Ozgur Cogulu

Background and Objectives: Pathogenic variants in genes encoding spliceosomal small nuclear RNAs (snRNAs) have recently emerged as a frequent cause of neurodevelopmental disorders (NDDs), yet these non-coding genes are commonly missed by standard diagnostic pipelines.,Methods: We investigated the diagnostic contribution of targeted snRNA gene analysis in 102 patients with global developmental delay and/or intellectual disability (GDD/ID) who remained undiagnosed after karyotyping, chromosomal microarray, and exome sequencing at a single tertiary pediatric genetics center. Existing exome data were re-evaluated for RNU2-2, RNU4-2, RNU5A-1, RNU5B-1, and RNU4ATAC, and targeted deep amplicon sequencing achieving 100% coverage at >1000× depth was performed where these loci were not captured; candidate variants were confirmed and segregated by Sanger sequencing.,Results: Rare variants were identified in eight patients (7.8%), and a definitive molecular diagnosis was established in three (2.9%). One patient carried the recurrent de novo RNU4-2 n.64_65insT variant and displayed the characteristic ReNU syndrome phenotype, including microcephaly, growth failure, distinctive facial features, and corpus callosum thinning. Two patients harbored biallelic pathogenic RNU4ATAC variants: a homozygous n.16G>A variant associated with a Roifman syndrome phenotype with transient infantile hypogammaglobulinemia, and compound heterozygous n.51G>A and n.111G>A variants in an adult with severe microcephaly, a molar tooth sign consistent with a Joubert-like ciliopathy phenotype, and relapsed Hodgkin lymphoma, an association not previously highlighted in RNU4atac-opathy.,Discussion: Our findings independently replicate the diagnostic relevance of snRNA genes in an unselected, consanguinity-enriched cohort and support incorporating these loci into routine diagnostic algorithms for unexplained NDD.

Objective. Detection of cell-free fetal DNA (cffDNA) in maternal plasma has paved the way for non-invasive prenatal testing. The ability to detect cffDNA in various body fluids has increased interest in alternative sampling methods. Exhaled breath condensate (EBC) is a non-invasive specimen that allows analysis of genetic materials such as DNA and RNA. This study aimed to investigate the presence of fetal DNA in EBC samples from pregnant women. Materials And Methods. Thirty pregnant women carrying male fetuses as confirmed by routine ultrasonography were included in the study. EBC samples were collected, and DNA was extracted. The presence of the SRY gene was analyzed using digital droplet PCR. Results. The mean maternal age was 30.1 years, mean gestational age was 37 weeks, and mean DNA concentration was 17 ng µ l ⁻¹ . The SRY gene was detected in 11–30 samples (36.6%). All newborns were phenotypically male. Conclusion. This study demonstrates the detectability of fetal DNA in EBC samples from pregnant women and supports the feasibility of EBC as a novel non-invasive sampling matrix for prenatal genetic analysis. Although further methodological optimization is required, these findings highlight the potential of EBC as an alternative source of fetal genetic material for future prenatal testing applications.

Epigenetic alterations are crucial in gastric cancer (GC) development and progression. As these modifications are reversible, targeting them may offer preventive and therapeutic benefits. Origanum onites L. essential oil (OOEO) has demonstrated anticancer properties in various cancers, but its epigenetic effects in GC remain unexplored. OOEO was extracted by water distillation, and its effects on gastric adenocarcinoma (AGS) and normal gastric epithelial (GES-1) cells were evaluated. Cytotoxicity was assessed via WST-8 assay, apoptosis by Annexin V staining, DNA damage by γ-H2AX test, and epigenetic modifications by methylation-specific PCR and histone modification analysis. Compared to GES-1 cells, OOEO exhibited cytotoxic activity even at lower concentrations in AGS cells. OOEO treatment induced apoptosis and DNA double-strand breaks and arrested cell cycle at S and G2/M phases compared to the untreated group. OOEO also caused a decrease in promoter methylation of LOX, TIMP3, CDH1 and RARB genes and was found to globally alter 16 histone modifications in AGS cells and 19 histone modifications in GES-1 cells. OOEO contributed to the reorganization of H3K9ac modification in the promoters of CDKN1A, MYC, RUNX3, RASSF1 and CDH1 genes and H3K27me3 modification in the promoters of CDKN1A and MYC genes. OOEO exhibits epigenetic regulatory properties that may contribute to GC prevention and treatment. Its potential in neoadjuvant or combinatory therapies warrants further investigation.

Purpose: Congenital cataracts (CC) are a preventable cause of childhood blindness, accounting for approximately 10% of cases. A significant portion of CC cases remains idiopathic. Genetic diagnosis can eliminate unnecessary tests and ensure appropriate follow-up and treatment. This study aimed to evaluate the etiology of CC without known etiological reasons in 10 families using whole exome sequencing (WES). Methods: Ten families participated in this study, with all patients undergoing comprehensive ophthalmological, metabolic, and genetic assessments. DNA samples from the probands were analyzed using WES, and variants were verified and validated through Sanger sequencing. Results: Of the 10 patients diagnosed with isolated CC, 9 (90%) had bilateral cataracts, and 1 (10%) had unilateral cataract. Nuclear type cataracts were detected in 8 (80%) patients, while polar type cataracts were found in 2 (20%) patients. Parental consanguinity was present in 7 out of the 10 families. An unidentified variant in the RAB3GAP1 gene (c.491C > G) associated with Martsolf syndrome was found in one patient. Two novel and one previously identified gene variants associated with CC were detected in 3 of the remaining 9 patients: a novel c.463C > T in CRYGD , a previously identified c.965dup in HSF4 , and a novel c.3330C > A in FYCO1 . Conclusion: The high rate of consanguineous marriages in Turkey (23.3%) increases the incidence of autosomal recessive (AR) diseases, explaining the higher prevalence of AR CC despite its usual autosomal dominant inheritance. In conclusion, WES is a valuable tool in determining the etiology of isolated CC.

Bainbridge‐Ropers Syndrome(BPRS) is a rare autosomal dominant genetic disorder resulting from heterozygous mutations in the ASXL3(Additional Sex Comb‐Like 3) gene located on chromosome 18q12. To date, only 45 cases have been documented in the literature. BPRS is characterized by a range of clinical features, including feeding difficulties, hypotonia, distinctive dysmorphic facial features, high‐arched palate, and intellectual disability. This case report aims to present two pediatric patients diagnosed with BPRS, emphasize newly identified oro‐dental manifestations, and propose a comprehensive dental management plan. In Case #1, a 10‐year‐old female patient presented to the clinic with concerns of developmental delay and spinal deformity. Physical examination revealed trigonocephaly, thoracic kyphosis, strabismus, hirsutism, bitemporal narrowing, and bilateral coxa valga. Additionally, the patient exhibited failure to thrive, language difficulties, and mild intellectual disability. Oral examination identified a high‐arched palate, fibrotic frenulum, narrow maxilla, and posterior crossbite. In Case #2, a 6‐year‐old female patient presented with developmental delay, language difficulties, and mouth breathing. Physical findings included trigonocephaly, bitemporal narrowing, strabismus, hirsutism, and arched eyebrows. Oral examination revealed a high‐arched palate, narrow maxilla, and open bite. For both cases, preventive dental interventions were implemented, including the application of fissure sealants, fluoride varnishes, dietary regulation, and the use of interceptive orthodontic appliances. Children diagnosed with BPRS require ongoing medical and dental management through a multidisciplinary approach to address the complex and varied manifestations of the disorder effectively.

Diagnostic Utility in Next-Generation Sequencing by Implicating CNV Analysis in Eleven Patients with Peters Plus Syndrome: A Single-Center Experience - Journal of Clinical Research in Pediatric Endocrinology

Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (EDFAOB) is a rare neuroectodermal syndrome caused by somatic mosaic mutations in the RHOA gene. It presents with linear skin hypopigmentation, facial and limb asymmetry, dental and acral anomalies, and leukoencephalopathy, generally preserving intellectual and neurological functions. We report two cases of EDFAOB. Both cases initially presented with notable facial‐body asymmetry, thin hair, dental issues, digital anomalies, and Blaschko's lines‐aligned hypopigmentation. A 6‐year‐old girl exhibited esotropia, visual center atrophy, and bilateral white matter hyperintensities on MRI. A 10‐year‐old girl had unilateral hyperintense lesions in the left cerebral hemisphere on MRI. Both had normal neuromotor development without intellectual impairment. RHOA gene sequencing from hypopigmented skin biopsies revealed the c.139G > A (p.Glu47Lys) mutation, with allele fractions of 20% and 10%, respectively, absent in blood leukocytes and parental DNA. These cases highlight the clinical and genetic features of EDFAOB and underscore the importance of thorough clinical evaluation to guide precise genetic testing. The identification of mutations exclusively in affected tissues supports a postzygotic mosaic distribution, refining the diagnostic approach for this syndrome.

Introduction: Williams syndrome (WS) cases have been reported to have with 25–100 times greater increased risk of sudden cardiac death (SCD). SCD has been reported in cases without any evidence of structural cardiovascular anomalies. Wolff–Parkinson–White (WPW) syndrome is characterized by short PR interval and delta wave. Ventricular preexcitations can develop paroxysmal reentrant tachycardia through Kent bundle or less frequent atrial fibrillation and in some cases with accessory pathway effective refractory period (APERP) under 250 ms considered as risky and may lead to SCD. WS associated with WPW has not been reported before.Case Report: An 11‐year‐old male who had been followed up with WS was referred to pediatric cardiology outpatient clinic with the complaint of palpitation. Electrocardiographic examination showed short PR interval and delta wave in the ECG consistent with WPW. He underwent electrophysiological study (EPS). Basic measurements were performed, and APERP was found at 280 ms cycle atrial pacing. RF energy was delivered using a 4 mm tip nonirrigated radiofrequency (RF) ablation catheter where the best ventriculoatrial (VA) signals were received and the AP was abolished within few seconds.Discussion and Conclusions: Although, WPW cases are usually asymptomatic or related to SVT, the risk of SCD should not be ignored. Thus, all patients with WPW deserve an EPS for assessing the AP conduction properties. Due to the increased risk of SCD in patients with WS compared to general population, in the presence of concomitant WPW, these patients should be evaluated with EPS even if they do not have symptoms.

Objectives: Osteogenesis imperfecta (OI) is a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. This study aimed to investigate the molecular genetic etiology and to determine the relationship between genotype and phenotype in OI patients with whole exome sequencing (WES). Methods: Multiplex-Ligation dependent Probe Amplification (MLPA) analysis of COL1A1 and COL1A2 and WES were performed on cases between the ages of 0 and 18 whose genetic etiology could not be determined before using a targeted next-generation sequencing panel, including 13 genes (COL1A1, COL1A2, IFITM5, SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, SP7, BMP1, MBTPS2, PLOD2) responsible for OI. Results: Twelve patients (female/male: 4/8) from 10 different families were included in the study. In 6 (50 %) families, consanguineous marriage was noted. The clinical typing based on Sillence classification; 3 (25 %) patients were considered to be type I, 7 (58.3 %) type III, and 2 (16.7 %) type IV. Deletion/duplication wasn’t detected in the COL1A1 and COL1A2 genes in the MLPA analysis of the patients. Twelve patients were molecularly analyzed by WES, and in 6 (50 %) of them, a disease-causing variant in three different genes (FKBP10, P3H1, and WNT1) was identified. Two (33.3 %) detected variants in all genes have not been previously reported in the literature and were considered deleterious based on prediction tools. In 6 cases, no variants were detected in disease-causing genes. Conclusions: This study demonstrates rare OI types’ clinical and molecular features; genetic etiology was determined in 6 (50 %) 12 patients with the WES analysis. In addition, two variants in OI genes have been identified, contributing to the literature.