ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation

Alber M, Kalscheuer VM, Marco E, Sherr E, Lesca G, Till M, Gradek G, Wiesener A, Korenke C, Mercier S, Becker F, Yamamoto T, Scherer SW, Marshall CR, Walker S, Dutta UR, Dalal AB, Suckow V, Jamali P, Kahrizi K, Najmabadi H, Minassian BA (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Neurology Genetics Lippincott, Williams & Wilkins

Book Volume: 3

Journal Issue: 3

DOI: 10.1212/NXG.0000000000000148

Abstract

OBJECTIVE: We aimed to generate a review and description of the phenotypic and genotypic spectra of ARHGEF9 mutations. METHODS: Patients with mutations or chromosomal disruptions affecting ARHGEF9 were identified through our clinics and review of the literature. Detailed medical history and examination findings were obtained via a standardized questionnaire, or if this was not possible by reviewing the published phenotypic features. RESULTS: A total of 18 patients (including 5 females) were identified. Six had de novo, 5 had maternally inherited mutations, and 7 had chromosomal disruptions. All females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. Symptoms presented in early childhood with delayed motor development alone or in combination with seizures. Intellectual disability was severe in most and moderate in patients with milder mutations. Males with severe intellectual disability had severe, often intractable, epilepsy and exhibited a particular facial dysmorphism. Patients with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy. CONCLUSIONS: ARHGEF9 encodes a crucial neuronal synaptic protein; loss of function of which results in severe intellectual disability, epilepsy, and a particular facial dysmorphism. Loss of only the protein's PH domain function is associated with the absence of epilepsy.

Involved external institutions

Hospices Civils de Lyon (CHU) FR France (FR) Nantes University Hospital / Centre hospitalier universitaire de Nantes (CHU) FR France (FR) Centre for DNA Fingerprinting and Diagnostics [CDFD] IN India (IN) Tokyo Women's Medical University JP Japan (JP) Max-Planck-Institut für molekulare Genetik / Max Planck Institute for Molecular Genetics DE Germany (DE) Klinikum Oldenburg DE Germany (DE) University of California San Francisco (UCSF) US United States (USA) (US) The Hospital for Sick Children (SickKids) CA Canada (CA) Haukeland University Hospital / Haukeland universitetssykehus NO Norway (NO) Universitätsklinikum Tübingen DE Germany (DE) University of Social Welfare and Rehabilitation Sciences IR Iran, Islamic Republic of (IR)

How to cite

APA:

Alber, M., Kalscheuer, V.M., Marco, E., Sherr, E., Lesca, G., Till, M.,... Minassian, B.A. (2017). ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation. Neurology Genetics, 3(3). https://dx.doi.org/10.1212/NXG.0000000000000148

MLA:

Alber, Michael, et al. "ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation." Neurology Genetics 3.3 (2017).

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