DNA microarray analysis identifies candidate regions and genes in unexplained mental retardation

Engels, Hartmut; Brockschmidt, Antje; Hoischen, Alexander; Landwehr, Christina; Bosse, K; Walldorf, Constanze; Toedt, Grischa; Radlwimmer, Bernhard; Propping, Peter; Lichter, Peter; Weber, Ruthild G.

doi:10.1212/01.wnl.0000256367.70365.e0

Cited by 82 publications

(66 citation statements)

References 33 publications

(30 reference statements)

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“…68 Copy number variation (CNV), including deletion and duplication, translocation, inversion of chromosomes, has been identified in some individuals with autism. 14,69 In fact, Engels et al 70 showed a direct association between the severity of physical anomalies and the chance to find mutant CNVs. The results of this meta-analysis suggest that MPAs in autism are, at least in part, related to the risk of developing the disease and that these MPAs may therefore precede the clinical onset of the disorder.…”

Section: Discussionmentioning

confidence: 99%

Minor physical anomalies in autism: a meta-analysis

et al. 2008

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Autism is a complex neurodevelopmental disorder in which the interactions of genetic, epigenetic and environmental influences play a causal role. Despite the compelling evidence for a strong heritability, the etiology and molecular mechanisms underlying autism remain unclear. High phenotypic variability and genetic heterogeneity confounds the identification of susceptibility genes. The lack of robust indicators to tackle this complexity in autism has led researchers to seek for novel diagnostic tools to create homogenous subgroups. Several studies have indicated that patients with autism have higher rates of minor physical anomalies (MPAs) and that MPAs may serve as a diagnostic tool; however, the results have been inconsistent. Using the cumulative data from seven studies on MPAs in autism, this metaanalysis seeks to examine whether the aggregate data provide evidence of a large mean effect size and statistical significance for MPAs in autism. It covers the studies using multiple research methods till June 2007. The current results from seven studies suggested a significant association of MPAs in autism with a robust pooled effect size (d = 0.84), and thereby provide the strongest evidence to date about the close association between MPAs and autism. Our results emphasize the importance of MPAs in the identification of heterogeneity in autism and suggest that the success of future autism genetics research will be exploited by the use of MPAs. Implications for the design of future studies on MPAs in autism are discussed and suggestions for further investigation of these important markers are proposed. Clarifying this relation might improve understanding of risk factors and molecular mechanisms in autism.

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Section: Discussionmentioning

confidence: 99%

Minor physical anomalies in autism: a meta-analysis

et al. 2008

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“…FISH was performed using BlueFISH tile BAC probes RP11-12D3 and RP11-29K14 from the deleted region according to manufacturer's instructions (BlueGnome Ltd, Cambridge, United Kingdom) and as published previously. 2 Figure 2b). qPCR analyses of patient 3 and her parents confirmed the deletion in patient 3 and demonstrated its de novo occurrence.…”

Section: Patientmentioning

confidence: 97%

“…4 Causative familial copy number changes with reduced penetrance have also been described, however. 2,5,6 Several patients with similar copy number changes and a similar clinical presentation are, therefore, needed to allow reliable genotype-phenotype correlation. Recently, some recurrent rearrangements have been described for, amongst others, chromosomal regions 1q21.1, 5 1q41q42, 7 2p15p16.1, 8 16p13.11, 9,10 18q21 11 -13 and 17q21.31.…”

Section: Introductionmentioning

confidence: 99%

A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients

et al. 2009

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Molecular karyotyping is being increasingly applied to delineate novel disease causing microaberrations and related syndromes in patients with mental retardation of unknown aetiology. We report on three unrelated patients with overlapping de novo interstitial microdeletions involving 5q14.3-q15. All three patients presented with severe psychomotor retardation, epilepsy or febrile seizures, muscular hypotonia and variable brain and minor anomalies. Molecular karyotyping revealed three overlapping microdeletions measuring 5.7, 3.9 and 3.6 Mb, respectively. The microdeletions were identified using single nucleotide polymorphism (SNP) arrays (Affymetrix 100K and Illumina 550K) and array comparative genomic hybridization (1 Mb Sanger array-CGH). Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative PCR. All three aberrations were confirmed and proven to have occurred de novo. The boundaries and sizes of the deletions in the three patients were different, but an overlapping region of around 1.6 Mb in 5q14.3 was defined. It included five genes: CETN3, AC093510.2, POLR3G, LYSMD3 and the proximal part of GPR98/MASS1, a known epilepsy gene. Haploinsufficiency of GPR98/MASS1 is probably responsible for the seizure phenotype in our patients. At least one other gene contained in the commonly deleted region, LYSMD3, shows a high level of central nervous expression during embryogenesis and is also, therefore, a good candidate gene for other central nervous system (CNS) symptoms, such as psychomotor retardation, brain anomalies and muscular hypotonia of the 5q14.3 microdeletion syndrome.

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“…De novo microdeletions detected by genome-wide array analysis at 19p13 have been reported in few patients, [1][2][3][4][5] all of whom had malformations and mental retardation (MR). We present the detailed clinical and molecular description of two new cases (cases 1 and 3) with partially overlapping 19p13 microdeletions identified by investigating patients with syndromic MR using array comparative genomic hybridization (aCGH).…”

Section: Introductionmentioning

confidence: 99%

Genotype–phenotype relationship in three cases with overlapping 19p13.12 microdeletions

et al. 2010

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We describe the detailed clinical and molecular characterization of three patients (aged 7, 8 4/12 and 31 years) with overlapping microdeletions in 19p13.12, extending to 19p13.13 in two cases. The patients share the following clinical features with a recently reported 10-year-old girl with a 19p13.12 microdeletion: mental retardation (MR), psychomotor and language delay, hearing impairment, brachycephaly, anteverted nares and ear malformations. All patients share a 359-kb deleted region in 19p13.12 harboring six genes (LPHN1, DDX39, CD97, PKN1, PTGER1 and GIPC1), several of which may be MR candidates because of their function and expression pattern. LPHN1 and PKN1 are the most appealing; LPHN1 for its interaction with Shank family proteins, and PKN1 because it is involved in a variety of functions in neurons, including cytoskeletal organization. Haploinsufficiency of GIPC1 may contribute to hearing impairment for its interaction with myosin VI. A behavioral phenotype was observed in all three patients; it was characterized by overactive disorder associated with MR and stereotyped movements (ICD10) in one patient and hyperactivity in the other two. As Ptger1-null mice show behavioral inhibition and impulsive aggression with defective social interaction, PTGER1 haploinsufficiency may be responsible for the behavioral traits observed in these patients.

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DNA microarray analysis identifies candidate regions and genes in unexplained mental retardation

Cited by 82 publications

References 33 publications

Minor physical anomalies in autism: a meta-analysis

Minor physical anomalies in autism: a meta-analysis

A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients

Genotype–phenotype relationship in three cases with overlapping 19p13.12 microdeletions

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