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Developmental delay AND while exome sequencing

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https://www.readbyqxmd.com/read/29574422/maternal-variants-in-nlrp-and-other-maternal-effect-proteins-are-associated-with-multilocus-imprinting-disturbance-in-offspring
#1
Matthias Begemann, Faisal I Rezwan, Jasmin Beygo, Louise E Docherty, Julia Kolarova, Christopher Schroeder, Karin Buiting, Kamal Chokkalingam, Franziska Degenhardt, Emma L Wakeling, Stephanie Kleinle, Daniela González Fassrainer, Barbara Oehl-Jaschkowitz, Claire L S Turner, Michal Patalan, Maria Gizewska, Gerhard Binder, Can Thi Bich Ngoc, Vu Chi Dung, Sarju G Mehta, Gareth Baynam, Julian P Hamilton-Shield, Sara Aljareh, Oluwakemi Lokulo-Sodipe, Rachel Horton, Reiner Siebert, Miriam Elbracht, Isabel Karen Temple, Thomas Eggermann, Deborah J G Mackay
BACKGROUND: Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance...
March 24, 2018: Journal of Medical Genetics
https://www.readbyqxmd.com/read/29558889/naa10-dysfunction-with-normal-nata-complex-activity-in-a-girl-with-non-syndromic-id-and-a-de-novo-naa10-p-v111g-variant-a-case-report
#2
Nina McTiernan, Svein Isungset Støve, Ingvild Aukrust, Marita Torrisen Mårli, Line M Myklebust, Gunnar Houge, Thomas Arnesen
BACKGROUND: The NAA10-NAA15 (NatA) protein complex is an N-terminal acetyltransferase responsible for acetylating ~ 40% of eukaryotic proteins. In recent years, NAA10 variants have been found in patients with an X-linked developmental disorder called Ogden syndrome in its most severe form and, in other familial or de novo cases, with variable degrees of syndromic intellectual disability (ID) affecting both sexes. CASE PRESENTATION: Here we report and functionally characterize a novel and de novo NAA10 (NM_003491...
March 20, 2018: BMC Medical Genetics
https://www.readbyqxmd.com/read/29547829/atypical-pyridoxine-dependent-epilepsy-resulting-from-a-new-homozygous-missense-mutation-in-aldh7a1
#3
Zahraa Haidar, Nadine Jalkh, Sandra Corbani, Ali Fawaz, Eliane Chouery, André Mégarbané
Pyridoxine dependent epilepsy (PDE) is a rare autosomal recessive neurometabolic disorder. In the classical form, seizures are observed within the first month of life, while in the atypical form seizures appear later in life, sometimes as late as at the age of 3 years of life. Both types are unresponsive to conventional anticonvulsant therapy, but can be controlled with pyridoxine monotherapy. Mutations in the ALDH7A1 gene, encoding α-aminoadipic semialdehyde dehydrogenase have been reported to cause this disease in most patients...
March 10, 2018: Seizure: the Journal of the British Epilepsy Association
https://www.readbyqxmd.com/read/29388673/expanding-the-clinical-and-genetic-spectra-of-nkx6-2-related-disorder
#4
C Baldi, A M Bertoli-Avella, N Al-Sannaa, M Alfadhel, K Al-Thilhi, S Alameer, A A Elmonairy, A M Al Shamsi, H A Abdelrahman, L Al-Gazali, A Shawli, F Al Hakami, H Yavuz, K K Kandaswamy, A Rolfs, O Brandau, P Bauer
Hypomyelinating leukodystrophies (HLDs) affect the white matter of the central nervous system, and manifest as neurological disorders. They are genetically heterogeneous. Very recently, biallelic variants in NKX6-2 have been suggested to cause a novel form of autosomal recessive HLD. Using whole exome or whole genome sequencing, we identified the previously reported c.196delC and c.487C>G variants in NKX6-2 in three and two unrelated index cases, respectively; the novel c.608G>A variant was identified in a sixth patient...
February 1, 2018: Clinical Genetics
https://www.readbyqxmd.com/read/29365063/de-novo-mutations-in-grin1-cause-extensive-bilateral-polymicrogyria
#5
Andrew E Fry, Katherine A Fawcett, Nathanel Zelnik, Hongjie Yuan, Belinda A N Thompson, Lilach Shemer-Meiri, Thomas D Cushion, Hood Mugalaasi, David Sims, Neil Stoodley, Seo-Kyung Chung, Mark I Rees, Chirag V Patel, Louise A Brueton, Valérie Layet, Fabienne Giuliano, Michael P Kerr, Ehud Banne, Vardiella Meiner, Tally Lerman-Sagie, Katherine L Helbig, Laura H Kofman, Kristin M Knight, Wenjuan Chen, Varun Kannan, Chun Hu, Hirofumi Kusumoto, Jin Zhang, Sharon A Swanger, Gil H Shaulsky, Ghayda M Mirzaa, Alison M Muir, Heather C Mefford, William B Dobyns, Amanda B Mackenzie, Jonathan G L Mullins, Johannes R Lemke, Nadia Bahi-Buisson, Stephen F Traynelis, Heledd F Iago, Daniela T Pilz
Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy...
January 22, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29304374/biallelic-mutations-in-fut8-cause-a-congenital-disorder-of-glycosylation-with-defective-fucosylation
#6
Bobby G Ng, Gege Xu, Nandini Chandy, Joan Steyermark, Deepali N Shinde, Kelly Radtke, Kimiyo Raymond, Carlito B Lebrilla, Ali AlAsmari, Sharon F Suchy, Zöe Powis, Eissa Ali Faqeih, Susan A Berry, David F Kronn, Hudson H Freeze
Fucosyltransferase 8 (FUT8) encodes a Golgi-localized α1,6 fucosyltransferase that is essential for transferring the monosaccharide fucose into N-linked glycoproteins, a process known as "core fucosylation." Here we describe three unrelated individuals, who presented with intrauterine growth retardation, severe developmental and growth delays with shortened limbs, neurological impairments, and respiratory complications. Each underwent whole-exome sequencing and was found to carry pathogenic variants in FUT8...
January 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29075935/novel-gfm2-variants-associated-with-early-onset-neurological-presentations-of-mitochondrial-disease-and-impaired-expression-of-oxphos-subunits
#7
Ruth I C Glasgow, Kyle Thompson, Inês A Barbosa, Langping He, Charlotte L Alston, Charu Deshpande, Michael A Simpson, Andrew A M Morris, Axel Neu, Ulrike Löbel, Julie Hall, Holger Prokisch, Tobias B Haack, Maja Hempel, Robert McFarland, Robert W Taylor
Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.569G>A, p.(Arg190Gln); c.636delA, p.(Glu213Argfs*3)) and homozygous (c.275A>C, p.(Tyr92Ser)) recessive variants in GFM2 identified by whole exome sequencing (WES) together with histochemical and biochemical findings to support the diagnoses of pathological GFM2 variants in each case...
December 2017: Neurogenetics
https://www.readbyqxmd.com/read/28815955/the-role-of-iqsec2-in-syndromic-intellectual-disability-narrowing-the-diagnostic-odyssey
#8
Benjamin M Helm, Zoe Powis, Carlos E Prada, Olga L Casasbuenas-Alarcon, Tonya Balmakund, G B Schaefer, Stephen G Kahler, Julie Kaylor, Susan Winter, Yuri A Zarate, Samantha A Schrier Vergano
While X-linked intellectual disability (XLID) syndromes pose a diagnostic challenge for clinicians, an increasing number of recognized disorders and their genetic etiologies are providing answers for patients and their families. The availability of clinical exome sequencing is broadening the ability to identify mutations in genes previously unrecognized as causing XLID. In recent years, the IQSEC2 gene, located at Xp11.22, has emerged as the cause of multiple cases of both nonsyndromic and syndromic XLID. Herein we present a case series of six individuals (five males, one female) with intellectual disability and seizures found to have alterations in IQSEC2...
October 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28807008/phenotypic-and-molecular-characterisation-of-cdk13-related-congenital-heart-defects-dysmorphic-facial-features-and-intellectual-developmental-disorders
#9
Bret L Bostwick, Scott McLean, Jennifer E Posey, Haley E Streff, Karen W Gripp, Alyssa Blesson, Nina Powell-Hamilton, Jessica Tusi, David A Stevenson, Ellyn Farrelly, Louanne Hudgins, Yaping Yang, Fan Xia, Xia Wang, Pengfei Liu, Magdalena Walkiewicz, Marianne McGuire, Dorothy K Grange, Marisa V Andrews, Marybeth Hummel, Suneeta Madan-Khetarpal, Elena Infante, Zeynep Coban-Akdemir, Karol Miszalski-Jamka, John L Jefferies, Jill A Rosenfeld, Lisa Emrick, Kimberly M Nugent, James R Lupski, John W Belmont, Brendan Lee, Seema R Lalani
BACKGROUND: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder. METHODS: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts...
August 14, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28747464/lethal-digenic-mutations-in-the-k-channels-kir4-1-kcnj10-and-slack-kcnt1-associated-with-severe-disabling-seizures-and-neurodevelopmental-delay
#10
Sonia Hasan, Ameera Balobaid, Alessandro Grottesi, Omar Dabbagh, Marta Cenciarini, Rifaat Rawashdeh, Afaf Al-Sagheir, Cecilia Bove, Lara Macchioni, Mauro Pessia, Mohammed Al-Owain, Maria Cristina D'Adamo
A 2-yr-old boy presented profound developmental delay, failure to thrive, ataxia, hypotonia, and tonic-clonic seizures that caused the death of the patient. Targeted and whole exome sequencing revealed two heterozygous missense variants: a novel mutation in the KCNJ10 gene that encodes for the inward-rectifying K + channel Kir4.1 and another previously characterized mutation in KCNT1 that encodes for the Na + -activated K + channel known as Slo2.2 or SLACK. The objectives of this study were to perform the clinical and genetic characterization of the proband and his family and to examine the functional consequence of the Kir4...
October 1, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28741757/equivalent-missense-variant-in-the-foxp2-and-foxp1-transcription-factors-causes-distinct-neurodevelopmental-disorders
#11
Elliot Sollis, Pelagia Deriziotis, Hirotomo Saitsu, Noriko Miyake, Naomichi Matsumoto, Mariëtte J V Hoffer, Claudia A L Ruivenkamp, Mariëlle Alders, Nobuhiko Okamoto, Emilia K Bijlsma, Astrid S Plomp, Simon E Fisher
The closely related paralogues FOXP2 and FOXP1 encode transcription factors with shared functions in the development of many tissues, including the brain. However, while mutations in FOXP2 lead to a speech/language disorder characterized by childhood apraxia of speech (CAS), the clinical profile of FOXP1 variants includes a broader neurodevelopmental phenotype with global developmental delay, intellectual disability, and speech/language impairment. Using clinical whole-exome sequencing, we report an identical de novo missense FOXP1 variant identified in three unrelated patients...
November 2017: Human Mutation
https://www.readbyqxmd.com/read/28645799/genotype-phenotype-evaluation-of-med13l-defects-in-the-light-of-a-novel-truncating-and-a-recurrent-missense-mutation
#12
Reza Asadollahi, Markus Zweier, Laura Gogoll, Raphael Schiffmann, Heinrich Sticht, Katharina Steindl, Anita Rauch
A decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextro-looped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation...
September 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28576131/analysis-of-31-year-old-patient-with-syngap1-gene-defect-points-to-importance-of-variants-in-broader-splice-regions-and-reveals-developmental-trajectory-of-syngap1-associated-phenotype-case-report
#13
Darina Prchalova, Marketa Havlovicova, Katalin Sterbova, Viktor Stranecky, Miroslava Hancarova, Zdenek Sedlacek
BACKGROUND: Whole exome sequencing is a powerful tool for the analysis of genetically heterogeneous conditions. The prioritization of variants identified often focuses on nonsense, frameshift and canonical splice site mutations, and highly deleterious missense variants, although other defects can also play a role. The definition of the phenotype range and course of rare genetic conditions requires long-term clinical follow-up of patients. CASE PRESENTATION: We report an adult female patient with severe intellectual disability, severe speech delay, epilepsy, autistic features, aggressiveness, sleep problems, broad-based clumsy gait and constipation...
June 2, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28475290/whole-exome-sequencing-of-families-with-1q21-1-microdeletion-or-microduplication
#14
Ying Qiao, Chansonette Badduke, Flamingo Tang, David Cowieson, Sally Martell, Suzanne M E Lewis, Maria S Peñaherrera, Wendy P Robinson, Allen Volchuk, Evica Rajcan-Separovic
Recurrent microduplications/microdeletions of 1q21.1 are characterized by variable phenotypes ranging from normal development to developmental delay (DD) and congenital anomalies. Their interpretation is challenging especially in families with affected and unaffected carriers. We used whole exome sequencing (WES) to look for sequence variants in two male probands with inherited 1q21.1 CNVs that could explain their more severe phenotypes. One proband had a 1q21.1 deletion transmitted from maternal grandmother, while the other had a paternal duplication...
May 5, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28328138/homozygous-mutation-in-ptrh2-gene-causes-progressive-sensorineural-deafness-and-peripheral-neuropathy
#15
Rajech Sharkia, Stavit A Shalev, Abdelnaser Zalan, Milit Marom-David, Nathan Watemberg, Jill E Urquhart, Sarah B Daly, Sanjeev S Bhaskar, Simon G Williams, William G Newman, Ronen Spiegel, Abdussalam Azem, Orly Elpeleg, Muhammad Mahajnah
PTRH2 is an evolutionarily highly conserved mitochondrial protein that belongs to a family of peptidyl-tRNA hydrolases. Recently, patients from two consanguineous families with mutations in the PTRH2 gene were reported. Global developmental delay associated with microcephaly, growth retardation, progressive ataxia, distal muscle weakness with ankle contractures, demyelinating sensorimotor neuropathy, and sensorineural hearing loss were present in all patients, while facial dysmorphism with widely spaced eyes, exotropia, thin upper lip, proximally placed thumbs, and deformities of the fingers and toes were present in some individuals...
April 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28007989/cad-mutations-and-uridine-responsive-epileptic-encephalopathy
#16
Johannes Koch, Johannes A Mayr, Bader Alhaddad, Christian Rauscher, Jörgen Bierau, Reka Kovacs-Nagy, Karlien L M Coene, Ingrid Bader, Monika Holzhacker, Holger Prokisch, Hanka Venselaar, Ron A Wevers, Felix Distelmaier, Tilman Polster, Steffen Leiz, Cornelia Betzler, Tim M Strom, Wolfgang Sperl, Thomas Meitinger, Saskia B Wortmann, Tobias B Haack
Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing in three families identified biallelic CAD mutations in four children with global developmental delay, epileptic encephalopathy, and anaemia with anisopoikilocytosis...
February 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/27878435/novel-phenotypes-and-loci-identified-through-clinical-genomics-approaches-to-pediatric-cataract
#17
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...
February 2017: Human Genetics
https://www.readbyqxmd.com/read/27640307/recurrent-de-novo-and-biallelic-variation-of-atad3a-encoding-a-mitochondrial-membrane-protein-results-in-distinct-neurological-syndromes
#18
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
https://www.readbyqxmd.com/read/27566442/exome-sequencing-based-identification-of-mutations-in-non-syndromic-genes-among-individuals-with-apparently-syndromic-features
#19
Eriko Nishi, Koji Masuda, Michiko Arakawa, Hiroshi Kawame, Tomoki Kosho, Masashi Kitahara, Noriko Kubota, Eiko Hidaka, Yuki Katoh, Katsuhiko Shirahige, Kosuke Izumi
In a clinical setting, the number of organ systems involved is crucial for the differential diagnosis of congenital genetic disorders. When more than one organ system is involved, a syndromic diagnosis is suspected. In this report, we describe three patients with apparently syndromic features. Exome sequencing identified non-syndromic gene mutations as a potential cause of part of their phenotype. The first patient (Patient 1) is a girl with cleft lip/palate, meningoencephalocele, tetralogy of Fallot, and developmental delay...
November 2016: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/27436265/de-novo-nonsense-and-frameshift-variants-of-tcf20-in-individuals-with-intellectual-disability-and-postnatal-overgrowth
#20
Johanna Schäfgen, Kirsten Cremer, Jessica Becker, Thomas Wieland, Alexander M Zink, Sarah Kim, Isabelle C Windheuser, Martina Kreiß, Stefan Aretz, Tim M Strom, Dagmar Wieczorek, Hartmut Engels
Recently, germline variants of the transcriptional co-regulator gene TCF20 have been implicated in the aetiology of autism spectrum disorders (ASD). However, the knowledge about the associated clinical picture remains fragmentary. In this study, two individuals with de novo TCF20 sequence variants were identified in a cohort of 313 individuals with intellectual disability of unknown aetiology, which was analysed by whole exome sequencing using a child-parent trio design. Both detected variants - one nonsense and one frameshift variant - were truncating...
December 2016: European Journal of Human Genetics: EJHG
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