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Genome-Wide Screening of Copy Number Variants in Children Born Small for Gestational Age Reveals Several Candidate Genes Involved in Growth Pathways

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Genome-Wide Screening of Copy Number Variants in Children Born Small for Gestational Age Reveals Several Candidate Genes Involved in Growth Pathways A P M Canton and others Copy number variants in 171:2 253–262 Clinical Study SGA children Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways Ana P M Canton, Sı´lvia S Costa1, Tatiane C Rodrigues1, Debora R Bertola1,2, Alexsandra C Malaquias, Fernanda A Correa3, Ivo J P Arnhold3, Carla Rosenberg1 and Alexander A L Jorge Unidade de Endocrinologia Genetica, Laboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Arnaldo, 455 58 Andar Sala 5340, CEP 01246-903 Sao Paulo, Brazil, 1Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias da Correspondence Universidade de Sao Paulo, 05508-900 Sao Paulo, Brazil, 2Unidade de Genetica, Instituto da Crianca, Faculdade de should be addressed Medicina da Universidade de Sao Paulo, 05403-000 Sao Paulo, Brazil and 3Unidade de Endocrinologia do to A A L Jorge Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42 do Hospital das Clinicas, Disciplina de Email Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil [email protected] Abstract Background: The etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders. Objective: To analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause. Patients and methods: A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs European Journal of Endocrinology was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature. Results: In 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation. Conclusion: Pathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition. European Journal of Endocrinology (2014) 171, 253–262 Introduction Children born small for gestational age (SGA) are defined and involve maternal, placental, and/or fetal factors (1). as those with birth weight and/or birth length at least 2 S.D. Fetal factors include several genetic causes commonly below the population mean for gestational age (1). The characterized by persistent short stature, dysmorphic causes of prenatal growth impairment are often unclear features, and developmental disorders (2). These genetic www.eje-online.org Ñ 2014 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-14-0232 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 08:54:10PM via free access Clinical Study A P M Canton and others Copy number variants in 171:2 254 SGA children syndromes of prenatal-onset growth impairment often informed consent. Candidates for aCGH were selected encompass complex clinical disorders of difficult from a total of 137 children followed at our outpatient diagnosis (3). clinic due to prenatal-onset short stature using the Array-based genomic copy number analysis has following criteria: i) birth weight and/or length S.D. recently become a research tool and a clinical genetic %K2.0; ii) persistent short stature after early infancy test in the diagnostic work-up of several clinical settings (height S.D. %K2.0 at the age of 4 years or above); and iii) (4). One of the most used genomic copy number analysis thepresenceofdysmorphicfeatures,developmental types is array-based comparative genomic hybridization delay, and/or intellectual disability, but without criteria (aCGH), a technique used for genome-wide screening of for the diagnosis of a recognized syndrome, including submicroscopic segmental genomic gains and losses. This Silver–Russell syndrome (14). The exclusion criteria for method enables a much higher resolution assay (greater selection were as follows: i) placental and maternal known than tenfold) of genomic imbalances than conventional factors of intrauterine growth retardation, including cytogenetic methods (4, 5). The imbalances characterized placental structural or perfusional factors and maternal by aCGH are called copy number variants (CNVs). A CNV infections, substance use/abuse, or medical conditions is an imbalance of a genomic sequence that alters the and ii) known causes of short stature, including endocri- diploid status of a particular locus in the human genome; nological diseases, skeletal dysplasias, hepatic diseases, essentially, it comprises deletions and duplications. systemic diseases, and established genetic diseases. All Currently, aCGH is indicated as a first-tier clinical patients had normal G-banded karyotyping. A total of diagnostic test in patients with unexplained develop- 51 patients, who fulfilled all inclusion criteria and no mental delay/intellectual disability, autism spectrum exclusion criteria, were selected for the molecular genetic disorders, and multiple congenital anomalies (5).Itis study. Among these patients, 11 were investigated for also becoming a powerful tool in the discovery of disease demethylation of the paternal imprinting center region genes, identification of new syndromes, and delineation one on chromosome 11p15 and 14 were investigated for of known deletion/duplication syndromes, known as insulin-like growth factor 1 (IGF1) and IGF1 receptor genomic disorders. In the field of endocrinology, gen- (IGF1R) mutations (15, 16). In all the selected patients, ome-wide analysis of CNVs has been evaluated as a tool these molecular genetic tests proved to be normal. to identify genetic causes in several clinical conditions, including premature ovarian failure (6), severe early-onset Array-based comparative genomic hybridization obesity (7), congenital hypothyroidism and thyroid European Journal of Endocrinology dysgenesis (8), ambiguous genitalia (9), skeletal defects Genomic DNA was extracted from peripheral blood with growth impairment (10), and Silver–Russell syn- leucocytes of all patients and 28 relatives (including 14 drome (11). Two recent studies have demonstrated the maternal samples, 11 paternal samples, and three other presence of causative and possible pathogenic CNVs in first-degree relatives’ samples) using standard procedures. short-stature children (12, 13). However, in both studies, aCGH was performed in a whole-genome customized 60K children were selected regardless of compromised birth oligonucleotide platform (SurePrint G3 Human CGH weight and/or length. Microarray Kit, 8!60K, Agilent Technologies, Inc., Santa In the present study, we performed aCGH in a group of Clara, CA, USA). The procedure was conducted according 51 children born SGA with persistent short stature without to the standard protocol of the manufacturer (17). Briefly, a recognized cause of prenatal and postnatal growth all standard quality assessments were implemented during impairment. Our results indicate that CNVs contribute DNA sample and array preparation. Microarray scanned to the genetic etiology of prenatal-onset short stature and images were processed using the Software Feature Extrac- reveal novel potential candidate genes and/or loci related tion, version 10.7.3.1 (Agilent Technologies, Inc.). The to this condition. Genomic Workbench 6.9 Software (Agilent Technologies, Inc.) was applied for calling CNVs using the Aberration Detection Method 2 analysis algorithm, with a sensitivity Patients and methods threshold of 6.7. To consider an aberration of a genomic segment as a duplication or a deletion, the log2 ratio of Patients cyanine 3:cyanine 5 intensities was used encompassing This study was approved by the Local Ethics Committee, at least three probes. Ratios O0.3 were considered dupli- and the patients and/or guardians gave their written cations, whereas ratios !K0.3 were considered deletions. www.eje-online.org Downloaded from Bioscientifica.com at 09/27/2021 08:54:10PM via free access Clinical Study A P M Canton and others Copy number variants in 171:2 255 SGA children All hybridizations were gender-matched and processed in this strategy, CNVs were categorized as pathogenic if they reverse-labeling duplicates, which means that all patients fulfilled all these criteria. CNVs were categorized as were evaluated twice for confirmation. CNVs not detected probably pathogenic if they fulfilled all these criteria, in both experiments were disregarded. except the overlap with genomic coordinates for a known genomic imbalance syndrome. CNVs were categorized as probably benign mainly if they did not segregate with the Copy number
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