Background Neurodevelopmental disorders are genetically heterogeneous pediatric conditions. The first tier diagnostic method for uncovering copy number variations (CNVs), one of the most common genetic etiologies in affected individuals, is chromosomal microarray (CMA). However, this methodology is not yet a routine molecular cytogenetic test in many parts of the world, including Hungary. Here we report clinical and genetic data of the first, relatively large Hungarian cohort of patients whose genetic testing included CMA. Methods Clinical data were retrospectively collected for 78 children who were analyzed using various CMA platforms. Phenotypes of patients with disease-causing variants were compared to patients with negative results using the chi squared/Fisher exact tests. Results A total of 30 pathogenic CNVs were identified in 29 patients (37.2%). Postnatal growth delay (p = 0.05564), pectus excavatum (p = 0.07484), brain imaging abnormalities (p = 0.07848), global developmental delay (p = 0.08070) and macrocephaly (p = 0.08919) were more likely to be associated with disease-causing CNVs. Conclusion Our results allow phenotypic expansion of 14q11.2 microdeletions encompassing SUPT16H and CHD8 genes. Variants of unknown significance (n = 24) were found in 17 patients. We provide detailed phenotypic and genetic data of these individuals to facilitate future classification efforts, and spotlight two patients with potentially pathogenic alterations. Our results contribute to unraveling the diagnostic value of rare CNVs.

Introduction: Sex chromosome aberrations (SCAs) and other gonadal dysgeneses (OGDs) compose a huge part of disorders of sex development (DSD), but a comprehensive pre- and perinatal picture of this wide spectrum is missing. Our aim was to support genetic counseling with evidence, and improve the feasibility of personalized medicine, genotype-phenotype specific clinical practice, management, and prevention of complications.Clinical data: We collected the pre- and perinatal data of 137 patients, who were diagnosed with SCAs and OGDs between 2009 and 2019 at the Genetic Division of Semmelweis University’s 2nd Department of Pediatrics, Hungary.Methods: Data of patients were systemized and analyzed according to karyotype, which involved the relative prevalence, risk factors, prenatal signs and genetic tests, possible perinatal complications, and suggestive neonatal signs. We reviewed the recent scientific literature in relation to SCAs and OGDs.Results: Relative ratio of Turner, Klinefelter, Triple/Poly X and Double Y syndromes was 4:2:1:1. Diagnostic prenatal tests (DPTs) were performed in 18%, mostly due to advanced maternal age. Four patients were conceived with in vitro fertilization (IVF). 20% of mothers were older than 35, whereas 18% of fathers were over 40 years of age. 25% of patients were premature, only one tenth had suggestive neonatal signs. Without prematures, 6% of the cohort had low and 3% had high birth weight, whereas 2% had low and 24% had high birth length. The main reason underlying the high prevalence (28%) of cesarean section (CS) was abnormal fetal development.Discussion: Advanced parental ages and IVF increase the risk for SCAs and OGDs, which are important to recognise in time because certain forms predispose to prematurity, abnormal somatic growth, perinatal complications and the need for CS. The diagnostic efficacy of SCAs and OGDs is poor due to the lack of prenatal ultrasound signs and characteristic neonatal symptoms, which could be offset by including paternal age in prenatal risk assessment and the further spread of noninvasive prenatal testing (NIPT).

Background: Neurodevelopmental disorders are genetically heterogeneous pediatric conditions. The first tier diagnostic method for uncovering copy number variations (CNVs), one of the most common genetic etiologies in affected individuals, is chromosomal microarray (CMA). However, this methodology is not yet a routine molecular cytogenetic test in many parts of the world, including Hungary. Here we report clinical and genetic data of the first, relatively large Hungarian cohort of patients whose genetic testing included CMA. Methods: Clinical data were retrospectively collected for 78 children who were analyzed using various CMA platforms. Phenotypes of patients with disease-causing variants were compared to patients with negative results using the chi squared/Fisher exact tests. Results: A total of 30 pathogenic CNVs were identified in 29 patients (37.2%). Postnatal growth delay (p=0.05564), pectus excavatum (p=0.07484), brain imaging abnormalities (p=0.07848), global developmental delay (p=0.08070) and macrocephaly (p=0.08919) were more likely to be associated with disease-causing CNVs. Conclusions: Our results allow phenotypic expansion of 14q11.2 microdeletions encompassing SUPT16H and CHD8 genes. Variants of unknown significance (n=24) were found in 17 patients. We provide detailed phenotypic and genetic data of these individuals to facilitate future classification efforts, and spotlight two patients with novel potentially pathogenic alterations. Our results contribute to unraveling the diagnostic value of rare CNVs.

Background: Neurodevelopmental disorders are genetically heterogeneous pediatric conditions. The first tier diagnostic method for uncovering copy number variations (CNVs), one of the most common genetic etiologies in affected individuals, is chromosomal microarray (CMA). However, this methodology is not yet a routine molecular cytogenetic test in many parts of the world, including Hungary. Here we report clinical and genetic data of the first, relatively large Hungarian cohort of patients whose genetic testing included CMA. Methods: Clinical data were retrospectively collected for 89 children who were analyzed using various CMA platforms. Phenotypes of patients with disease-causing variants were compared to patients with negative results using the chi squared/Fisher exact tests. Results: A total of 41 pathogenic CNVs were identified in 36 patients (40.4%). Abnormal height (p=0.0050), short stature (p=0.0250), brain imaging abnormalities (p=0.0277), complicated perinatal adaptation (p=0.0346), postnatal growth delay (0.0387), abnormal weight (p=0.0865), global developmental delay (p=0.0918) and pectus excavatum (p=0.0968) were more likely to be associated with disease-causing CNVs. Conclusions: Our results allow phenotypic expansion of 14q11.2 microdeletions encompassing SUPT16H and CHD8 genes. Variants of unknown significance (n=32) were found in 22 patients. We provide detailed phenotypic and genetic data of these individuals to facilitate future classification efforts, and spotlight two patients with novel potentially pathogenic alterations. Our results contribute to unraveling the diagnostic value of rare CNVs.