Delineation of 15q13.3 microdeletions. Clin Genet

Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d'Enfants, CHU, Dijon.
Clinical Genetics (Impact Factor: 3.93). 02/2010; 78(2):149-61. DOI: 10.1111/j.1399-0004.2010.01374.x
Source: PubMed


The increasing use of array-comparative genomic hybridization (array-CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4-BP5 microdeletion out of a series of 4625 patients screened by array-CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical ~1.5 Mb BP4-BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.

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    • "recurrent microdeletion, resulting in the loss of a 1.5 Mb region between low-copy repeat (LCR) sequences designated as breakpoints 4 and 5 (BP4 and BP5), contains six genes (MTMR15, MTMR10, TRPM1, KLF13, OTUD7A, and CHRNA7) and an miRNA gene (hsa-mir-211). Strong evidence supporting CHRNA7 as responsible for the majority of neurodevelopmental phenotypes resulting from deletion , comes from the identification of individuals carrying smaller deletions which encompass the entire CHRNA7 gene and the first exon of OTUD7A [Shinawi et al., 2009] or even smaller deletions, including only CHRNA7 [Masurel-Paulet et al., 2010; Mikhail et al., 2011; Hoppman-Chaney et al., 2013], and conveying most or all of the phenotypic abnormalities associated with the larger 15q13.3 recurrent deletions. "
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    ABSTRACT: Chromosome 15q13.3 recurrent microdeletions are causally associated with a wide range of phenotypes, including autism spectrum disorder (ASD), seizures, intellectual disability, and other psychiatric conditions. Whether the reciprocal microduplication is pathogenic is less certain. CHRNA7, encoding for the alpha7 subunit of the neuronal nicotinic acetylcholine receptor, is considered the likely culprit gene in mediating neurological phenotypes in 15q13.3 deletion cases. To assess if CHRNA7 rare variants confer risk to ASD, we performed copy number variant analysis and Sanger sequencing of the CHRNA7 coding sequence in a sample of 135 ASD cases. Sequence variation in this gene remains largely unexplored, given the existence of a fusion gene, CHRFAM7A, which includes a nearly identical partial duplication of CHRNA7. Hence, attempts to sequence coding exons must distinguish between CHRNA7 and CHRFAM7A, making next-generation sequencing approaches unreliable for this purpose. A CHRNA7 microduplication was detected in a patient with autism and moderate cognitive impairment; while no rare damaging variants were identified in the coding region, we detected rare variants in the promoter region, previously described to functionally reduce transcription. This study represents the first sequence variant analysis of CHRNA7 in a sample of idiopathic autism. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 02/2015; 167(4). DOI:10.1002/ajmg.a.36847 · 2.16 Impact Factor
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    • "15q13.3 microdeletion, between BP4 and BP5; comprising CHRNA7 gene causes mild to moderate intellectual disabilities associated to epilepsy with a variable phenotype [Masurel-Paulet et al., 2010; Shinawi et al., 2009]. "
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    ABSTRACT: Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, `de novo` microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies. Copyright © 2015. Published by Elsevier Masson SAS.
    European Journal of Medical Genetics 01/2015; 58(3). DOI:10.1016/j.ejmg.2015.01.002 · 1.47 Impact Factor
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    • "Recent genetic work shows that a rare genetic mutation can lead to either epilepsy or schizophrenia. A micro-deletion in the genomic area 15q 13–14 containing the nicotine receptor was linked to development of either schizophrenia or juvenile epilepsy [68,69,71]. The gene leucine-rich glioma-inactivated 1 gene (LGI1) in autosomal dominant partial epilepsy with auditory features, [72,73] may also play a role in regulating glutaminergic synaptic transmission, a process that is involved in the pathophysiology of schizophrenia [74]. "
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    ABSTRACT: Epilepsy has long been considered to be a risk factor for psychosis. However there is a lack of consistency in findings across studies on the effect size of this risk which reflects methodological differences in studies and changing diagnostic classifications within neurology and psychiatry. The aim of this study was to assess the prevalence of psychosis in epilepsy and to estimate the risk of psychosis among individuals with epilepsy compared with controls. A systematic review and meta-analysis was conducted of all published literature pertaining to prevalence rates of psychosis in epilepsy using electronic databases PUBMED, OVIDMEDLINE, PsychINFO and Embase from their inception until September 2010 with the following search terms: prevalence, incidence, rate, rates, psychosis, schizophrenia, schizophreniform illness, epilepsy, seizures, temporal lobe epilepsy. The literature search and search of reference lists yielded 215 papers. Of these, 58 (27%) had data relevant to the review and 157 were excluded following a more detailed assessment. 10% of the included studies were population based studies. The pooled odds ratio for risk of psychosis among people with epilepsy compared with controls was 7.8. The pooled estimate of prevalence of psychosis in epilepsy was found to be 5.6% (95% CI: 4.8-6.4). There was a high level of heterogeneity. The prevalence of psychosis in temporal lobe epilepsy was 7% (95% CI: 4.9-9.1). The prevalence of interictal psychosis in epilepsy was 5.2% (95% CI: 3.3-7.2). The prevalence of postictal psychosis in epilepsy was 2% (95% CI: 1.2-2.8). Our systematic review found that up to 6% of individuals with epilepsy have a co-morbid psychotic illness and that patients have an almost eight fold increased risk of psychosis. The prevalence rate of psychosis is higher in temporal lobe epilepsy (7%). We suggest that further investigation of this association could give clues to the aetiology of psychosis.
    BMC Psychiatry 03/2014; 14(1):75. DOI:10.1186/1471-244X-14-75 · 2.21 Impact Factor
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