PURPOSE:The ERBB4 gene encodes a tyrosine kinase receptor for neuregulins and EGF family members, and plays a crucial role in various neurobiological processes. At present, the phenotypic manifestations of genetic variants that disrupt ERBB4 gene function (null variants) are not well established. METHODS:A search for new patients with null variants in ERBB4 was initiated through an international data-sharing collaboration via GeneMatcher, and by searching the databases Decipher and ClinVar. Diagnosis had been performed using chromosomal microarray analysis, whole-exome sequencing, or whole-genome sequencing. RESULTS:Twenty-four new patients from 13 unrelated families with null variants in ERBB4 were identified. Genetic findings included single- or multiple-exon deletions in eight families, a reciprocal translocation disrupting ERBB4 in one family, and sequence variants in four. Variants arose de novo in four probands, were inherited in eight, and had an unknown inheritance pattern in one. Co-segregation of variants with clinical manifestations was observed within families. The predominant clinical features included neurodevelopmental disorders (intellectual disability, neurodevelopmental delay, autism spectrum disorder, and attention deficit hyperactivity disorder), speech delay, challenging behaviors, hypotonia, psychiatric conditions and seizures. CONCLUSION:This study represents the largest case series of patients with neurological disorders and null variants in the ERBB4 gene. Our findings support haploinsufficiency as the most plausible pathophysiological mechanism underlying ERBB4-related disorders and broaden the spectrum of associated phenotypes. Autism spectrum disorders and psychiatric manifestations have emerged as frequent, previously underrecognized features. Penetrance appears to be high but incomplete, and expressivity is highly variable, with a tendency toward intrafamilial phenotypic conservation.

Background: A two-year-old female patient was referred to our clinic due to speech and gait disturbances, strabismus, vacant staring, truncal hypotonia, and spasticity in the extremities. The patient had a history of a complicated delivery resulting in perinatal asphyxia. Electrocardiogram (ECG), echocardiogram (ECHO) and abdominal ultrasound findings reported no abnormalities. Previously performed spinal muscular atrophy (SMA) test, chromosomal microarray and karyotype analyses yielded normal results. On clinical examination, facial dysmorphic features included: prominently low-set ears, strabismus, downslanting palpebral fissures, micrognathia, and tapering fingers. Methods: To elucidate the patient’s phenotype, trio exome sequencing was performed using DNA samples of the patient and her parents. Analysis revealed a homozygous variant in the AMPD2 gene (NM_001368809.2) c.353 + 11 C > T, with both parents identified as heterozygous carriers. The phenotype was found to be partially consistent with pontocerebellar hypoplasia type 9 (PCH9), a condition associated with the AMPD2 gene. The variant was suspected to create a novel splicing site; therefore, blood samples were collected from the patient and her parents for RNA extraction. Subsequent cDNA analyses via gel electrophoresis and Sanger sequencing confirmed the alternative splicing event. Quantitative PCR study was applied to evaluate expression. Conclusions: This study designates the early-onset phenotype of PCH9 in a patient carrying a splice-altering variant in AMPD2. It also highlights the feasibility of functional studies in evaluating intronic variants of uncertain significance. Functional validation of such variants, which are often challenging to classify, can provide critical insights for clinical decision-making for the patient and further reproductive planning for the family.

Introduction: Breast cancer (BC) is a heterogeneous disease with a hereditary component, but the impact of non-BRCA germline variants on tumor subtypes remains underexplored, particularly in diverse populations. This study aims to describe the distribution of immunohistochemical (IHC) subtypes in a Turkish BC patient cohort with pathogenic or likely pathogenic variants (PVs/LPVs) in non-BRCA susceptibility genes.Materials and methods: We retrospectively analyzed next-generation sequencing (NGS) data from 2274 patients tested for hereditary BC at a tertiary hospital (2021–2024), identifying 58 patients with PVs/LPVs in nine BC-predisposing genes (CHEK2, ATM, BAP1, BARD1, STK11, PTEN, PALB2, NTHL1, RAD51D). Tumors were classified into Luminal A, Luminal B, CERBB2-overexpressing, or triple-negative breast cancer based on IHC markers. A descriptive approach was used to explore subtype distributions.Results: Among the 58 patients (96.6% female, median age at diagnosis 48.4 years), CHEK2 (41.3%), ATM (25.8%), and PALB2 (10.3%) were the most frequently mutated genes. Luminal B was the predominant IHC subtype overall (46.6%), with trends of CHEK2 and ATM variants associating with Luminal B (45.8% and 66.7%, respectively) and BARD1/RAD51D variants linking to TNBC (100% and 66.7%, respectively). Invasive ductal carcinoma was the most common histological subtype (75.8%). Five novel PVs/LPVs were identified in ATM, BARD1, and STK11.Conclusions: This study provides preliminary insights into gene-specific IHC subtype patterns in Turkish BC patients with non-BRCA germline variants, suggesting trends such as Luminal B predominance for CHEK2 and ATM and TNBC association for BARD1 and RAD51D. The Turkish cohort’s unique genetic and environmental context highlights the need for larger, population-based studies to validate these observations and inform genetic counseling and precision medicine in this population.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by marked heterogeneity in cognitive functioning. This study aimed to examine the associations between polymorphisms in the DAT1 and DRD4 genes and neurocognitive performance in children and adolescents with ADHD. A total of 336 participants aged 6-18 years (244 with ADHD and 92 healthy controls) were included. Variable number tandem repeat (VNTR) polymorphisms in the 3' UTR of DAT1 and exon 3 of DRD4 were genotyped. Neurocognitive performance was assessed using standardized scores derived from the CNS Vital Signs battery. Associations between genotypes and cognitive domains were examined using analysis of covariance (ANCOVA), adjusting for age and gender. Homozygosity for the DRD4 4-repeat allele was significantly associated with poorer cognitive flexibility, whereas a trend-level difference was observed for complex attention. In contrast, DAT1 10R/10R homozygosity and DRD4 7-repeat allele carriage were not associated with significant differences in reaction time, complex attention or cognitive flexibility. These findings suggest that DRD4, rather than DAT1, may represent a more salient dopaminergic genetic marker of executive dysfunction in ADHD. The results underscore the domain-specific and modest nature of genetic influences on cognition and highlight the importance of integrating genetic markers with cognitive endophenotypes to better characterize heterogeneity in ADHD.

Glioblastoma, a prevalent and aggressive brain tumor in adults, recurs due to local invasiveness, radiation therapy failure, drug resistance, and cancer stem cell presence. The Hippo signaling pathway, regulating organ size and growth, features YAP as a key effector with oncogenic implications in various cancers, including glioma. This study aimed to explore YAP1 as a therapeutic target in glioblastoma by silencing it using siRNA and evaluating the potential of a new inhibitor, CA3 (CIL56), through advanced in vitro analyses. Investigations were conducted on brain cancer and stem cells, alongside healthy brain stem cells and human brain microvascular endothelial cells. Effects of CA3 (CIL56) and YAP1 siRNA on cell lines were gauged through Annexin V-FITC assay, ferroptosis assay (GPX activity), and cell cycle analysis. Invasion and migration assays, along with epithelial-mesenchymal transition marker evaluations, assessed cell movement effects. Spheroid formation examined stemness effects, with qRT-PCR measuring gene expression changes. Findings indicate that siRNA-mediated YAP1 silencing and CA3 (CIL56) inhibition exert significant, though varying, anti-tumoral effects on glioblastoma cell viability, motility, and stemness. Notably, CA3’s impact on stem cells highlights its potential as a promising therapeutic target, meriting further investigation.

Primary adrenal insufficiency (PAI) in children, outside of congenital adrenal hyperplasia (CAH), represents a rare and genetically diverse group of disorders often leading to diagnostic delays. Advances in molecular genetics have uncovered a wide spectrum of non-CAH etiologies, yet real-world data from pediatric cohorts remain limited. We retrospectively reviewed 11 children diagnosed with non-CAH PAI at a single tertiary care center between March 2015 and December 2024. Clinical, biochemical, and genetic findings were evaluated using targeted Sanger sequencing or next-generation sequencing panels. Variants were classified according to ACMG/AMP criteria. Pathogenic or likely pathogenic variants were identified in MC2R (n = 3), NR0B1 (n = 2), ABCD1 (n = 2), MRAP (n = 1), AIRE (n = 1), and AAAS (n = 1) genes, while one patient remained genetically undiagnosed. In total, five novel variants were identified: one in MC2R (shared by two siblings), and one each in NR0B1, ABCD1, and AAAS. Clinical presentations ranged from neonatal adrenal crisis to later-onset symptoms such as fatigue, hyperpigmentation, or hypoglycemia. Consanguinity was present in 45

Myopathy with extrapyramidal signs (MPXPS) is a rare, autosomal-recessive, multisystem disorder caused by biallelic loss-of-function (LOF) variants in MICU1, the calcium-sensing gatekeeper of the mitochondrial calcium uniporter. We clinically and genetically characterized seven affected individuals from six Iranian-Turkish consanguineous families and combined these data with 54 previously published cases (total of 62). The targeted neuromuscular assessment, along with muscle biopsy and exome sequencing, identified six pathogenic MICU1 variants, including c.355C>T; p.Arg119*, c.493 + 1G>A, c.508C>T; p.Gln170*, c.547C>T; p.Gln183*, c.1226C>G; p.Ser409*, and c.553C>T; p.Arg185*. Notably, we report one adult-onset patient whose symptoms began at age 29 and progressed more rapidly than those in childhood-onset cases. A separate pedigree contained monozygotic twins who exhibited an indistinguishable clinical course, emphasizing the consistency of the genotype-driven phenotype. Across the combined cohort, the mean age at onset was 5.9 ± 7.3 years (median = 3 years); 61.5% presented before age 5, while 9.5% manifested after 15 years. Deep phenotyping of 61 patients from different ethnic backgrounds revealed that common symptoms included learning difficulties (72%), myopathy (51%), and speech impairments (51%). Functional studies targeting MCU modulation may provide future therapeutic options.

BACKGROUND:This study investigated the relationship between circulating tumor DNA (ctDNA) parameters and metabolic parameters from FDG PET/CT in advanced breast cancer (ABC) patients. METHODS:In this retrospective single-center study, 47 ABC patients who underwent both liquid biopsy and FDG PET/CT were analyzed. RESULTS:Results showed that 27 patients (57.4%) had detectable ctDNA. Patients with detectable ctDNA demonstrated significantly higher whole-body metabolic tumor volume (WB-MTV) (p = 0.002) and whole-body total lesion glycolysis (WB-TLG) (p = 0.006) compared to those without ctDNA, while no significant difference was found in SUVmax or SUVmean. A moderate correlation was observed between variant allele frequency (VAF) values and metabolic parameters: maximum VAF correlated with SUVmax, WB-MTV, and WB-TLG (r = 0.407, p = 0.005; r = 0.457, p = 0.001; r = 0.415, p = 0.004, respectively). Mean VAF correlated with SUVmax, WB-MTV, and WB-TLG (r = 0.406, p = 0.005; r = 0.446, p = 0.002; r = 0.404, p = 0.005, respectively). The total VAF correlated with SUVmax, WB-MTV, and WB-TLG (r = 0.394, p = 0.006; r = 0.465, p = 0.001; r = 0.430, p = 0.003, respectively). When excluding patients without detectable ctDNA, the correlation between VAF values and WB-MTV, WB-TLG disappeared, while the correlation with SUVmax persisted. Total alteration number in ctDNA showed a moderate correlation with WB-MTV and WB-TLG (r = 0.563, p < 0.001; r = 0.459, p = 0.001, respectively). Correlation with WB-MTV remained significant when excluding patients without detectable ctDNA (r = 0.500, p = 0.008). CONCLUSIONS:These findings suggest that metabolic tumor burden correlates with ctDNA detection and characteristics, potentially offering complementary information for disease monitoring, treatment selection, and response assessment in ABC. The combined use of these parameters may improve prognostic evaluation and guide personalized treatment strategies.

BACKGROUND:Familial hypercholesterolemia (FH) is a genetic disorder characterized by impaired clearance of low-density lipoprotein cholesterol (LDL-C), leading to severe hypercholesterolemia and increased risk of premature cardiovascular disease (CVD). Our study aims to describe and compare the clinical, biochemical, and genetic profiles of pediatric patients diagnosed with FH based on LDL-C levels exceeding 400 mg/dL (10.4 mmol/L) and confirmed by biallelic pathogenic variants in low-density lipoprotein receptor (LDLR) or low-density lipoprotein receptor adapter protein-1 (LDLRAP1) genes. METHODS:This retrospective cohort study included 39 pediatric patients diagnosed with FH at a tertiary care center. Clinical data were analyzed, including age at diagnosis, family history, lipid profile, presence of xanthomas, and cardiovascular complications. Molecular analysis was conducted using next-generation sequencing (NGS) and Sanger sequencing to confirm pathogenic variants. Statistical comparisons were performed between the LDLR and LDLRAP1 variant groups regarding lipid profiles, treatment response, and cardiovascular outcomes. RESULTS:Among 39 patients, 32 and 7 had pathogenic variants in LDLR and LDLRAP1 genes, respectively. Genetic analysis identified 27 unique pathogenic variants in LDLR (including 5 novel mutations) and 4 in LDLRAP1 causal for autosomal recessive hypercholesterolemia (ARH), highlighting the molecular diversity of FH. Compared to the LDLR variant group, LDLRAP1 variant patients had significantly lower untreated LDL-C levels (640.0 ± 155.6 mg/dL [16.6 ± 4.0 mmol/L] vs 506.9 ± 130.1 mg/dL [13.1 ± 3.4 mmol/L], P = .026] and showed a superior response to lipid-lowering therapy (LLT), with a greater percentage (70.6% ± 12.0%) reduction in LDL-C levels (P = .015). While xanthomas were present in 62.5% of LDLR variant patients, they were less frequent (42.9%) in the LDLRAP1 group (P = .107). Cardiovascular complications were observed exclusively in LDLR variant patients. Fourteen patients required lipoprotein apheresis (LA), and one underwent liver transplantation due to severe aortic stenosis. CONCLUSION:This study highlights the importance of genetic testing in differentiating classical semidominant homozygous FH from ARH, given their phenotypic overlap but distinct treatment responses. LDLRAP1 variant patients with ARH exhibit better LDL-C reductions with conventional LLT, suggesting a milder phenotype. Early diagnosis, aggressive LLT, and novel treatments are essential to mitigate cardiovascular risk. Future studies with larger cohorts and long-term follow-ups are needed to refine treatment strategies for pediatric FH.

Objectives: This study aimed to expand our understanding of the genetic basis of Parkinson's disease (PD) by investigating individuals diagnosed with early onset PD (EOPD) or those with a suspected genetic predisposition to PD. Patients and methods: Thirty patients (18 females, 12 males; mean age: 33.2 +/- 6.4 years; range, 15 to 48 years) diagnosed with EOPD between January 2018 and December 2019 were included in the study. A targeted next-generation sequencing analysis was conducted on 10 genes (SNCA, LRRK2, VPS35, PARK2, PINK1, PARK7, ATP13A2, PLA2G6, FBXO7, DNAJC6) known to be associated with PD etiology. Additionally, the MLPA method was used to investigate eight genes (SNCA, PARK7, LRRK2, ATP13A2, PINK1, GCH1, PRKN, and UCHL1) for large deletions and duplications. Results: Mutations in PD-associated genes were identified in seven out of the 30 patients included in the study. Four patients exhibited mutations in the PRKN gene: three had defined deletion mutations (exon 5 deletion, exon 2 deletion, and exon 3 and 4 deletion), and one had a splice site mutation newly identified in this study (c.1083+1delG). Two patients displayed a point mutation in the PLA2G6 gene (c.1705C>T), and one patients had a point mutation in the PINK1 gene (c.1247C>T). The clinical and genetic characteristics of these patients were analyzed to explore genotype-phenotype correlations. Conclusion: This study is one of the few in T & uuml;rkiye to examine the molecular etiology of EOPD. The identified mutations in the PRKN, PLA2G6, and PINK1 genes provide valuable insights into genotype-phenotype correlations in PD cases and contribute to the existing literature.

Generalized glucocorticoid resistance (GGCR) is caused by variants in the NR3C1 gene, which encodes the human glucocorticoid receptor (hGR). To date, 39 pathogenic variants of NR3C1 have been reported, primarily in the ligand-binding domain (LBD). This study presents a novel case of the NR3C1 variant located in the N-terminal domain (NTD) of hGR, highlighting its clinical and molecular significance in glucocorticoid resistance. The patient was a 21-year-old woman presenting with chronic fatigue, irregular menstrual cycles, and osteopenia, though without any clinical signs of Cushing’s syndrome. She underwent a standard evaluation of the hypothalamic-pituitary-adrenal (HPA) axis. Endocrinological tests revealed elevated levels of ACTH, morning serum cortisol, aldosterone, DHEAS, 11-deoxycortisol, pregnenolone, and corticosterone, as well as increased urinary-free cortisol excretion. The low-dose dexamethasone suppression test (LDDST) showed suppression of cortisol levels. Molecular analysis via Whole Exome Sequencing (WES) identified a novel heterozygous pathogenic variant, c.220 C > T (p.Gln74Ter), in the NR3C1 gene. This confirmed the diagnosis of glucocorticoid resistance syndrome. This case contributes to expanding the mutational spectrum of NR3C1 in glucocorticoid resistance syndrome, supporting more accurate diagnosis and genetic counseling for affected individuals.

INTRODUCTION:Short rib polydactyly syndrome (SRPS), with or without polydactyly, also known as Verma-Naumoff/Saldino-Noonan syndrome, is a type of skeletal ciliopathy. Initially, variants in the IFT80 gene were implicated; however, approximately half of the SRPS cases are associated with variants in the DYNC2H1 gene. Additionally, digenic variants involving DYNC2H1 and NEK1 can contribute to the syndrome. MATERIALS AND METHODS:This case report describes a male patient presenting with characteristic SRPS features, including a constricted thorax and shortened limbs. Exome sequencing was performed to identify causative variants, followed by functional analyses to assess the pathogenicity of the identified variants, including a synonymous variant. RESULTS:Exome sequencing identified compound heterozygous variants in the DYNC2H1 gene: a novel missense variant c.6439G>T p.(Asp2147Tyr) and a synonymous variant c.6477G>A p.(Gln2159=). Functional analyses confirmed that the synonymous variant triggers nonsense-mediated decay of the affected allele. CONCLUSION:This study expands the spectrum of DYNC2H1 variants associated with SRPS and emphasizes the importance of functional analyses in genetic diagnostics. Demonstrating pathogenicity for a synonymous variant highlights the necessity for comprehensive variant assessments to improve diagnostic accuracy and enable early intervention. These findings have significant implications for molecular diagnostics and personalized therapy strategies in skeletal ciliopathies.