Altuğ Koç

Background/Objectives: Standard hereditary breast cancer gene panels fail to identify causative variants in some patients meeting hereditary breast and ovarian cancer (HBOC) criteria. This exploratory, hypothesis-generating study characterised germline variants in MCPH1, functionally related DNA damage response genes, and selected low-evidence candidate genes in breast cancer patients with uninformative standard panel results. Methods: A total of 185 patients meeting NCCN/ACMG criteria, with normal 42-gene panel and BRCA1/2/PALB2 MLPA results, underwent second-tier targeted sequencing. Group 1 comprised MCPH1 and related genes (TP53BP1, MDC1, TOPBP1, UBE2N, RAD52); Group 2 consisted of Genomics England PanelApp candidates (ATRIP, ESR1, PPM1D, RAD54L, RRAS2, XRCC2). No ethnically matched control cohort was available. Variants were classified per ACMG 2015 guidelines and confirmed by Sanger sequencing. Results: Rare variants meeting reporting criteria were identified in 20/185 patients (10.8%): one likely pathogenic (LP) MCPH1 frameshift deletion (c.1869_1870del) in a luminal B invasive ductal carcinoma patient, nineteen variants of uncertain significance (VUS), and one unconfirmed copy number variant. ATRIP was the most frequently implicated Group 2 gene (4 patients), including a homozygous variant; RAD54L variants were identified in three patients, including the only male breast cancer case. Conclusions: These descriptive findings identify MCPH1, ATRIP, MDC1, TOPBP1, and RAD54L as candidates warranting evaluation in case–control studies with ancestry-matched cohorts, functional validation, and family segregation analysis before any consideration for panel inclusion.

Multilocus Inherited Neoplasia Allelic Syndrome (MINAS) is a rare genetic syndrome characterized by the presence of multiple pathogenic/likely pathogenic(P/LP) variants in different cancer predisposition genes within the same individual. Patients with MINAS may face early age at onset and multiple primary malignancies. In our study, we aimed to characterize the prevalence and clinical landscape of MINAS in a major Turkish hereditary cancer cohort. We retrospectively analyzed NGS oncorisk panel results of 5000 individuals who presented to the Medical Genetics Unit of İzmir City Hospital between 2024 and 2025 with a preliminary diagnosis of hereditary cancer syndrome due to a personal and/or family history of malignancy. Our diagnostic workflow uniquely integrated Single Nucleotide Variant (SNV) detection with Copy Number Variation (CNV) calling. MINAS prevalence was 0.86% (43/5000). Dual-gene alterations were detected in 42 patients, while one featured a triple-gene alteration (BRIP1-CHEK2-MUTYH). The most frequent combination was BRCA2-CHEK2 (n = 6). Notably, CNVs were identified in 7% of cases, highlighting the necessity of structural variant analysis. Malignancy was present in 70% (30/43) of carriers, with a median age at first diagnosis of 47 years (range: 31-77). Early-onset cancer (< 40 years) was observed in 32% of cases. Our findings represents the largest Turkish MINAS cohort to date. While phenotypes often align with the most penetrant allele, spesific instances may hint at the potential for synergistic effects in certain individuals. Management should transition toward personalized, multi-variant surveillance strategies incorporating both SNV and CNV data.

Aim: Congenital myasthenic syndromes (CMS) represent an ultra‐rare group of neuromuscular disorders. The most frequently implicated genes in CMS etiology include CHRNE, RAPSN, DOK7, COLQ, and CHAT. Methods and Results: In this study, we aimed to contribute novel data to the literature to enhance genotype–phenotype correlations in CMS. Molecular genetic analysis data from 787 patients were evaluated, and 29 distinct variants were identified in 29 individuals. Fourteen patients carried homozygous or compound heterozygous variants in CHRNE (5 patients), PLEC (2 patients), CHRND (1 patient), RAPSN (1 patient), DOK7 (1 patient), SCN4A (1 patient), CHAT (1 patient), COLQ (1 patient), and GMPPB (1 patient) genes. Variants accounting for the clinical features were confirmed in only 14 patients (1.7%) of the cohort, with 65% of these variants detected in the five most common genes. Conclusion: Overall, our findings suggest that although CMS is a clinically heterogeneous group, targeted NGS panels should be prioritized for patients presenting with characteristic features such as ptosis, respiratory distress, hypotonia, and joint contractures. Nevertheless, given the phenotypic overlap of CMS with other neuromuscular disorders, broader molecular approaches such as whole‐exome sequencing may also be required. Furthermore, the identification of additional contributors, including potential modifier genes, is essential for accurate diagnosis, effective genetic counseling, and future therapeutic strategies.

Introduction: Dyslipidemia is a heterogeneous group of disorders that typically presents asymptomatically during childhood but increases the risk of atherosclerotic cardiovascular disease later in life. Understanding the genetic basis can provide valuable insights for early diagnosis and may support more tailored therapeutic approaches. This study aimed to investigate the genetic etiology of childhood‐onset dyslipidemia and explore genotype–phenotype correlations. Methods: We retrospectively analyzed genetic data from 133 pediatric patients evaluated for suspected dyslipidemia between 2018 and 2023. Targeted next‐generation sequencing (NGS) was performed using a panel covering 20 genes associated with lipid metabolism. Only pathogenic or likely pathogenic variants were included in the analysis. Results: Pathogenic or likely pathogenic variants were identified in 17% of patients ( n = 23). The most frequently affected gene was LDLR (74%), followed by significant variants in APOB , APOA5 , LDLRAP1 , and ALMS1 . Three novel pathogenic variants were identified in this cohort: a splice‐site variant in LDLRAP1 (c.231+2T>C) and two truncating variants in APOB (p.Tyr992Ter and p.Lys576Ter). Genotype–phenotype analysis revealed distinct impacts of variant types on lipid profiles. Notably, APOB variants were associated with both hypercholesterolemia and hypocholesterolemia. Conclusion: Our findings highlight the substantial contribution of genetic factors to childhood dyslipidemia and underscore the clinical utility of genetic testing in guiding diagnostic and therapeutic decisions.

Silverman–Handmaker type dyssegmental dysplasia (DDSH) is a rare and lethal skeletal dysplasia caused by biallelic null variations in the HSPG2 gene, which encodes the extracellular matrix proteoglycan perlecan. Here, we report a prenatal case of DDSH identified at 18 weeks of gestation, referred due to ultrasonographic findings of limb shortening, retrognathia, and irregularities in the lumbar vertebrae. Targeted skeletal dysplasia panel testing via next‐generation sequencing (NGS) revealed a novel homozygous splice site variant, c.1355 + 1 G>T, located at the canonical donor site of intron 11 in HSPG2. The fetus died shortly after birth, consistent with the expected DDSH phenotype. Our case expands the mutational spectrum of HSPG2‐related skeletal dysplasias and underscores the diagnostic and prognostic challenges of novel splicing variants in prenatal genetic counseling. It also emphasizes the value of combining prenatal imaging with molecular diagnostics to improve diagnostic accuracy and support informed reproductive decision‐making.

Background and Purpose: Recently, the “Epidermal Growth Factor Receptor” gene and its related pathways are potential targets in precision medicine for “Non-Small Cell Lung Cancer” cases. The presented study is a proof of concept study, which utilizes exosomal miRNAs as an easy and cheap liquid biopsy approach. We aim to investigate, 4 exosomal miRNAs: miR-30b, miR-30c, miR-221-3p, miR-22-3p; and miR-1288 as control. They are defined in the literature previously. Methods: Thirty-six samples from distinct Non-Small Cell Lung Cancer cases are analyzed. Exosomes are extracted from the plasma of the patients; miRNA isolation, cDNA synthesis, and real-time quantitative polymerase chain reactions are done and ∆/∆ Ct method is used for relative quantification. Results: The control miR1288 is expressed in all of the samples except one. The two miRNA targets miR-30c and miR-22-3p produced polymerase chain reaction curves successfully. The remaining two miRNAs (miR-30b, miR-221-3p) produce weak polymerase chain reaction curves. Conclusion: miR-30b, miR-221-3p, miR-30c, and miR-22-3p are reported to be associated with lung cancer previously, but they have not been studied in a patient series before. In our study, the exosomal miR-30c, and miR-22-3p are successfully derived from the plasma of cancer cases and they could be potential biomarkers.

Background/Aims: Peutz–Jeghers syndrome (PJS) is a rare hereditary disorder linked to increased cancer risk due to specific genetic variants in the STK11 gene. This study aimed to assess disease manifestations, genetic profiles, and genotype–phenotype correlations in PJS patients. Materials and Methods: Twenty patients from 14 families with PJS who were followed up at our clinic between 2011 and 2021 were included. Genetic susceptibility to hereditary cancers was assess–ed using targeted next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) of the STK11 gene. Clinical data were also collected and analyzed in conjunction with the genetic findings. Results: Initial symptoms appeared around 18.9 years, predominantly abdominal pain and intussusception. Mucocutaneous lesions were found in 85%, and hamartomatous polyps in 90%. Dysplastic polyps were found in 4 patients, with 3 cases of malignancy. Nextgeneration sequencing identified 11 pathogenic and 3 likely pathogenic mutations, including 3 novel STK11 variants (LRG_319: c.598- 8_601del, LRG_319: c.708_718del, and LRG_319: c.146_147del). Next-generation sequencing diagnostic rate was 78.5% (11/14), and the overall diagnostic rate with NGS and MLPA studies was 85.7% (12/14). Patients without STK11 mutations had later symptom onset and potentially lower cancer risk. Truncated mutations are associated with earlier symptoms and elevated cancer risk. Conclusion: This is the first PJS case series in Turkey using the NGS and MLPA methods. It reports 3 novel mutations and emphasizes the genotype–phenotype relationship of PJS. With further studies, the genotype–phenotype relationship of STK11 variants will be better understood. Cite this article as: Günay Aslan P, Çağlayan AO, Bora E, et al. Clinical and molecular analysis in patients with peutz–jeghers syndrome. Turk J Gastroenterol. 2024;35(5):374-384.

The results of karyotype analysis and 22q11.2 ( DiGeorge Syndrome critical region) deletion investigation in fetal cardiac system anomalies Objective: We aimed to determine the presence of accompanying chromosomal anomalies and 22q11.2 deletion in patients with cardiac system anomalies. Material and Methods: In our retrospective and cross-sectional study, 99 fetuses born with cardiac anomalies were evaluated in terms of chromosomal anomalies. 36 fetuses were evaluated for 22q11.2 deletion. Fetuses who were diagnosed with prenatal congenital heart defect and underwent invasive prenatal diagnostic tests for fetal karyotyping between 01.01.2010 and 30.06.2017 at a tertiary cancer center were included in the study. Results: Of 99 cases, 48 (48.4%) had only cardiac anomalies and 51 (51.5%) had non-cardiac anomalies. Chromosomal anomalies were found in 37 (37.4%) of the cases. Autosomal trisomy 18(43.2%) and autosomal trisomy 21(32.4%) were the most common chromosomal anomalies. The study results support the strong association of chromosomal changes and cardiac malformation, especially in septal defects, atrioventricular septal defects, and conotruncal malformations. Deletion was detected in one(2.8%) of 36 cases evaluated for 22q11.2 deletion. The fetus with this deletion had isolated tetralogy of fallot and had no extracardiac anomaly. Conclusion: In cases with cardiac anomalies, isolated or accompanied by extracardiac anomalies, investigations should be made in terms of underlying chromosomal diseases in the perinatal evaluation. In addition, the investigation of 22q11.2 deletion in fetuses with conotruncal cardiac anomalies should be included in prenatal genetic examination. Keywords: DiGeorge Syndrome, Fetal Anomalies, karyotype, trisomy, 22q11.2 Deletion Syndrome

Objectives Nephrocalcinosis is associated with conditions that cause hypercalcemia and the increased urinary excretion of calcium, phosphate, and/or oxalate. A monogenic etiology is found in almost 30% of childhood-onset nephrocalcinosis which is also a common manifestation of primary hyperparathyroidism. We discuss a child with nephrocalcinosis and features mimicking primary hyperparathyroidism. Case Presentation A 7-year-old girl presented with nephrocalcinosis. Hypercalciuria, hyperphosphaturia, mild hypercalcemia, hypophosphatemia and elevated parathyroid hormone levels along with normal serum creatinine and absence of hypokalemic alkalosis suggested primary hyperparathyroidism. However, she was ultimately diagnosed with Bartter syndrome type 2 based on the presence of homozygous pathogenic variation in KCNJ1gene. Conclusions This is the second reported case of late-onset Bartter syndrome type 2 without hypokalemic alkalosis. Patients with Bartter syndrome may present with high parathyroid hormone levels and hypercalcemia in addition to hypercalciuria. Thus, the present case suggests that the KCNJ1 gene should be included in genetic analysis even in older children with isolated nephrocalcinosis.