Dataset Information

Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual disabilities, epilepsy, and neurobehavioral problems.

ABSTRACT: We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ?1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) genes and that is flanked by large complex low-copy repeats, we identified sites for nonallelic homologous recombination in two patients. There were no cases of this ?1.2 Mb distal 7q11.23 deletion copy number variant identified in over 20,000 control samples surveyed. Three individuals with smaller, nonrecurrent deletions (?180-500 kb) that include HIP1 but not YWHAG suggest that deletion of HIP1 is sufficient to cause neurological disease. Mice with targeted mutation in the Hip1 gene (Hip1?(/)?) develop a neurological phenotype characterized by failure to thrive, tremor, and gait ataxia. Overall, our data characterize a neurodevelopmental and epilepsy syndrome that is likely caused by recurrent and nonrecurrent deletions, including HIP1. These data do not exclude the possibility that YWHAG loss of function is also sufficient to cause neurological phenotypes. Based on the current knowledge of Hip1 protein function and its proposed role in AMPA and NMDA ionotropic glutamate receptor trafficking, we believe that HIP1 haploinsufficiency in humans will be amenable to rational drug design for improved seizure control and cognitive and behavioral function.

SUBMITTER: Ramocki MB

PROVIDER: S-EPMC2997378 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual disabilities, epilepsy, and neurobehavioral problems.

Ramocki Melissa B MB Bartnik Magdalena M Szafranski Przemyslaw P Kołodziejska Katarzyna E KE Xia Zhilian Z Bravo Jaclyn J Miller G Steve GS Rodriguez Diana L DL Williams Charles A CA Bader Patricia I PI Szczepanik Elżbieta E Mazurczak Tomasz T Antczak-Marach Dorota D Coldwell James G JG Akman Cigdem I CI McAlmon Karen K Cohen Melinda P MP McGrath James J Roeder Elizabeth E Mueller Jennifer J Kang Sung-Hae L SH Bacino Carlos A CA Patel Ankita A Bocian Ewa E Shaw Chad A CA Cheung Sau Wai SW Mazurczak Tadeusz T Stankiewicz Paweł P

American journal of human genetics 20101125 6

We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ∼1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monoo ...[more]

PMID: 21109226

Similar Datasets

Project description:Background:PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency. Methods:Diagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation. Results:We have identified seven heterozygous coding mutations, among which six are de novo (not maternal in one). Mutations include four frameshifts, one nonsense mutation in two patients, and one heterozygous missense mutation in the AT Hook domain, predicted to be deleterious and likely to cause loss of PHF21A function. We also found a new C-terminal domain composed of an intrinsically disordered region. This domain is truncated in six patients and thus likely to play an important role in the function of PHF21A, suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients. Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems. Furthermore, PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype. Conclusion:Deleterious nonsense, frameshift, and missense mutations disrupting the AT Hook domain and/or an intrinsically disordered region in PHF21A were found to be associated with autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies. This suggests that PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype.

Project description:ObjectiveMental health problems are more prevalent in people with than without intellectual disabilities, yet treatment options have received little attention. The aim of this study was to identify and evaluate the effectiveness of pharmacological and psychological interventions in the treatment of mental health problems in children and adults with severe and profound intellectual disabilities, given their difficulties in accessing standard mental health interventions, particularly talking therapies, and difficulties reporting drug side effects.DesignA systematic review using electronic searches of PsycINFO, PsycTESTS, EMBASE, MEDLINE, CINAHL, ERIC, ASSIA, Science Citation Index, Social Science Citation Index and CENTRAL was conducted to identify eligible intervention studies. Study selection, data extraction and quality appraisal were performed by two independent reviewers.ParticipantsStudy samples included at least 70% children and/or adults with severe or profound intellectual disabilities or reported the outcomes of this subpopulation separate from participants with other levels of intellectual disabilities.InterventionsEligible intervention studies evaluated a psychological or pharmacological intervention using a control condition or pre-post design.OutcomesSymptom severity, frequency or other quantitative dimension (e.g., impact), as assessed with standardised measures of mental health problems.ResultsWe retrieved 41 232 records, reviewed 573 full-text articles and identified five studies eligible for inclusion: three studies evaluating pharmacological interventions, and two studies evaluating psychological interventions. Study designs ranged from double-blind placebo controlled crossover trials to single-case experimental reversal designs. Quality appraisals of this very limited literature base revealed good experimental control, poor reporting standards and a lack of follow-up data.ConclusionsMental ill health requires vigorous treatment, yet the current evidence base is too limited to identify with precision effective treatments specifically for children or adults with severe and profound intellectual disabilities. Clinicians therefore must work on the basis of general population evidence, while researchers work to generate more precise evidence for people with severe and profound intellectual disabilities.Prospero registration numberCRD 42015024469.

Dataset Information

Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual disabilities, epilepsy, and neurobehavioral problems.

Publications

Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual disabilities, epilepsy, and neurobehavioral problems.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets