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Research Note Cryptic De Novo Deletion at 2Q23.3-Q24.1 in a Patient with Intellectual Disability

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Research Note Cryptic De Novo Deletion at 2Q23.3-Q24.1 in a Patient with Intellectual Disability Research Note Cryptic de novo deletion at 2q23.3-q24.1 in a patient with intellectual disability Jamileh Malbin1*, Mohammad-SadeghFallah2-3*, Zohreh Sharif2, Mahsa Shafaei4, Hamideh Bagherian2, Tahereh PourMostafaei2, Ramiz Aliev1 Sirous Zainali2,5** 1. Azerbaijan National Academy of Science (ANAS), Genetic Resources Institute, Baku, Azerbaijan 2. Kawsar Human Genetics Research Center (KHGRC), Tehran, Iran 3. Cellular and Molecular Endocrine Research Center (CMER), Research Institute for Endocrine Sciences (RIES), Shahid Beheshti University of Medical Sciences, Tehran, Iran 4. Department of pathology and Molecular medicine McMaster Immunology Research Center, McMaster University, Hamilton, Ontario, Canada 5. Department of Molecular Medicine, Biotech Research Center, Pasteur Institute of Iran, Tehran, Iran * These authors contributed equally to the work as the 1st author. **Corresponding author Introduction: Structural abnormalities of chromosomes are one of the most common fndings in individuals with mental disability. Conventional and molecular cytogenetic testing has been applied to detect correlation between these abnormalities and genetic diseases, especially intellectual disability. Interstitial and sub-telomeric deletions in long arm of chromosome 2 have been reported in correlation with intellectual disability (ID) by some of these methods. Here we describe a 3.7 Mb deletion in the long arm of chromosome 2 in a woman with intellectual disability. Array comparative genomic hybridization (array CGH) revealed a deletion in 2q23.3-q24.1 region. Haplo-insufciency in three genes in this region (GPD2, FMNL2 and NR4A2) can be considered as causative factors for ID in our patient. Intellectual disability (ID) is a common disorder affecting 1- 3% of general population. Any chromosomal change, affecting gene copy number or function, could play an important role in the brain development and intellectual ability. Techniques such as MLPA and array CGH have been used to screen chromosomal imbalances in patients with mental disability and normal karyotype. Large chromosomal deletions and duplications usually change brain function and mental ability (Mulatinho et al., 2012). Several deletions and/or duplications have revealed that chromosome 2 contains many genes participating in brain function (El-Bassyouni et al., 2014; Gijsbers et al., 2009). The 2q24.1 and 2q23.1 regions contain the most repetitious regions, including several genes which are considered as candidate genes responsible for ID. Here we report a patient with 3.7 Mb deletions in 2q23.3-q24.1 region. Patient A family with non-consanguineous marriage and history of two affected cases (a son and a daughter) with ID was referred for molecular investigation. They also have 5 healthy children and three early childhood deaths (two sons and a daughter) with an unknown diagnosis (Figure-1A).The affected son refused to be evaluated and we could just test the affected daughter. She was a 35 years old female with history of developmental delay, seizures, speech difficulty, and self-mutilation behavior (Figure-1B). At the time of examination, her head circumference, weight and height were 58 cm, 83 Kg, and 166 cm respectively. No other dysmorphic feature was seen except having long fngers. She developed secondary sexual characteristic at the age of 15 and she had regular menstrual period. Methods Conventional chromosomal study was carried out on peripheral blood at 450-band resolution using GTG banding. DNA was extracted from peripheral blood using salting out techniques (Aljanabi & Martinez, 1997). DNA quality was determined by Nano Drop 2000 spectrophotometer (Nano-Drop Thermo Fisher Scientifc, USA). MLPA study was performed using P245-Kit for microdeletion syndromes screening and P036 & P070 kits (MRC- Holland, Amsterdam; The Netherlands) for sub-telomeric rearrangement as described before (Jehee et al., 2011). Amplifcation products were identifed and quantifed by capillary electrophoresis on an ABI 3130 genetic analyzer (Life Technologies, ABI, USA). Raw data were analyzed using Gene Marker Software V1.85 (Soft Genetics, State College, PA, USA). Microarray based comparative genomic hybridization (array CGH) analysis was carried out using the Gene Chip ISCA 4X44 whole genome oligo array version 1.1 (Blue Gnome UK ). The array consists of 44000 spots with average resolution of 75 Kbs. Sample was hybridized twice against female and male samples used as controls. DNA was processed according to the manufacturer’s instructions. Total purifed and quantifed genomic DNA was digested, amplifed and then labeled with a biotinylated nucleotide analogue [dUTP/oligo] using terminal deoxynucleotidyltransferase and hybridized. The slides were scanned using Innopsys 700 laser scanner (Innopsys, USA). Images were imported and analyzed by BlueFuse Multi software (Bluefuse systems ltd, USA http://support.illumina.com/array/array_software/bluefuse-multi- software.html). Copy number variations were screened against database of genomic variants and reported variations were excluded. Results Conventional chromosomal study showed normal karyotype in the affected case. Screening for 21 micro-deletion syndromes and sub-telomeric rearrangement was performed using MLPA method. There were no deletions or duplications in the MLPA study but a sub-telomeric duplication at 4q containing the FRG1 gene was observed using the P070 kit (Figure 2). Array CGH were performed to confrm the MLPA result. Results showed a 3.7 Mb deletion in 2q23.3-q24.1 region from nucleotide 154,247,108 to 158,021,127 (NCBI36/hg18) (Figure 3). Array CGH in her parents did not show any deletion for this region. Discussion Chromosome 2 (mainly 2q chromosomal region) has been cited frequently in patients with ID and there are many reports which have found abnormalities in 2q23.1-q24.1 regions (Magri et al., 2011; Takatsuki et al., 2010). The applications of newer technologies like array CGH and MLPA have enabled researchers to investigate patients with ID leading to the identifcation of deletions/duplications which may be causative in nature. Since the deleted or duplicated region contain many genes, it is not possible to narrow down the actual causative gene. A more thorough investigation is needed, in most cases, to identify the defnite candidate gene for a given disorder. In our patient, based on NCBI Human Genome Browser Resources database (NCBI36/hg18) there are six coding genes (GALNT13 (KIAA1918), KCNJ3 (GIRK1), NR4A2, GPD2, GALNT5 and ERMIN) in the deleted 2q23.3-q24.1 region (Table-1). Our fnding is very similar to a previously reported 3.9 Mb deletion in 2q23.3- q24.1 chromosomal region in a mentally retarded patient (Lybæk et al., 2009). Of the seven candidate genes that were reported to be deleted, six of them are also deleted in our case. Among these ERMIN, NR4A2 and GPD2 genes are considered to be the causative genes of our patient’s symptoms (Lybæk et al., 2009). Deletions of the GALNT13 gene, which is expressed in different parts of brain (Zhang et al., 2003), and the GALNT5 gene (Guzman-Aranguez, Mantelli, & Argueso, 2009) have been reported previously to be copy number variations (http://projects.tcag.ca/variation). The gene KCNJ3 has been reported to be related to neurologic problems like Schizophrenia (Yamada et al., 2012) and Ataxia (Genini et al., 2007) but there are no reports relating their abnormalities to ID. Mutations in NR4A2 (Nuclear receptor subfamily 4 group A member 2 gene), a member of the steroid–thyroid hormone and retinoid receptor super family are associated with disorders related to dopaminergic dysfunction, including Parkinson disease, Schizophrenia, and Manic depression (Baron et al., 2012), and its deletion may be responsible for self- mutilation observed in our patient; however, the hemizygosity of NR4A2 seems not to cause any signifcant clinical manifestations (Barge-Schaapveld et al., 2013). Mutations in the GPD2 (glycerol- 3-phosphate dehydrogenase 2) gene have been reported in a patient with intellectual disability (Daoud et al., 2009), who had a balanced translocation with breakpoints in the GPD2 (2q24.1) region. They suggested that this gene could be responsible for mental ability and thus it is possible that GPD2 haplo-insfficiency could be related to ID. As this gene is also expressed in the brain, it is hypothesized that GPD2 defciency may lead to ID in a similar way by decreasing ATP production (Barge-Schaapveld et al., 2013). NR4A2 and GPD2 gene deletions have also been described in a patient with 298 kb deletion at chromosome 2q24.1 (Barge- Schaapveld et al., 2013). ERM-like protein gene (ERMIN) which is located at the boundary of the above deletion, codes for a cytoskeletal protein that is expressed exclusively in oligodendrocytes of the human brain. It was introduced as a novel gene with low expression in an epileptic patient (Wang et al., 2011). Seizures in our patient, can be due to the deletions of NR4A2, GPD2, and ERMIN, while the ID can be explained by haplo- insufficiency of the GPD2 gene (Barge-Schaapveld et al., 2013; Motobayashi et al., 2012). To identify genes to explain variation in the range of normal intelligence, genome wide linkage study (Posthuma et al., 2005) has revealed signifcant evidence for linkage on chromosome 2q (2q24.1-q31.1) for intelligence. Although deletions of large parts of a chromosome could cause disorders in patients, it needs more patients to study in order to perform exact correlations between genotype and phenotype. In addition, some haplo-insufficient
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