DETECTION OF A RARE MUTATION IN A NOONAN SYNDROME SUSPECTED PATIENT: A CASE REPORT

Noonan syndrome (NS) is a genetic autosomal dominant condition, caused by mutations in PTPN11 and other genes. The aim of this report is to highlight a finding of a rare mutation in the RAF1 gene in a six-year-old child evaluated for Noonan Syndrome. An Ampliseq Research Panel covering A2ML1, BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1 and SPRED1 genes was used on the Ion Torrent platform. Out of 54 variants detected, a single nucleotide missense mutation c.483T>G in the RAF1 gene was classified as likely pathogenic, based on a single previous submission to Clinvar. Further investigations may shed light on the possible role of this variant in the pathogenesis of Noonan Syndrome and other RASopathies

Correlation of Serum Adiponectin and Leptin Concentrations with Anthropometric Parameters in Newborns

Introduction It has been shown that some adipocytokines and their mutual relationship can be indicators of fetal and neonatal growth. Physiological role of leptin and adiponectin in fetal and neonatal growth is not well established. Objectives The aim of this study was to assess the correlation of the anthropometrics parameters and serum concentration of leptin and adiponectin levels in healthy newborns. Methods A cohort of 110 neonates, born after uncomplicated singleton pregnancies at term, were classified as AGA (n=60), SGA (n=30) and LGA (n=20) according to the Lubchenco curves. Anthropometric parameters of the neonates: birth weight (BW), birth length (BL), body weight/body length ratio (BW/ BL), Body Mass Index (BMI) and Ponderal Index (PI) were recorded after birth. Results Mean serum leptin and adiponectin levels in both sexes were not significantly different (male: 1.85±0.75; 29.51±22.89 and female: 2.06±0.99; 31.60±23.51 ng/mL). There was a significant difference between leptin levels in AGA and LGA newborns (1.93±0.84 vs. 3.12±1.50 ng/mL) (p<0.05), and in adiponectin levels between AGA and LGA compared to SGA newborns (32.8±23.29 and 43.40±31.24 vs. 12.67±2.43 ng/mL, respectivel; p<0.05; p<0.05). Leptin and adiponectin levels were positively correlated with BW (r=0.63 and r=0.41), BL (r=0.63, r=0.42), BW/BL (r=0.61, r=0.41), BMI (r=0.54, r=0.35), and PI (r=0.47, r=0.29, (p<0.01). Conclusion Significantly higher adiponectin levels were found in AGA neonates compared to SGA neonates. Leptin and adiponectine levels were positively correlated with birth weight. These findings suggest that these adipocytokines may be involved in fetal growth regulation. Keywords: leptin; adiponektin; anthropometric parameters; newbor

Demographic, Clinical and Biochemical Characteristics of Pediatric Obesity: Interim Analysis of a Larger Prospective Study

Introduction: Pediatric obesity is a common nutritional disorder that affects more than a third of the young population and predis-poses individuals to greater future morbidity and mortality. Materials and methods: Sixty-two children were recruited in the study. Demographic and clinical information regarding the pa-tients and their parents was collected. Data about the weight, height, systolic (SP) and diastolic (DP) blood pressure, lipid metabolic profile, thyroid hormone levels, glucose and insulin levels before and after oral glucose tolerance test (OGTT) of participants were also collected. Body mass index (BMI) was calculated and patients were classified into groups according to the International Obesity Task Force criteria. Descriptive, comparative parametric, non-parametric tests and Spearman’s ranked correlations were used in the statistical analysis. Results: The study sample consisted of 34 males and 28 females aged 11.6 and 11.8 years, respectively (p=0.781). The mean BMI was 30.5 (SD 5.5): 8 of participant had normal weight (≤25 BMI), 22 were overweight (25-30 BMI), and 32 were obese (≥30 BMI). The chil-dren’s BMIs were significantly associated with parental BMIs (r=0.395, p=0.004). Both SP and DP were significantly different between BMI subgroups (p=0.005 and p=0.001, respectively) with the obese group having the highest values (post-hoc Benjamini,  p=0.004). Obese children had lower average T4 levels when compared to the comparators (7.5 µg/dL vs. 9.9 µg/dL, p=0.021). Obese children had significantly lower baseline glucose levels and higher insulin levels when compared to the overweight/normal BMI children (73.8 mg/dL vs. 86.4 mg/dL, p<0.001 and 21.8 µgU/mL vs. 132 µgU/mL, p=0.003). Obese children had the greatest numerical increase in glucose levels during the OGTT (Δ63.0 mg/dL vs. Δ43.2 mg/dL, p=0.063) and numerically smaller absolute insulin response (Δ86.1 µIU/mL vs. Δ125.7 µIU/mL, p=0.307).  Conclusions: Pediatric patients demonstrate familial type of obesity and premorbid asymptomatic endocrine impairments. In order to maintain normal glucose levels, obese pediatric patients demonstrate high levels of resting insulin levels and diminished response after OGTT load

Correlation of serum adiponectin and leptin concentrations with anthropometric parameters in newborns

Introduction It has been shown that some adipocytokines and their mutual relationship can be indicators of fetal and neonatal growth. Physiological role of leptin and adiponectin in fetal and neonatal growth is not well established. Objectives The aim of this study was to assess the correlation of the anthropometrics parameters and serum concentration of leptin and adiponectin levels in healthy newborns. Methods A cohort of 110 neonates, born after uncomplicated singleton pregnancies at term, were classified as AGA (n=60), SGA (n=30) and LGA (n=20) according to the Lubchenco curves. Anthropometric parameters of the neonates: birth weight (BW), birth length (BL), body weight/body length ratio (BW/ BL), Body Mass Index (BMI) and Ponderal Index (PI) were recorded after birth. Results Mean serum leptin and adiponectin levels in both sexes were not significantly different (male: 1.85±0.75; 29.51±22.89 and female: 2.06±0.99; 31.60±23.51 ng/mL). There was a significant difference between leptin levels in AGA and LGA newborns (1.93±0.84 vs. 3.12±1.50 ng/mL) (p<0.05), and in adiponectin levels between AGA and LGA compared to SGA newborns (32.8±23.29 and 43.40±31.24 vs. 12.67±2.43 ng/mL, respectivel; p<0.05; p<0.05). Leptin and adiponectin levels were positively correlated with BW (r=0.63 and r=0.41), BL (r=0.63, r=0.42), BW/BL (r=0.61, r=0.41), BMI (r=0.54, r=0.35), and PI (r=0.47, r=0.29, (p<0.01). Conclusion Significantly higher adiponectin levels were found in AGA neonates compared to SGA neonates. Leptin and adiponectine levels were positively correlated with birth weight. These findings suggest that these adipocytokines may be involved in fetal growth regulation. Keywords: leptin; adiponektin; anthropometric parameters; newbor

Identification of DNA methylation episignature for the intellectual developmental disorder, autosomal dominant 21 syndrome, caused by variants in the CTCF gene

Purpose: The main objective of this study was to assess clinical features and genome-wide DNA methylation profiles in individuals affected by intellectual developmental disorder, autosomal dominant 21 (IDD21) syndrome, caused by variants in the CCCTC-binding factor (CTCF) gene. Methods: DNA samples were extracted from peripheral blood of 16 individuals with clinical features and genetic findings consistent with IDD21. DNA methylation analysis was performed using the Illumina Infinium Methylation EPIC Bead Chip microarrays. The methylation levels were fitted in a multivariate linear regression model to identify the differentially methylated probes. A binary support vector machine classification model was constructed to differentiate IDD21 samples from controls. Results: We identified a highly specific, reproducible, and sensitive episignature associated with CTCF variants. Six variants of uncertain significance were tested, of which 2 mapped to the IDD21 episignature and clustered alongside IDD21 cases in both heatmap and multidimensional scaling plots. Comparison of the genomic DNA methylation profile of IDD21 with that of 56 other neurodevelopmental disorders provided insights into the underlying molecular pathophysiology of this disorder. Conclusion: The robust and specific CTCF/IDD21 episignature expands the growing list of neurodevelopmental disorders with distinct DNA methylation profiles, which can be applied as supporting evidence in variant classification.</p

Identification of DNA methylation episignature for the intellectual developmental disorder, autosomal dominant 21 syndrome, caused by variants in the CTCF gene

Purpose: The main objective of this study was to assess clinical features and genome-wide DNA methylation profiles in individuals affected by intellectual developmental disorder, autosomal dominant 21 (IDD21) syndrome, caused by variants in the CCCTC-binding factor (CTCF) gene. Methods: DNA samples were extracted from peripheral blood of 16 individuals with clinical features and genetic findings consistent with IDD21. DNA methylation analysis was performed using the Illumina Infinium Methylation EPIC Bead Chip microarrays. The methylation levels were fitted in a multivariate linear regression model to identify the differentially methylated probes. A binary support vector machine classification model was constructed to differentiate IDD21 samples from controls. Results: We identified a highly specific, reproducible, and sensitive episignature associated with CTCF variants. Six variants of uncertain significance were tested, of which 2 mapped to the IDD21 episignature and clustered alongside IDD21 cases in both heatmap and multidimensional scaling plots. Comparison of the genomic DNA methylation profile of IDD21 with that of 56 other neurodevelopmental disorders provided insights into the underlying molecular pathophysiology of this disorder. Conclusion: The robust and specific CTCF/IDD21 episignature expands the growing list of neurodevelopmental disorders with distinct DNA methylation profiles, which can be applied as supporting evidence in variant classification.</p

Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype

Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene

Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype

Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene