An Inherited Small Microdeletion at 15q13.3 in a Patient with Early- Onset Obsessive-Compulsive Disorder

Cappi, Carolina; Hounie, Ana Gabriela; Mariani, Daniel; Diniz, Juliana Belo; Silva, Aderbal R.T.; Reis, Viviane Neri de Souza; Busso, Ariane Fidelis; Silva, Amanda Gonçalves; Fidalgo, Felipe; Rogatto, Sílvia Regina; Miguel, Eurí­pedes Constantino; Krepischi, Ana Cristina Victorino; Brentani, Helena

doi:10.1371/journal.pone.0110198

Cited by 17 publications

(11 citation statements)

References 57 publications

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“…The FMN1 gene encodes for formin1, a protein involved in the formation of adherent junctions and the polymerization of linear actin cables; it also plays a role in dendritogenesis and synaptogenesis in mouse hippocampal neurons [ 23 ], where its expression levels are related to the number of primary dendrites and glutamatergic synaptic inputs. A microdeletion encompassing part of the FMN1 gene has been recently reported in a patient with early-onset obsessive-compulsive disorder [ 26 ]; interestingly, this deletion includes the FMN1 exon (exon 5) containing the described mutation.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways

et al. 2017

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Inbreeding is a known risk factor for recessive Mendelian diseases and previous studies have suggested that it could also play a role in complex disorders, such as psychiatric diseases. Recent inbreeding results in the presence of long runs of homozygosity (ROHs) along the genome, which are also defined as autozygosity regions. Genetic variants in these regions have two alleles that are identical by descent, thus increasing the odds of bearing rare recessive deleterious mutations due to a homozygous state. A recent study showed a suggestive enrichment of long ROHs in schizophrenic patients, suggesting that recent inbreeding could play a role in the disease. To better understand the impact of autozygosity on schizophrenia risk, we selected, from a cohort of 180 Italian patients, seven subjects with extremely high numbers of large ROHs that were likely due to recent inbreeding and characterized the mutational landscape within their ROHs using Whole Exome Sequencing and, gene set enrichment analysis. We identified a significant overlap (17%; empirical p-value = 0.0171) between genes inside ROHs affected by low frequency functional homozygous variants (107 genes) and the group of most promising candidate genes mutated in schizophrenia. Moreover, in four patients, we identified novel and extremely rare damaging mutations in the genes involved in neurodevelopment (MEGF8) and in GABA/glutamatergic synaptic transmission (GAD1, FMN1, ANO2). These results provide insights into the contribution of rare recessive mutations and inbreeding as risk factors for schizophrenia. ROHs that are likely due to recent inbreeding harbor a combination of predisposing low-frequency variants and extremely rare variants that have a high impact on pivotal biological pathways implicated in the disease. In addition, this study confirms that focusing on patients with high levels of homozygosity could be a useful prioritization strategy for discovering new high-impact mutations in genetically complex disorders.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways

et al. 2017

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“…There have been few studies examining rare variants in OCD. 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 The first genome-wide investigation of rare copy number variation (CNV) in OCD and Tourette syndrome reported a 3.3-fold increase in large (>500 kb) deletions that overlap with CNVs reported in other neurodevelopmental disorders. An overall DN CNV rate of 1.4% was reported in OCD, slightly higher than the estimated frequency for controls, suggesting that rare DN variation may have a role in OCD pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways

et al. 2016

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Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein–protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10−8 per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular biological pathways and functions.

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“…The genes encompassed by the CNVs in our patients are listed in Tables 3 , 4 and 5 . Notably, several genes had been reported to be associated with autism or the other major psychiatric disorders, such as TACR1 52 , CNTNAP5 53 , 54 , ADGRL3 55 , ZNF827 56 , POU6F2 20 , KMT2E 57 , KCND2 58 , SND1 59 , CNTNAP2 60 , 61 , CSMD1 62 , 63 , PARD3 64 , HERC2 65 , FMN1 66 , and RBFOX1 67 . These findings not only provide further clues to indicate the highly genetic heterogeneity of ASD but also indicate the pleiotropic clinical effects of the mutation of these genes.…”

Section: Discussionmentioning

confidence: 99%

High resolution analysis of rare copy number variants in patients with autism spectrum disorder from Taiwan

Chen

Chien

et al. 2017

Sci Rep

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Rare genomic copy number variations (CNVs) (frequency <1%) contribute a part to the genetic underpinnings of autism spectrum disorders (ASD). The study aimed to understand the scope of rare CNV in Taiwanese patients with ASD. We conducted a genome-wide CNV screening of 335 ASD patients (299 males, 36 females) from Taiwan using Affymetrix Genome-Wide Human SNP Array 6.0 and compared the incidence of rare CNV with that of 1093 control subjects (525 males, 568 females). We found a significantly increased global burden of rare CNVs in the ASD group compared to the controls as a whole or when the rare CNVs were classified by the size and types of CNV. Further analysis confirmed the presence of several rare CNVs at regions strongly associated with ASD as reported in the literature in our sample. Additionally, we detected several new private pathogenic CNVs in our samples and five patients carrying two pathogenic CNVs. Our data indicate that rare genomic CNVs contribute a part to the genetic landscape of our ASD patients. These CNVs are highly heterogeneous, and the clinical interpretation of the pathogenic CNVs of ASD is not straightforward in consideration of the incomplete penetrance, varied expressivity, and individual genetic background.

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An Inherited Small Microdeletion at 15q13.3 in a Patient with Early- Onset Obsessive-Compulsive Disorder

Cited by 17 publications

References 57 publications

Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways

Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways

Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways

High resolution analysis of rare copy number variants in patients with autism spectrum disorder from Taiwan

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