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Article ; Online: Autism questionnaire scores do not only rise because of autism.

Fombonne, Eric / Morotti, Hadley / Mastel, Sarah / Keller, Kory / Barnard, Rebecca A / Hall, Trevor / O'Roak, Brian J

Developmental medicine and child neurology

2020 Volume 63, Issue 2, Page(s) 235–236

MeSH term(s)	Attention Deficit Disorder with Hyperactivity ; Autistic Disorder/diagnosis ; Child ; Humans ; Neurofibromatosis 1 ; Psychometrics ; Surveys and Questionnaires
Language	English
Publishing date	2020-10-28
Publishing country	England
Document type	Letter ; Comment
ZDB-ID	80369-8
ISSN	1469-8749 ; 0012-1622
ISSN (online)	1469-8749
ISSN	0012-1622
DOI	10.1111/dmcn.14725
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Article ; Online: Autism and attention-deficit/hyperactivity disorders and symptoms in children with neurofibromatosis type 1.

Morotti, Hadley / Mastel, Sarah / Keller, Kory / Barnard, Rebecca A / Hall, Trevor / O'Roak, Brian J / Fombonne, Eric

Developmental medicine and child neurology

2020 Volume 63, Issue 2, Page(s) 226–232

Abstract: Aim: To evaluate if autism symptoms and diagnoses are more common in children with neurofibromatosis type 1 (NF1) than in typically developing children, to which levels, and to determine if co-occurring attention-deficit/hyperactivity disorder (ADHD) ... ...

Abstract	Aim: To evaluate if autism symptoms and diagnoses are more common in children with neurofibromatosis type 1 (NF1) than in typically developing children, to which levels, and to determine if co-occurring attention-deficit/hyperactivity disorder (ADHD) symptomatology accounts for this increase. Method: We searched hospital electronic medical records (EMR) for International Classification of Diseases, 10th Revision NF1 and co-occurring diagnoses codes. We recruited a subsample of 45 children (mean age 9y 2mo; SD 2y 7mo; range 5-12y; 22 males, 23 females) and collected parental reports of autism symptomatology, adaptive behavior, and behavioral problems that were compared to those of 360 age- and sex-matched controls from the Simons Simplex Collection (SSC) with autism spectrum disorder (ASD; SSC-ASD) or typically developing (SSC-TD). Results: The EMR search identified 968 children with NF1; 8.8% had ADHD and 2.1% had ASD co-occurring diagnoses. In the subsample, the mean autism scale score for participants with NF1 was below cut-off for significant autism symptoms. Participants with NF1 had significantly more autism and behavioral symptoms than SSC-TD participants, and significantly less than SSC-ASD participants, with one exception: ADHD symptom levels were similar to those of SSC-ASD participants. In analyses that controlled for internalizing, ADHD, and communication scores, the difference in autism symptom levels between participants with NF1 and typically developing controls disappeared almost entirely. Interpretation: Our results do not support an association between NF1 and autism, both at the symptom and disorder levels. What this paper adds: Diagnoses of attention-deficit/hyperactivity disorder (ADHD) were more common in children with neurofibromatosis type 1 (NF1) than in the general child population. Diagnoses of autism spectrum disorder were no more common in children with NF1 than in the general child population. Increases in autism symptoms did not reach clinically significant thresholds. Co-occurring ADHD symptoms accounted for increased autism questionnaire scores. Adaptive behavior in participants with NF1 showed normal socialization but lower communication proficiency.
MeSH term(s)	Attention Deficit Disorder with Hyperactivity/epidemiology ; Attention Deficit Disorder with Hyperactivity/physiopathology ; Autism Spectrum Disorder/epidemiology ; Autism Spectrum Disorder/physiopathology ; Child ; Child, Preschool ; Comorbidity ; Electronic Health Records ; Female ; Humans ; Male ; Neurofibromatosis 1/epidemiology
Language	English
Publishing date	2020-05-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80369-8
ISSN	1469-8749 ; 0012-1622
ISSN (online)	1469-8749
ISSN	0012-1622
DOI	10.1111/dmcn.14558
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Article ; Online: De novo apparent loss-of-function mutations in PRR12 in three patients with intellectual disability and iris abnormalities.

Leduc, Magalie S / Mcguire, Marianne / Madan-Khetarpal, Suneeta / Ortiz, Damara / Hayflick, Susan / Keller, Kory / Eng, Christine M / Yang, Yaping / Bi, Weimin

Human genetics

2018 Volume 137, Issue 3, Page(s) 257–264

Abstract: PRR12 encodes a proline-rich protein nuclear factor suspected to be involved in neural development. Its nuclear expression in fetal brains and in the vision system supports its role in brain and eye development more specifically. However, its function ... ...

Abstract	PRR12 encodes a proline-rich protein nuclear factor suspected to be involved in neural development. Its nuclear expression in fetal brains and in the vision system supports its role in brain and eye development more specifically. However, its function and potential role in human disease has not been determined. Recently, a de novo t(10;19) (q22.3;q13.33) translocation disrupting the PRR12 gene was detected in a girl with intellectual disability and neuropsychiatric alterations. Here we report on three unrelated patients with heterozygous de novo apparent loss-of-function mutations in PRR12 detected by clinical whole exome sequencing: c.1918G>T (p.Glu640), c.4502_4505delTGCC (p.Leu1501Argfs146) and c.903_909dup (p.Pro304Thrfs*46). All three patients had global developmental delay, intellectual disability, eye and vision abnormalities, dysmorphic features, and neuropsychiatric problems. Eye abnormalities were consistent among the three patients and consisted of stellate iris pattern and iris coloboma. Additional variable clinical features included hypotonia, skeletal abnormalities, sleeping problems, and behavioral issues such as autism and anxiety. In summary, we propose that haploinsufficiency of PRR12 is associated with this novel multisystem neurodevelopmental disorder.
MeSH term(s)	Child ; Child, Preschool ; Exome/genetics ; Eye Abnormalities/genetics ; Eye Abnormalities/physiopathology ; Female ; Haploinsufficiency/genetics ; Heterozygote ; Humans ; Intellectual Disability/genetics ; Intellectual Disability/physiopathology ; Iris Diseases/genetics ; Iris Diseases/physiopathology ; Loss of Function Mutation/genetics ; Male ; Membrane Proteins/genetics ; Phenotype ; Proline-Rich Protein Domains/genetics ; Translocation, Genetic/genetics ; Whole Exome Sequencing
Chemical Substances	Membrane Proteins ; PRR12 protein, human
Language	English
Publishing date	2018-03-19
Publishing country	Germany
Document type	Journal Article
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-018-1877-0
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Article ; Online: Two de novo novel mutations in one SHANK3 allele in a patient with autism and moderate intellectual disability.

Zhu, Wenmiao / Li, Jianli / Chen, Stella / Zhang, Jinglan / Vetrini, Francesco / Braxton, Alicia / Eng, Christine M / Yang, Yaping / Xia, Fan / Keller, Kory L / Okinaka-Hu, Leila / Lee, Chung / Holder, J Lloyd / Bi, Weimin

American journal of medical genetics. Part A

2018 Volume 176, Issue 4, Page(s) 973–979

Abstract: SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan-McDermid syndrome, ... ...

Abstract	SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan-McDermid syndrome, also called 22q13.3 deletion syndrome, a neurodevelopmental disorder with common features including global developmental delay, absent to severely impaired language, autistic behavior, and minor dysmorphic features. By whole exome sequencing, we identified two de novo novel variants including one frameshift pathogenic variant and one missense variant of unknown significance in a 14-year-old boy with delayed motor milestones, delayed language acquisition, autism, intellectual disability, ataxia, progressively worsening spasticity of the lower extremities, dysmorphic features, short stature, microcephaly, failure to thrive, chronic constipation, intrauterine growth restriction, and bilateral inguinal hernias. Both changes are within the CpG island in exon 21, separated by a 375 bp sequence. Next generation sequencing of PCR products revealed that the two variants are most frequently associated with each other. Sanger sequencing of the cloned PCR products further confirmed that both changes were on a single allele. The clinical presentation in this individual is consistent with other patients with a truncating mutation in exon 21, suggesting that the missense change contributes none or minimally to the phenotypes. This is the first report of two de novo mutations in one SHANK3 allele.
MeSH term(s)	Adolescent ; Alleles ; Autistic Disorder/diagnosis ; Autistic Disorder/genetics ; DNA Mutational Analysis ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Intellectual Disability/diagnosis ; Intellectual Disability/genetics ; Male ; Mutation ; Nerve Tissue Proteins/genetics ; Phenotype ; Whole Exome Sequencing
Chemical Substances	Nerve Tissue Proteins ; SHANK3 protein, human
Language	English
Publishing date	2018-02-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1493479-6
ISSN	1552-4833 ; 1552-4825
ISSN (online)	1552-4833
ISSN	1552-4825
DOI	10.1002/ajmg.a.38622
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Article: Concurrence of fragile X syndrome and 47, XYY in an individual with a Prader-Willi-like phenotype.

Stalker, Heather J / Keller, Kory L / Gray, Brian A / Zori, Roberto T

American journal of medical genetics. Part A

2002 Volume 116A, Issue 2, Page(s) 176–178

Abstract: We report on a 34-year-old developmentally disabled man referred to our clinic for evaluation of possible Prader-Willi syndrome on the basis of obesity and voracious appetite. Cytogenetic and molecular analysis revealed a 47, XYY karyotype and the ... ...

Abstract	We report on a 34-year-old developmentally disabled man referred to our clinic for evaluation of possible Prader-Willi syndrome on the basis of obesity and voracious appetite. Cytogenetic and molecular analysis revealed a 47, XYY karyotype and the presence of a trinucleotide repeat expansion resulting in fragile X syndrome. To our knowledge, this is the first report of concurrence of XYY and fragile X syndrome in the medical literature. Review of sex chromosome abnormalities associated with fragile X syndrome and phenotypic considerations are presented.
MeSH term(s)	Abnormalities, Multiple/genetics ; Abnormalities, Multiple/pathology ; Adult ; Fragile X Syndrome/genetics ; Fragile X Syndrome/pathology ; Humans ; Intellectual Disability/pathology ; Male ; Obesity/pathology ; Phenotype ; Prader-Willi Syndrome/genetics ; Prader-Willi Syndrome/pathology ; XYY Karyotype/genetics ; XYY Karyotype/pathology
Language	English
Publishing date	2002-12-18
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	2108614-X
ISSN	1552-4825
ISSN	1552-4825
DOI	10.1002/ajmg.a.10001
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Article ; Online: PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features.

Low, Karen J / Ansari, Morad / Abou Jamra, Rami / Clarke, Angus / El Chehadeh, Salima / FitzPatrick, David R / Greenslade, Mark / Henderson, Alex / Hurst, Jane / Keller, Kory / Kuentz, Paul / Prescott, Trine / Roessler, Franziska / Selmer, Kaja K / Schneider, Michael C / Stewart, Fiona / Tatton-Brown, Katrina / Thevenon, Julien / Vigeland, Magnus D /

Vogt, Julie / Willems, Marjolaine / Zonana, Jonathan / Study, D D D / Smithson, Sarah F

European journal of human genetics : EJHG

2017 Volume 25, Issue 5, Page(s) 552–559

Abstract: PUF60 encodes a nucleic acid-binding protein, a component of multimeric complexes regulating RNA splicing and transcription. In 2013, patients with microdeletions of chromosome 8q24.3 including PUF60 were found to have developmental delay, microcephaly, ... ...

Abstract	PUF60 encodes a nucleic acid-binding protein, a component of multimeric complexes regulating RNA splicing and transcription. In 2013, patients with microdeletions of chromosome 8q24.3 including PUF60 were found to have developmental delay, microcephaly, craniofacial, renal and cardiac defects. Very similar phenotypes have been described in six patients with variants in PUF60, suggesting that it underlies the syndrome. We report 12 additional patients with PUF60 variants who were ascertained using exome sequencing: six through the Deciphering Developmental Disorders Study and six through similar projects. Detailed phenotypic analysis of all patients was undertaken. All 12 patients had de novo heterozygous PUF60 variants on exome analysis, each confirmed by Sanger sequencing: four frameshift variants resulting in premature stop codons, three missense variants that clustered within the RNA recognition motif of PUF60 and five essential splice-site (ESS) variant. Analysis of cDNA from a fibroblast cell line derived from one of the patients with an ESS variants revealed aberrant splicing. The consistent feature was developmental delay and most patients had short stature. The phenotypic variability was striking; however, we observed similarities including spinal segmentation anomalies, congenital heart disease, ocular colobomata, hand anomalies and (in two patients) unilateral renal agenesis/horseshoe kidney. Characteristic facial features included micrognathia, a thin upper lip and long philtrum, narrow almond-shaped palpebral fissures, synophrys, flared eyebrows and facial hypertrichosis. Heterozygote loss-of-function variants in PUF60 cause a phenotype comprising growth/developmental delay and craniofacial, cardiac, renal, ocular and spinal anomalies, adding to disorders of human development resulting from aberrant RNA processing/spliceosomal function.
MeSH term(s)	Abnormalities, Multiple/diagnosis ; Abnormalities, Multiple/genetics ; Cells, Cultured ; Child ; Codon, Terminator/genetics ; Exome ; Female ; Heterozygote ; Humans ; Intellectual Disability/diagnosis ; Intellectual Disability/genetics ; Male ; Microcephaly/diagnosis ; Microcephaly/genetics ; Mutation, Missense ; Phenotype ; RNA Splicing Factors/genetics ; Repressor Proteins/genetics ; Syndrome
Chemical Substances	Codon, Terminator ; RNA Splicing Factors ; Repressor Proteins ; poly-U binding splicing factor 60KDa
Language	English
Publishing date	2017-03-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/ejhg.2017.27
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Article ; Online: Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?

Morimoto, Marie / Myung, Clara / Beirnes, Kimberly / Choi, Kunho / Asakura, Yumi / Bokenkamp, Arend / Bonneau, Dominique / Brugnara, Milena / Charrow, Joel / Colin, Estelle / Davis, Amira / Deschenes, Georges / Gentile, Mattia / Giordano, Mario / Gormley, Andrew K / Govender, Rajeshree / Joseph, Mark / Keller, Kory / Lerut, Evelyne /

Levtchenko, Elena / Massella, Laura / Mayfield, Christy / Najafian, Behzad / Parham, David / Spranger, Jurgen / Stenzel, Peter / Yis, Uluc / Yu, Zhongxin / Zonana, Jonathan / Hendson, Glenda / Boerkoel, Cornelius F

Orphanet journal of rare diseases

2016 Volume 11, Issue 1, Page(s) 149

Abstract: Background: Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression ...

Abstract	Background: Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. Results: We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated β-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways. Conclusions: We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.
MeSH term(s)	Animals ; Arteriosclerosis/genetics ; Arteriosclerosis/metabolism ; Child ; Child, Preschool ; DNA Helicases/genetics ; DNA Helicases/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Fluorescent Antibody Technique, Indirect ; Glomerulosclerosis, Focal Segmental/genetics ; Glomerulosclerosis, Focal Segmental/metabolism ; Humans ; Immunologic Deficiency Syndromes/genetics ; Immunologic Deficiency Syndromes/metabolism ; Kidney Diseases/genetics ; Kidney Diseases/metabolism ; Male ; Nephrotic Syndrome/genetics ; Nephrotic Syndrome/metabolism ; Osteochondrodysplasias/genetics ; Osteochondrodysplasias/metabolism ; Pulmonary Embolism/genetics ; Pulmonary Embolism/metabolism ; Receptors, Notch/metabolism ; Wnt Proteins/genetics ; Wnt Proteins/metabolism
Chemical Substances	Receptors, Notch ; Wnt Proteins ; SMARCAL1 protein, human (EC 2.7.7.-) ; DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2016--05
Publishing country	England
Document type	Journal Article
ISSN	1750-1172
ISSN (online)	1750-1172
DOI	10.1186/s13023-016-0519-7
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Article ; Online: Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Gillentine, Madelyn A / Wang, Tianyun / Hoekzema, Kendra / Rosenfeld, Jill / Liu, Pengfei / Guo, Hui / Kim, Chang N / De Vries, Bert B A / Vissers, Lisenka E L M / Nordenskjold, Magnus / Kvarnung, Malin / Lindstrand, Anna / Nordgren, Ann / Gecz, Jozef / Iascone, Maria / Cereda, Anna / Scatigno, Agnese / Maitz, Silvia / Zanni, Ginevra /

Bertini, Enrico / Zweier, Christiane / Schuhmann, Sarah / Wiesener, Antje / Pepper, Micah / Panjwani, Heena / Torti, Erin / Abid, Farida / Anselm, Irina / Srivastava, Siddharth / Atwal, Paldeep / Bacino, Carlos A / Bhat, Gifty / Cobian, Katherine / Bird, Lynne M / Friedman, Jennifer / Wright, Meredith S / Callewaert, Bert / Petit, Florence / Mathieu, Sophie / Afenjar, Alexandra / Christensen, Celenie K / White, Kerry M / Elpeleg, Orly / Berger, Itai / Espineli, Edward J / Fagerberg, Christina / Brasch-Andersen, Charlotte / Hansen, Lars Kjærsgaard / Feyma, Timothy / Hughes, Susan / Thiffault, Isabelle / Sullivan, Bonnie / Yan, Shuang / Keller, Kory / Keren, Boris / Mignot, Cyril / Kooy, Frank / Meuwissen, Marije / Basinger, Alice / Kukolich, Mary / Philips, Meredith / Ortega, Lucia / Drummond-Borg, Margaret / Lauridsen, Mathilde / Sorensen, Kristina / Lehman, Anna / Lopez-Rangel, Elena / Levy, Paul / Lessel, Davor / Lotze, Timothy / Madan-Khetarpal, Suneeta / Sebastian, Jessica / Vento, Jodie / Vats, Divya / Benman, L Manace / Mckee, Shane / Mirzaa, Ghayda M / Muss, Candace / Pappas, John / Peeters, Hilde / Romano, Corrado / Elia, Maurizio / Galesi, Ornella / Simon, Marleen E H / van Gassen, Koen L I / Simpson, Kara / Stratton, Robert / Syed, Sabeen / Thevenon, Julien / Palafoll, Irene Valenzuela / Vitobello, Antonio / Bournez, Marie / Faivre, Laurence / Xia, Kun / Earl, Rachel K / Nowakowski, Tomasz / Bernier, Raphael A / Eichler, Evan E

Genome medicine

2021 Volume 13, Issue 1, Page(s) 63

Abstract: Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with ... ...

Abstract	Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. Methods: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. Results: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Conclusions: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.
MeSH term(s)	Brain/metabolism ; DNA Copy Number Variations/genetics ; Gene Expression Regulation ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genetic Variation ; Heterogeneous-Nuclear Ribonucleoproteins/genetics ; Heterogeneous-Nuclear Ribonucleoproteins/metabolism ; Humans ; Inheritance Patterns/genetics ; Mutation/genetics ; Mutation, Missense/genetics ; Neurodevelopmental Disorders/genetics ; Phenotype ; RNA Processing, Post-Transcriptional/genetics ; Single-Cell Analysis
Chemical Substances	Heterogeneous-Nuclear Ribonucleoproteins
Language	English
Publishing date	2021-04-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-021-00870-6
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Article ; Online: Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations.

Rosenfeld, Jill A / Leppig, Kathleen / Ballif, Blake C / Thiese, Heidi / Erdie-Lalena, Christine / Bawle, Erwati / Sastry, Sujatha / Spence, J Edward / Bandholz, Anne / Surti, Urvashi / Zonana, Jonathan / Keller, Kory / Meschino, Wendy / Bejjani, Bassem A / Torchia, Beth S / Shaffer, Lisa G

Genetics in medicine : official journal of the American College of Medical Genetics

2009 Volume 11, Issue 11, Page(s) 797–805

Abstract: Purpose: Pitt-Hopkins syndrome is characterized by severe mental retardation, characteristic dysmorphic features, and susceptibility to childhood-onset seizures and intermittent episodes of hyperventilation. This syndrome is caused by haploinsufficiency ...

Abstract	Purpose: Pitt-Hopkins syndrome is characterized by severe mental retardation, characteristic dysmorphic features, and susceptibility to childhood-onset seizures and intermittent episodes of hyperventilation. This syndrome is caused by haploinsufficiency of TCF4, which encodes a basic helix-loop-helix transcription factor. Missense, nonsense, splice-site mutations, and gene deletions have been found in individuals with Pitt-Hopkins syndrome. Previous reports have suggested that the Pitt-Hopkins syndrome phenotype is independent of mutation or deletion type. Methods: We screened 13,186 individuals with microarray-based comparative genomic hybridization. We also conducted a review of the literature and statistical analysis of the phenotypic features for all individuals with confirmed mutations or deletions of TCF4. Results: We identified seven individuals with TCF4 deletions. All patients have features consistent with Pitt-Hopkins syndrome, although only three have breathing anomalies, and none has seizures. Our review of previously reported cases with TCF4 mutations and deletions showed that all patients with Pitt-Hopkins syndrome reported to date have severe psychomotor retardation, the onsets of seizures and hyperventilation episodes are limited to the first decade in most reported patients with Pitt-Hopkins syndrome, hyperventilation episodes are more common than seizures and are seen in the oldest patients, and individuals with missense TCF4 mutations are more likely to develop seizures. Conclusions: On the basis of an analysis of published cases, we propose a genotype-phenotype correlation of increased seizure activity with missense TCF4 mutations.
MeSH term(s)	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Child ; Female ; Genotype ; Humans ; Intellectual Disability/genetics ; Intellectual Disability/physiopathology ; Male ; Mutation, Missense ; Phenotype ; Seizures/genetics ; Seizures/physiopathology ; Sequence Deletion ; Syndrome ; Transcription Factor 4 ; Transcription Factors/genetics
Chemical Substances	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; TCF4 protein, human ; Transcription Factor 4 ; Transcription Factors
Language	English
Publishing date	2009-08-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	1455352-1
ISSN	1530-0366 ; 1098-3600
ISSN (online)	1530-0366
ISSN	1098-3600
DOI	10.1097/GIM.0b013e3181bd38a9
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Article: Ovotestes and XY sex reversal in a female with an interstitial 9q33.3-q34.1 deletion encompassing NR5A1 and LMX1B causing features of Genitopatellar syndrome.

Schlaubitz, Silke / Yatsenko, Svetlana A / Smith, Laurie D / Keller, Kory L / Vissers, Lisenka E / Scott, Daryl A / Cai, Wei Wen / Reardon, William / Abdul-Rahman, Omar A / Lammer, Edward J / Lifchez, Caroline A / Magenis, Ellen / Veltman, Joris A / Stankiewicz, Pawel / Zabel, Bernhard U / Lee, Brendan

American journal of medical genetics. Part A

2007 Volume 143A, Issue 10, Page(s) 1071–1081

Abstract: We describe our findings in a 46,XY female with a clinical features of Genitopatellar syndrome (GPS) and confirmed hermaphroditism with ovotestes, and five additional patients with GPS. GPS is a genetic disorder characterized by renal and genital ... ...

Abstract	We describe our findings in a 46,XY female with a clinical features of Genitopatellar syndrome (GPS) and confirmed hermaphroditism with ovotestes, and five additional patients with GPS. GPS is a genetic disorder characterized by renal and genital anomalies, joint dislocation, aplastic or hypoplastic and often displaced patellae, minor facial anomalies, and mental retardation. The genital anomalies clearly distinguish GPS from nail-patella syndrome (NPS) that has similar features, but additionally shows hypoplastic finger- and toenails as found in the 46,XY female. In our patients no mutation was found in the coding regions of WNT4, WNT7A, TBX4, and LMX1B. Fluorescent in situ hybridization (FISH) and array-based comparative genome hybridization (aCGH) analysis showed a 3 Mb deletion of LMX1B, NR6A1, and NR5A1 (SF1) in the 46,XY female. This is the first report of a microdeletion causing haploinsuffiency of LMX1B and NR5A1. The deletion of LMX1B is responsible for the knee anomalies and the deletion of NR5A1 likely causes the sex reversal. Cytogenetic analysis of the five additional patients with diagnosed GPS failed to identify a similar microdeletion, or inversion of a potentially regulatory element between the two genes. This suggests that the locus 9q33-9q34 can be excluded for GPS and that the presented case is unique in its combination of GPS and NPS features caused by a microdeletion associated with loss of function of LMX1B and NR5A1.
MeSH term(s)	Abnormalities, Multiple/genetics ; Child ; Child, Preschool ; Chromosome Banding ; Chromosome Deletion ; Chromosomes, Human, Pair 9 ; DNA Mutational Analysis ; Disorders of Sex Development ; Female ; Gonads/abnormalities ; Homeodomain Proteins/genetics ; Humans ; Infant ; LIM-Homeodomain Proteins ; Male ; Patella/abnormalities ; Receptors, Cytoplasmic and Nuclear/genetics ; Steroidogenic Factor 1 ; Syndrome ; Transcription Factors/genetics
Chemical Substances	Homeodomain Proteins ; LIM homeobox transcription factor 1 beta ; LIM-Homeodomain Proteins ; Receptors, Cytoplasmic and Nuclear ; Steroidogenic Factor 1 ; Transcription Factors
Language	English
Publishing date	2007-04-13
Publishing country	United States
Document type	Case Reports ; Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2108614-X
ISSN	1552-4825
ISSN	1552-4825
DOI	10.1002/ajmg.a.31685
Database	MEDical Literature Analysis and Retrieval System OnLINE

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