016: Obesity Research & Clinical Practice
Tamar Harel, Wan Hee Yoon, Caterina Garone, Shen Gu, Zeynep Coban-Akdemir, Mohammad K Eldomery, Jennifer E Posey, Shalini N Jhangiani, Jill A Rosenfeld, Megan T Cho, Stephanie Fox, Marjorie Withers, Stephanie M Brooks, Theodore Chiang, Lita Duraine, Serkan Erdin, Bo Yuan, Yunru Shao, Elie Moussallem, Costanza Lamperti, Maria A Donati, Joshua D Smith, Heather M McLaughlin, Christine M Eng, Magdalena Walkiewicz, Fan Xia, Tommaso Pippucci, Pamela Magini, Marco Seri, Massimo Zeviani, Michio Hirano, Jill V Hunter, Myriam Srour, Stefano Zanigni, Richard Alan Lewis, Donna M Muzny, Timothy E Lotze, Eric Boerwinkle, Richard A Gibbs, Scott E Hickey, Brett H Graham, Yaping Yang, Daniela Buhas, Donna M Martin, Lorraine Potocki, Claudio Graziano, Hugo J Bellen, James R Lupski
ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C...
October 6, 2016: American Journal of Human Genetics
Karin Weiss, Paulien A Terhal, Lior Cohen, Michael Bruccoleri, Melita Irving, Ariel F Martinez, Jill A Rosenfeld, Keren Machol, Yaping Yang, Pengfei Liu, Magdalena Walkiewicz, Joke Beuten, Natalia Gomez-Ospina, Katrina Haude, Chin-To Fong, Gregory M Enns, Jonathan A Bernstein, Judith Fan, Garrett Gotway, Mohammad Ghorbani, Koen van Gassen, Glen R Monroe, Gijs van Haaften, Lina Basel-Vanagaite, Xiang-Jiao Yang, Philippe M Campeau, Maximilian Muenke
Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2β, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions...
October 6, 2016: American Journal of Human Genetics
Toshiyuki Yamamoto, Keiko Shimojima, Yumiko Ondo, Katsumi Imai, Pin Fee Chong, Ryutaro Kira, Mitsuhiro Amemiya, Akira Saito, Nobuhiko Okamoto
Next-generation sequencing (NGS) is widely used for the detection of disease-causing nucleotide variants. The challenges associated with detecting copy number variants (CNVs) using NGS analysis have been reported previously. Disease-related exome panels such as Illumina TruSight One are more cost-effective than whole-exome sequencing (WES) because of their selective target regions (~21% of the WES). In this study, CNVs were analyzed using data extracted through a disease-related exome panel analysis and the eXome Hidden Markov Model (XHMM)...
2016: Human Genome Variation
Maya Kuperberg, Dorit Lev, Lubov Blumkin, Ayelet Zerem, Mira Ginsberg, Ilan Linder, Nirit Carmi, Sarah Kivity, Tally Lerman-Sagie, Esther Leshinsky-Silver
Whole exome sequencing enables scanning a large number of genes for relatively low costs. The authors investigate its use for previously undiagnosed pediatric neurological patients. This retrospective cohort study performed whole exome sequencing on 57 patients of "Magen" neurogenetic clinics, with unknown diagnoses despite previous workup. The authors report on clinical features, causative genes, and treatment modifications and provide an analysis of whole exome sequencing utility per primary clinical feature...
August 29, 2016: Journal of Child Neurology
Rachel Webster, Megan T Cho, Kyle Retterer, Francisca Millan, Catherine Nowak, Jessica Douglas, Ayesha Ahmad, Gerald V Raymond, Maria R Johnson, Aurora Pujol, Amber Begtrup, Dianalee McKnight, Orrin Devinsky, Wendy K Chung
Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X-linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss-of-function KIAA2022 mutations have been described previously in fifteen males, born from unaffected carrier mothers, but few females...
August 28, 2016: Clinical Genetics
Eric G Bend, Yue Si, David A Stevenson, Pinar Bayrak-Toydemir, Tara M Newcomb, Erik M Jorgensen, Kathryn J Swoboda
OBJECTIVE: To perform genotype-phenotype analysis in an infant with congenital arthrogryposis due to a de novo missense mutation in the NALCN ion channel and explore the mechanism of pathogenicity using a Caenorhabditis elegans model. METHODS: We performed whole-exome sequencing in a preterm neonate with congenital arthrogryposis and a severe life-threatening clinical course. We examined the mechanism of pathogenicity of the associated NALCN mutation by engineering the orthologous mutation into the nematode C elegans using CRISPR-Cas9...
September 13, 2016: Neurology
Ali Dursun, Dilek Yalnizoglu, Omer F Gerdan, Didem Yucel-Yilmaz, Mahmut S Sagiroglu, Bayram Yuksel, Safak Gucer, Serap Sivri, Riza K Ozgul
We present a novel multisystem disease in two siblings with clinical features resembling a lysosomal storage disease. These included coarse face, dysostosis multiplex, respiratory difficulty, proteinuria with glomerular foamy cells, neurological involvement with developmental delays, pyramidal signs, and severe chronic anemia. Detailed enzymatic analysis for lysosomal diseases and whole-exome sequencing studies excluded known lysosomal storage diseases in the proband. Subsequently, genome-wide genotyping and exome sequencing analysis of the family indicated two large homozygous regions on chromosomes 5 and 12, and strongly suggested that a homozygous p...
August 19, 2016: Clinical Dysmorphology
Jennifer M Bain, Megan T Cho, Aida Telegrafi, Ashley Wilson, Susan Brooks, Christina Botti, Gordon Gowans, Leigh Anne Autullo, Vidya Krishnamurthy, Marcia C Willing, Tomi L Toler, Bruria Ben-Zev, Orly Elpeleg, Yufeng Shen, Kyle Retterer, Kristin G Monaghan, Wendy K Chung
Via whole-exome sequencing, we identified six females from independent families with a common neurodevelopmental phenotype including developmental delay, intellectual disability, autism, hypotonia, and seizures, all with de novo predicted deleterious variants in the nuclear localization signal of Heterogeneous Nuclear Ribonucleoprotein H2, encoded by HNRNPH2, a gene located on the X chromosome. Many of the females also have seizures, psychiatric co-morbidities, and orthopedic, gastrointestinal, and growth problems as well as common dysmorphic facial features...
September 1, 2016: American Journal of Human Genetics
Loai Elsaadany, Mahmoud El-Said, Rehab Ali, Hussein Kamel, Tawfeg Ben-Omran
BACKGROUND: WW domain containing oxidoreductase (WWOX) gene was cloned in 2000; alteration has been seen in many cancer cells. It acts as a tumor suppresser by blocking cell growth and causing apoptosis. WWOX protein showed different expression of mice brain and spinal cord, for which deletion causes seizure and early death. CASE PRESENTATION: Clinical and molecular characteristics of a consanguineous family show a homozygous mutation of WWOX gene at specific bases, causing a debilitating syndrome characterized by growth retardation, intractable epilepsy, intellectual disability, and early death...
2016: BMC Medical Genetics
Indu Sivaraman, Neil R Friedman, Richard A Prayson
Mutation in NALCN (Sodium leak channel, non-selective) gene in humans has been shown to present with a wide spectrum of clinical manifestations including neurodevelopmental impairment, hypotonia and congenital contractures. Distinctive features including episodic ataxia and neuroaxonal dystrophy have also been reported. In this case report, we describe the muscle biopsy findings of a 3-year-old boy who presented with congenital arthrogryposis, hypotonia and developmental delay who has a heterozygous de novo C...
July 26, 2016: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Candice Cornelis, Aad Tibben, Wybo Dondorp, Mieke van Haelst, Annelien L Bredenoord, Nine Knoers, Marcus Düwell, Ineke Bolt, Marieke van Summeren
Parents' preferences for unsolicited findings (UFs) from diagnostic whole-exome sequencing (WES) for their children remain largely unexplored. Our aim was to gain insight into parental considerations favoring acceptance/decline of UFs pertaining to their child. We conducted 20 qualitative, semistructured interviews with parents (n=34) of children with a developmental delay, aged <1 to 17 years, after consenting to WES, but before feedback of results. Key findings from our study were that all parents favored acceptance of UFs for medically actionable conditions in childhood, but that preferences and considerations diverged for UFs with no medical actionability, or only in adulthood, and regarding carrier-status...
July 27, 2016: European Journal of Human Genetics: EJHG
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