title: 3p25.3 microdeletion of GABA transporters SLC6A1 and SLC6A11 results in intellectual disability, epilepsy and stereotypic behavior.
abstract: Small interstitial deletions affecting chromosome region 3p25.3 have been reported in only five patients so far, four of them with overlapping telomeric microdeletions 3p25.3 and variable features of 3p- syndrome, and one patient with a small proximal microdeletion and a distinct phenotype with intellectual disability (ID) and multiple congenital anomalies. Here we report on three novel patients with overlapping proximal microdeletions 3p25.3 of 1.1-1.5 Mb in size showing a consistent non-3p- phenotype with ID, epilepsy/EEG abnormalities, poor speech, ataxia and stereotypic hand movements. The smallest region of overlap contains two genes encoding sodium- and chloride-dependent GABA transporters which have not been associated with this disease phenotype in humans so far. The protein function, the phenotype in transporter deficient animal models and the effects of specific pharmacological transporter inhibition in mice and humans provide evidence that these GABA transporters are plausible candidates for seizures/EEG abnormalities, ataxia and ID in this novel group of patients. A fourth novel patient deleted for a 3.16 Mb region, both telomeric and centromeric to 3p25.3, confirms that the telomeric segment is critical for the 3p- syndrome phenotype. Finally, a region of 643 kb is suggested to harbor one or more genes causative for polydactyly which is part of the 3p- syndrome.
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Dikow
authors.forename: Bianca
authors.initials: B
authors.lastname: Maas
authors.forename: Stephanie
authors.initials: S
authors.lastname: Karch
authors.forename: Martin
authors.initials: M
authors.lastname: Granzow
authors.forename: Johannes W G
authors.initials: JW
authors.lastname: Janssen
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.forename: Katrin
authors.initials: K
authors.lastname: Hinderhofer
authors.forename: Christian
authors.initials: C
authors.lastname: Sutter
authors.forename: Susanne
authors.initials: S
authors.lastname: Schubert-Bast
authors.forename: Britt Marie
authors.initials: BM
authors.lastname: Anderlid
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Nathalie
authors.initials: N
authors.lastname: Van der Aa
authors.forename: Ute
authors.initials: U
authors.lastname: Moog
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics*; D007621:Karyotyping; D008297:Male; D013239:Stereotyped Behavior
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; C493413:SLC6A1 protein, human; C493416:SLC6A11 protein, human
keywords: Ataxia, epilepsy; GABA transporter; intellectual disability; microdeletion 3p25.3