High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L–DOCK4 gene region in autism susceptibility

Maestrini, Elena; Pagnamenta, Alistair T.; Lamb, Janine A.; Bacchelli, Elena; Sykes, Nuala; Sousa, Inês; Toma, Claudio; Barnby, Gabrielle; Butler, Helen; Winchester, Laura; Scerri, Thomas; Minopoli, Fiorella; Reichert, Jennifer; Cai, Guiqing; Buxbaum, Joseph D.; Korvatska, Olena; Schellenberg, G D; Dawson, Geraldine; Bildt, Annelies de; Minderaa, Ruud B.; Mulder, E.; Morris, Andrew P.; Bailey, Anthony; Monaco, Anthony P.

doi:10.1038/mp.2009.34

Cited by 129 publications

(127 citation statements)

References 61 publications

(91 reference statements)

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“…38 CNVs encompassing other members of the DOCK (Dedicator of CytoKinesis) family, such as DOCK4 and DOCK8 (located in the 9p24 deletion), have been reported in ASDs. 5,39 However, additional cases of ASD with mutations in this gene need to be identified to confirm that autosomal recessive mutations in DOCK10 can cause ASD.…”

Section: Discussionmentioning

confidence: 99%

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

et al. 2013

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Copy number variants (CNVs) have repeatedly been found to cause or predispose to autism spectrum disorders (ASDs). For diagnostic purposes, we screened 194 individuals with ASDs for CNVs using Illumina SNP arrays. In several probands, we also analyzed candidate genes located in inherited deletions to unmask autosomal recessive variants. Three CNVs, a de novo triplication of chromosome 15q11-q12 of paternal origin, a deletion on chromosome 9p24 and a de novo 3q29 deletion, were identified as the cause of the disorder in one individual each. An autosomal recessive cause was considered possible in two patients: a homozygous 1p31.1 deletion encompassing PTGER3 and a deletion of the entire DOCK10 gene associated with a rare hemizygous missense variant. We also identified multiple private or recurrent CNVs, the majority of which were inherited from asymptomatic parents. Although highly penetrant CNVs or variants inherited in an autosomal recessive manner were detected in rare cases, our results mainly support the hypothesis that most CNVs contribute to ASDs in association with other CNVs or point variants located elsewhere in the genome. Identification of these genetic interactions in individuals with ASDs constitutes a formidable challenge.

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Section: Discussionmentioning

confidence: 99%

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

et al. 2013

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“…IMMP2L has previously been associated with autism 21,22 and ADHD. 23 Furthermore, in the Decipher database, deletions and duplications spanning IMMP2L are reported in patients with developmental delay and ASD.…”

Section: Discussionmentioning

confidence: 96%

Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome

et al. 2014

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Tourette syndrome is a neurodevelopmental disorder characterized by multiple motor and vocal tics, and the disorder is often accompanied by comorbidities such as attention-deficit hyperactivity-disorder and obsessive compulsive disorder. Tourette syndrome has a complex etiology, but the underlying environmental and genetic factors are largely unknown. IMMP2L (inner mitochondrial membrane peptidase, subunit 2) located on chromosome 7q31 is one of the genes suggested as a susceptibility factor in disease pathogenesis. Through screening of a Danish cohort comprising 188 unrelated Tourette syndrome patients for copy number variations, we identified seven patients with intragenic IMMP2L deletions (3.7%), and this frequency was significantly higher (P ¼ 0.0447) compared with a Danish control cohort (0.9%). Four of the seven deletions identified did not include any known exons of IMMP2L, but were within intron 3. These deletions were found to affect a shorter IMMP2L mRNA species with two alternative 5 0 -exons (one including the ATG start codon). We showed that both transcripts (long and short) were expressed in several brain regions, with a particularly high expression in cerebellum and hippocampus. The current findings give further evidence for the role of IMMP2L as a susceptibility factor in Tourette syndrome and suggest that intronic changes in disease susceptibility genes should be investigated further for presence of alternatively spliced exons.

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“…24 A recent casecontrol study in families linked to the autism susceptibility locus 1 (AUTS1) detected single-nucleotide polymorphisms (SNPs) and CNV within DOCK4 and IMMP2L, implicating them in autism susceptibility. 20 A DOCK4 deletion segregating in a family with dyslexia, and undetectable in 42500 controls, suggested that DOCK4 may have a role in the aetiology of dyslexia. 25 The GPR85 gene (MIM 605188) is predominantly expressed in the central nervous system, especially in structures exhibiting high levels of plasticity (eg, hippocampal dentate gyrus); it has high evolutionary conservation across three mammalian species, 26 and has been implicated as a potential risk factor for psychiatric disorders.…”

Section: Fish Confirmation Of Partial Deletion Of Immp2lmentioning

confidence: 99%

“…The IMMP2L gene (along with numerous other neurodevelopmental genes) has also recently been implicated in structural variation studies carried out on cohorts of patients with autistic spectrum disorder, 20 and ADHD. 21 Our case does not display any of the classical features of autism, except speech impairment (which is likely to be accounted for by deletion of the FOXP2 gene) or ADHD.…”

Section: Fish Confirmation Of Partial Deletion Of Immp2lmentioning

confidence: 99%

Translocation breakpoint at 7q31 associated with tics: further evidence for IMMP2L as a candidate gene for Tourette syndrome

et al. 2011

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Gilles de la Tourette syndrome is a complex neuropsychiatric disorder with a strong genetic basis. We identified a male patient with Tourette syndrome-like tics and an apparently balanced de novo translocation [46,XY,t(2;7)(p24.2;q31)]. Further analysis using array comparative genomic hybridisation (CGH) revealed a cryptic deletion at 7q31.1-7q31.2. Breakpoints disrupting this region have been reported in one isolated and one familial case of Tourette syndrome. In our case, IMMP2L, a gene coding for a human homologue of the yeast inner mitochondrial membrane peptidase subunit 2, was disrupted by the breakpoint on 7q31.1, with deletion of exons 1-3 of the gene. The IMMP2L gene has previously been proposed as a candidate gene for Tourette syndrome, and our case provides further evidence of its possible role in the pathogenesis. The deleted region (7q31.1-7q31.2) of 7.2 Mb of genomic DNA also encompasses numerous genes, including FOXP2, associated with verbal dyspraxia, and the CFTR gene.

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High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L–DOCK4 gene region in autism susceptibility

Cited by 129 publications

References 61 publications

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome

Translocation breakpoint at 7q31 associated with tics: further evidence for IMMP2L as a candidate gene for Tourette syndrome

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