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MLPA Analysis in a Cohort of Patients with Autism Sara Peixoto1,2,3*, Joana B

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MLPA Analysis in a Cohort of Patients with Autism Sara Peixoto1,2,3*, Joana B Peixoto et al. Molecular Cytogenetics (2017) 10:2 DOI 10.1186/s13039-017-0302-z RESEARCH Open Access MLPA analysis in a cohort of patients with autism Sara Peixoto1,2,3*, Joana B. Melo1,4,5, José Ferrão1, Luís M. Pires1, Nuno Lavoura1, Marta Pinto1, Guiomar Oliveira2,6† and Isabel M. Carreira1,4,5*† Abstract Background: Autism is a global neurodevelopmental disorder which generally manifests during the first 2 years and continues throughout life, with a range of symptomatic variations. Epidemiological studies show an important role of genetic factors in autism and several susceptible regions and genes have been identified. The aim of our study was to validate a cost-effective set of commercial Multiplex Ligation dependent Probe Amplification (MLPA) and methylation specific multiplex ligation dependent probe amplification (MS-MLPA) test in autistic children refered by the neurodevelopmental center and autism unit of a Paediatric Hospital. Results: In this study 150 unrelated children with autism spectrum disorders were analysed for copy number variation in specific regions of chromosomes 15, 16 and 22, using MLPA. All the patients had been previously studied by conventional karyotype and fluorescence in situ hybridization (FISH) analysis for 15(q11.2q13) and, with these techniques, four alterations were identified. The MLPA technique confirmed these four and identified further six alterations by the combined application of the two different panels. Conclusions: Our data show that MLPA is a cost effective straightforward and rapid method for detection of imbalances in a clinically characterized population with autism. It contributes to strengthen the relationship between genotype and phenotype of children with autism, showing the clinical difference between deletions and duplications. Keywords: Autism, Autism spectrum disorders, Copy number variants, Genotype, Multiplex Ligation-dependent Probe Amplification (MLPA), Methylation Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA), Phenotype Background studies identified the importance of genetic factors in Autism is a global neurodevelopment disorder which, in autism, specifically the existence of a higher rate of simi- most cases, manifests during the first 2 years and prolongs larities in monozygotic twins (60 to 90%) in contrast to throughout life, having clinical variances with aging. It only 3 to 10% in dizygotic twins [3–6]. Structural chromo- belongs to a large family of disorders - autism spectrum somic imbalances - copy number variants (CNVs) – seams disorder (ASD), clinically characterized by difficulties with to be a key player in the disorder and a risk factor for communication and social interaction, verbal language autism especially in the sporadic forms [7–11]. CNVs deficiencies and by repetitive and stereotype behaviour [1]. associated with autism may be inherited or de novo, Epidemiological studies revealed that the number of affecting preferentially the chromosomes regions: 1q21, children with ASD has been increasing throughout the 2p16.3, 3p25-26, 7q36.2, 15q11-13, 15q24, 16p11.2, world. In Portugal, a published study in 2007, suggested a 16p13.11, 17q12 and 22q11.2 [12–14]. A recent genome prevalence of 9,2/10 000 cases, in the main land, and 15,6/ wide copy number variation analysis projected between 10 000 in the Azores Islands [2]. Several epidemiologic 156 and 280 genomic intervals contributing to autism. Exome sequencing of over 900 individuals provided an * Correspondence: [email protected]; [email protected] estimate of nearly 1.000 contributing genes [15–18]. † Equal contributors The most consistently reported submicroscopic chromo- 1Cytogenetics and Genomics Laboratory, Faculty of Medicine, University of Coimbra, Coimbra, Portugal some abnormalities detected by chromosomal microarray Full list of author information is available at the end of the article (10–20%) are recurrent CNVs at 16p11.2, 15q11-13 and © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Peixoto et al. Molecular Cytogenetics (2017) 10:2 Page 2 of 10 22q11.2 [12, 19, 20]. Submicroscopic rearrangements as Diagnostic Observation Schedule, ADOS [33]), both his- deletions or duplications in 15q11-13 region, and especially tory and observation for rating (Childhood Autism Rating proximal 15q duplications containing the critical regions of Scale, CARS [34]) and clinical examination performed by Prader-Willi and Angelman Syndrome (PWS/AS), have an experienced neurodevelopmental Paediatrician. The been reported in various patients with autism representing latter allows the classification of the degree of autism into the majority of chromosome alterations described in this mild to moderate (score between 30 and 37) and severe population [12, 21]. (38–60). The current diagnostic criteria for autism were Microdeletions of the short arm of chromosome revised according to the Diagnostic and Statistical Manual 16p11.2 were also identified in up to 1% of patients with of Mental Disorders fifth edition, DSM-5 [1]. It was consi- autism [22–25]. The microduplication of this region was dered a diagnosis of autism (this term being used synonym- also observed in a similar percentage of individuals, ously to ASD) any case where ADI-R and ADOS presented however the association with autism is less convincing as positive scores and all patients met the criteria for ASD due to the increased frequency observed in the control from the DSM-5. groups [25, 26]. Deletions and duplications in the region An EDTA blood sample from each child was collected 22q13.3 also appear to be risk factors for ASD. Among for the genetic evaluation by MLPA and MS-MLPA for the three genes (ACR, RABL2B, SHANK3) in 22q subtelo- chromosomes 15q11-13, 16p11 and 22q13. A more meric region, SHANK3 is the candidate gene for neurobe- detailed clinical evaluation was done for the ten children havioral symptoms observed in affected individuals with that presented alterations in the MLPA study, proceeding 22q13 deletions. This gene has a mutation frequency of to the analysis of the relative clinical relevant data to the 0.5 to 1% in individuals with ASD [27–29]. current clinical history of autism, accordingly to Table 1. It is well accepted that array comparative genomic Whenever possible, laboratory studies were done on the hybridization (CGH) should be the first genetic test to parents of the children with chromosome alterations. be offered for detection of genomic imbalances in patients with intellectual disability and ASD [30, 31], Conventional cytogenetic and fluorescence in situ however access to these costly methods and techniques hybridization can be difficult especially given the current economic All 150 children participating in this study, had been and financial context in many countries and conse- previously evaluated by high resolution conventional quently the pressure from the hospital administrations to contain expense. Clinicians often are confronted Table 1 Clinical data relevant to the clinical history of the with this economical and financial issues and have diffi- cohort culties to respond to families request to find the cause Personal history: pre and perinatal of these children pathology. One of the aims of this Parturition type study was to evaluate the detection rate of MLPA tech- Gestational age nique that could allow a rapid and cost-saving response Apgar index in a large consultation of children with ASD. We analysed the presence of CNVs in the most common Somatometry birth (weight/height/head circumference) described chromosomic regions associated with ASD Personal history: Acquisition of neurodevelopment (15q11-q13, 16p11.2 and 22q13) in 150 children using Walking age MLPA and MS-MLPA techniques. A clinical assessment of First words each case was also done to allow genotype-phenotype First sentences correlations in the cases with genetic alterations. Global developmental quotient (GDQ) - Griffiths scale (between 2 and 6 years of age) Methods Global intelligence quotient (GIQ) - WISC-III Clinical assessment (between 6 and 16 years of age) For this study, a pilot population of 150 children was Pathological personal history analysed. They were clinically diagnosed with autism by Visual or auditory deficits the Unit of Neurodevelopment and Autism of the Paediat- ric Hospital, Coimbra Hospital and University Centre, Epilepsy (two or more critical episodes in apyrexia) Portugal. The diagnosis was based on a clinical observa- Family history tion by a multidisciplinary team coordinated by a neuro- Physical exam developmental paediatrician. ASD diagnosis was assigned Dysmorphisms and signs of neurocutaneous syndromes on the basis of the gold standard instruments: parental or Collection of anthropometric measurements (actual growing) caregiver interview (Autism Diagnostic Interview-Revised, Classical neurologic exam ADI-R [32]), direct structured proband assessment (Autism Peixoto et al. Molecular Cytogenetics (2017) 10:2 Page 3 of 10 cytogenetic
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