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Copy Number Variations of Chromosome 17P11.2 Region In Zhang et al. BMC Med Genomics (2021) 14:215 https://doi.org/10.1186/s12920-021-01065-z RESEARCH Open Access Copy number variations of chromosome 17p11.2 region in children with development delay and in fetuses with abnormal imaging fndings Yuanyuan Zhang, Xiaoliang Liu, Haiming Gao, Rong He, Guoming Chu and Yanyan Zhao* Abstract Background: Deletion and duplication of the 3.7 Mb region in 17p11.2 result in two syndromes, Smith-Magenis syn- drome and Potocki-Lupski syndrome, which are well-known development disorders. The purpose of this study was to determine the prevalence, genetic characteristics and clinical phenotypes of 17p11.2 deletion/duplication in Chinese children with development delay and in fetuses with potential congenital defects. Methods: 7077 children with development delay and/or intellectual disability were screened by multiplex ligation- dependent probe amplifcation P245 assay. 7319 fetuses with potential congenital defects were tested using next generation sequencing technique. Results: 417 of 7077 pediatric patients were determined to carry chromosome imbalance. 28 (28/7077, 0.4%) cases had imbalance at chromosome 17p11.2. Among them, 12 cases (42.9%) had heterozygous deletions and 16 cases (57.1%) had heterozygous duplications. The clinical phenotypes were variable, including neurobehavioral disorders, craniofacial/skeletal anomalies, immunologic defects, ocular problems and organ malformations. 263 of 7319 fetuses were recognized to have genomic copy number variations. Only 2 of them were found to harbor 17p11.2 imbalance. The fetus with deletion presented with ventricular septal defect and the fetus with duplication had cerebral ventricle dilation. Conclusion: Our study highlights the phenotypic variability associated with 17p11.2 variations in China. The results further expand the phenotypic spectrum of SMS/PTLS and increase awareness of these disruptive mutations among clinicians. Keywords: 17p11.2 imbalance, Copy number variation, Development delay, MLPA, NGS Background (CNV) of corresponding gene clusters [1]. Genomic Chromosome 17 band p11.2 is an unstable region that is disorders map to this region are two syndromes, Smith- prone to nonallelic homologous recombination (NAHR). Magenis syndrome (SMS, OMIM #182290) and Potocki- Tis can produce recurrent deletion or duplication within Lupski syndrome (PTLS, OMIM #610883) [2, 3], which the region and contribute to copy number variation are caused in most cases by an approximately 3.7 Mb reciprocal deletion and duplication [4]. SMS is a well known and complex neurobehavioral disorder character- *Correspondence: [email protected] ized by developmental delay, intellectual disability, sleep Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, China disturbances and self-injurious behaviors [5, 6]. Patients © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhang et al. BMC Med Genomics (2021) 14:215 Page 2 of 11 generally have craniofacial features [6]. While, the symp- Best Practice Guidelines 2009 v1.00), were recruited from toms of PTLS are considered to be infantile hypotonia, outpatient of obstetrics from April 2018 to December sleep apnea, congenital cardiovascular anomalies, learn- 2020. Reasons for referral were the following: abnormal ing disabilities, short stature, and failure to thrive [7]. ultrasound scan; carrier of a chromosomal structural Te incidences of SMS and PTLS are predicted to be rearrangement; elevated risk of aneuploidy indicated by 1 in 25,000 [8]. However, they are likely to be underesti- biochemical and / or ultrasound screening, and previ- mated, given the poor resolution of conventional G-band ous chromosome anomaly. Te whole peripheral blood karyotyping analysis in detecting subtle abnormalities. and amniotic fuid were retrieved from clinic genetics G-band karyotyping has been the method of choice for of Shengjing Hospital of China Medical University. Tis cytogenetic test, accurately detecting chromosomal aber- study was approved by Ethics Committee of Shengjing rations larger than 5 Mb [9]. Before the utilization of Hospital of China Medical University. Written informed array comparative genomic hybridization (aCGH) and consents to participate were obtained from all of the par- next generation sequencing (NGS) in the clinic labora- ticipants in this study (written informed consent to par- tory, multiplex ligation-dependent probe amplifcation ticipate of individuals younger than the age of 16 were (MLPA) assay was widely used to detect chromosome obtained from their parents or legal guardians). sub-microscopic deletions and duplications of tar- geted regions [10, 11]. Specifcally, the MLPA P245 kit DNA extraction is designed to screen patients presenting with develop- Genomic DNA was extracted from the whole peripheral mental delay and/or intellectual disability for 31 kinds of blood and amniotic fuid using Automatic nucleic acid common microdeletion or microduplication syndromes. extractor (Allsheng Auto-Pure 32A) with UPure Blood P245 probe mix includes 3 probes in 17p11.2 region, DNA Extraction Kit (M2002-A32) and UPure Tissue which are RAI1 (retinoic acid induced 1), LRRC48 DNA Extraction Kit (M2012-02) (BioBase Technologies (DRC3, dynein regulatory complex subunit 3) and LLGL1 Co., LTD) following the manufacturer’s instructions. Te (LLGL scribble cell polarity complex component 1). Ratio concentration of DNA was detected using a spectropho- anomalies of these probes indicate copy number varia- tometry method (NanoDrop 1000, Termo Scientifc, tions at chromosome 17p11.2. USA). A concentration of 10–50 ng/μL DNA was pre- In this study, we presented an overview of the genetic pared for MLPA and NGS assay. and clinical characteristics of Chinese patients that were identifed to carry 17p11.2 imbalance by MLPA and Multiplex ligation‑dependent probe amplifcation (MLPA) NGS. Te aim of this study was to estimate the preva- assay lence and detailed clinical characteristics of 17p11.2 dele- MLPA assay and the subsequent results analyses were tions/duplications in children with development delay as performed as previously described [12]. Briefy, Te well as in fetuses with potential congenital defects, which SALSA MLPA KIT P245 (MRC Holland, Amsterdam, could contribute to provide basic information for clinical Netherlands) were used for MLPA analysis according to evaluation. the manufacturer’s instructions. PCR amplifcation prod- ucts were separated by capillary electrophoresis using Methods ABI 3730 Genetic Analyser (Applied Biosystems, USA). Patients and samples Cofalyser. Net software (MLPA Holland, Amsterdam, From July 2013 to December 2020, 7077 pediatric Netherlands) was used to analyze and give an interpreta- patients were enrolled through the outpatients of pedi- tion of the raw MLPA data. Te detailed information of atrics and clinic genetics of Shengjing Hospital of China the probes included in MLPA kits was described in the Medical University. Te range of their ages was from manufacture’s instructions. 30 days to 12 years. Te phenotypes were collected by consulting their medical records. Most of these patients Chromosome karyotype analysis manifested intellectual disability and/or development Conventional chromosome G-band karyotyping analy- delay. Other phenotypes also could be seen, including sis of the cultures of peripheral blood and amniotic congenital malformation, hypotonia and feeding difcul- fuid blood cells was performed as previously described ties, speech and motor defcits, cardiovascular defects, [12]. Leica CytoVision (Leica, USA) was used to cap- epilepsy, hearing impairment, craniofacial and skeletal ture images of mitotic metaphase chromosomes. Te features and behavioral issues. 7129 pregnant women karyotyping results were identifed and described upon (7319 fetuses), who required amniocentesis for inva- agreement of the two examiners, with reference to the sive prenatal diagnosis based on guideline published by International System for Human Cytogenetic Nomencla- Association for Clinical Cytogenetics (Prenatal Diagnosis ture (ISCN 2016) [13]. Zhang et al. BMC Med Genomics (2021) 14:215 Page 3 of 11 Next generation sequencing (NGS) assay duplications (Fig. 1a). Teir ages ranged from 30 days to Copy number variation was detected by next genera- 10 years. 12 of the 28 (42.9%) patients had heterozygous tion sequencing (NGS) based CNV-seq as previously deletions and the rest 16 (57.1%) patients had heterozy- described [14]. Briefy,
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