Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disorder. Between 85% and 90% of cases result from variations in the PKD1 and PKD2 genes. Over 30 genes have been associated with ADPKD, contributing to its heterogeneity. This study aimed to investigate novel variations in the PKD1, PKD2, and ADPKD-related genes through whole-exome sequencing (WES) and combine the genotype and phenotype data of the patients. WES was performed on peripheral blood samples from 44 ADPKD patients, and variations were evaluated and classified based on ACMG criteria. A heterozygous pathogenic/likely pathogenic (P/LP) PKD1 variant was identified in 33 patients (75%). Seven patients had a heterozygous P/LP PKD2 variant (15.9%). No heterozygous P/LP PKD1 or PKD2 variant was found in 4 patients (9.1%), and one of them (2.3%) had a heterozygous pathogenic PKHD1 variant. Thirteen novel PKD1 variations were identified, with nine associated with fast estimated glomerular filtration rate (eGFR) decline. Potentially pathogenic Variants of Uncertain Significance in ALG9, CEP290, NPHP4, WDR19, and TTC21B were identified in three patients lacking PKD1/PKD2 variants. Survival analysis indicated that patients with PKD1 or PKD2 or without any PKD1/PKD2 mutations experienced a similar age of onset for end-stage kidney disease. The annual decline in eGFR was significantly higher in patients with a PKD1 mutation than in those with a PKD2 mutation, along with a higher Mayo Class. Genetic studies evaluating novel variants in the PKD1, PKD2, and ADPKD-related genes alongside patients’ clinical data are essential for a deeper understanding of ADPKD diagnosis, prognosis, and pathology.

Osteopetrosis is a rare metabolic bone disease that can lead to progressive bone marrow failure if left untreated. Resulting cytopenia and extramedullary hematopoiesis are frequently encountered in autosomal recessive form of the disease (ARO) and may result in death. Recurrent bone fractures and skeletal deformities are mostly seen in autosomal dominant form osteopetrosis (ADO) and cause significant morbidity. In this report, clinical, laboratory, and radiological findings of 5 patients with osteopetrosis were presented. Three had cytopenias, typical peripheral smear, and bone marrow aspiration findings regarding bone marrow failure as well as extensively increased bone density which was a classical radiological appearance. Two of them had TCIRG1 mutations associated with ARO, died because of severe infections. One with certain findings of ARO without genetic analysis is alive after hematopoietic stem cell transplantation. Two siblings had novel variants of CLCN7 (NM_001114331) p.Val755Serfs*4 (c.2263del) heterozygocity, associated with ADO and severe skeletal problems. One had been followed up also for nephrotic syndrome. Detection of genetic abnormalities is important as well as typical physical examination findings and, presence of hematological or radiological indicators in definitive diagnosis of the disease. Although osteopetrosis is rare, it is a potentially fatal disease that should be considered in the differential diagnosis.

INTRODUCTION:Lung cancer is a global health concern. Molecular analysis of tumor tissues, especially in non-small cell lung cancers, has become an integral part of a holistic approach to the management of the disease. Here, molecular genetic data obtained from tumor tissues collected from 373 male and 89 female patients referred to our clinic with a diagnosis of non-small cell lung cancer are presented. METHODS:Patient samples (n = 462) were assessed via next-generation sequencing using an RNA-based kit containing 36 genes. Data obtained were analyzed using relevant software, and results of analysis are presented together with the demographic characteristics of the patients. RESULTS:Significant somatic variations were detected in 208 of 462 patients. KRAS and EGFR had the greatest variations. Rearrangements, mostly involving ALK, were observed in 37 patients, and rare complex changes involving different genes were detected in 10 patients. CONCLUSION:This study presents the comprehensive molecular data obtained using an RNA-based kit that provided information on single-nucleotide variation/insertion-deletion variants (InDel) and rearrangements in a large-patient series from a single center. Somatic variants were detected in approximately 45% of all patients. According to the Catalogue Of Somatic Mutations In Cancer (COSMIC) database, our rate of variants detected in KRAS and FGFR3 genes was higher. The rate of variants detected in other genes was lower. In addition, fusions not reported in COSMIC were detected. With the development of next-generation sequencing-based tests and an increase in their use, a broad perspective has been provided to many disease groups, including solid tissue cancers, especially non-small cell lung cancers.

INTRODUCTION:The development of genomic sequencing techniques has led to the effective diagnosis of genetic diseases. In this study, clinical exome sequencing (CES) results applied to genetic disorders are reported. METHODS:The CES results of pediatric patients with different system involvements and whose complaints were thought to be of genetic origin were evaluated retrospectively. RESULTS:Significant variants associated with complaints were detected in 41 (60%) of 68 patients. Copy number variations were detected in two patients, and single nucleotide variants (SNVs) were detected in the other 39 patients. A total of 46 SNVs were detected in these 39 patients. Sixteen of the detected SNVs were previously reported in the literature, but 30 were novel. CONCLUSIONS:This study shows that CES can provide a high diagnosis rate (60%) in childhood genetic diseases. Novel mutations (30) have contributed to the mutation profiles of genetic disorders.

Nivolumab is an inhibitor of programmed cell death 1 (PD-1), which enables activated T cells to attack the tumor cells. Although the utilization of nivolumab in adulthood cancers is more common, experience in childhood has been increasing recently. Herein, pediatric cases received nivolumab for distinct cancers are presented. The data of nine patients under the age of 18 years who received nivolumab for various cancers in the Pediatric Oncology clinic between January 2019-December 2022 were obtained. Nivolumab was administered intravenously at a dose of 3 mg/kg with 30 minutes infusion every two weeks. Patients' clinical, cancer types, response to primary treatment, comorbidities, and outcomes of nivolumab were evaluated. Nivolumab was utilized for non-Hodgkin lymphoma, classical Hodgkin lymphoma (cHL), central nervous system, germ cell and gastrointestinal system cancers. Four out of nine patients had constitutional mismatch repair deficiency (CMMRD) syndrome and 2/4 patients developed secondary cancers during the nivolumab. The median dose and duration of nivolumab were 10 doses (4-32 doses) and 6 months (2 to 17 months), respectively. The median follow-up period was 25 months (2-46 months). Nivolumab achieved progression free survival in immature teratoma, cHL and T-Lymphoblastic lymphoma (T-LBL) with 46 months, 22 months, and 31 months, respectively. Only one patient had severe generalize edema attributed to nivolumab. We observed that although encouraging outcomes with nivolumab in cHL, immature teratoma and T-LBL, it failed to prevent glioblastoma progression in children with CMMRD. In summary, nivolumab may be effective in selected childhood cancers.

Amaç: Ksenobiyotiklerin biyotransformasyonunda yer alan enzimleri kodlayan genlerin polimorfizmleri ile çeşitli kanserlere yatkınlık arasındaki ilişkiler, farklı çalışmalarda gösterilmiştir

Çocuklarda Nörometabolik ve Nörodejeneratif Hastalıklarda Öykü, Muayene ve Temel Yaklaşımlar Cengiz HAVALI Kalıtsal Metabolizma Hastalıklarında Laboratuvar İncelemeleri Mehmet Şerif CANSEVER Çocuklarda Temel Radyolojik Görüntüleme Yöntemleri ve Beyin Görüntülemesinde Uygun Yaklaşım Seçimi Derya BAKO Çocuklarda Beyin Manyetik Rezonans Görüntüleme Özge YAPICI Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklara Manyetik Rezonans Görüntüleme Temelli Radyolojik Yaklaşım Derya BAKO Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklarda Manyetik Rezonans Spektroskopi Sinan GENÇ Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklara Genetik Yaklaşım Orhan GÖRÜKMEZ Mitokondriyal Hastalıklarda Heteroplazmi Dinamikleri ve Moleküler Genetik Testlerin Kullanımı Ali TOPAK Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklarda Kardiyak Değerlendirme Mete Han KIZILKAYA Çocukluk Çağı Nörodejeneratif ve Nörometabolik Hastalıklarda Göz Bulguları Asiye EKİNCİ Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklarda Hematolojik Bulgular Bilgen IŞIK Nöroenflamasyon Eren ÇAĞAN Nörodejeneratif Hastalıklar ve İmmün Sistem Eren ÇAĞAN Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklarda Kök Hücre Nakli Bilgen IŞIK Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklarda Gen Tedavisi Özlem GÖRÜKMEZ OLGU 1 Cengiz HAVALI OLGU 2 Mine Çiğdem ŞENOĞLU OLGU 3 Sevil DORUM OLGU 4 Esra SARIGEÇİLİ OLGU 5 Dilek GÜNEŞ OLGU 6 Rabia TÜTÜNCÜ TOKER OLGU 7 Pembe SOYLU ÜSTKOYUNCU, Songül GÖKAY OLGU 8 Fatma KAYA OLGU 9 Beyza Belde DOĞAN OLGU 10 Sebile KILAVUZ OLGU 11 Ayfer SAKARYA GÜNEŞ OLGU 12 Sevim TÜRAY OLGU 13 Ayşe Ergül BOZACI OLGU 14 Didem SOYDEMİR OLGU 15 Aliye GÜLBAHÇE OLGU 16 Ayfer SAKARYA GÜNEŞ OLGU 17 Elif Perihan ÖNCEL OLGU 18 Emine GÖKSOY OLGU 19 Pınar ÖZBUDAK OLGU 20 Hülya İNCE OLGU 21 Serçin TAŞAR OLGU 22 Habibe KOÇ UÇAR, Berrak BİLGİNER GÜRBÜZ OLGU 23 Rabia TÜTÜNCÜ TOKER OLGU 24 Gülhan KARAKAYA MOLLA OLGU 25 Ayşenur METİN OLGU 26 Gülşah KALAY OLGU 27 Canan ÜSTÜN OLGU 28 Zeynep Beyza KUŞKU OLGU 29 Özgen HÜR OLGU 30 Beyza Belde DOĞAN OLGU 31 Cumali ALAN OLGU 32 Pınar ÖZBUDAK OLGU 33 Serkan KIRIK OLGU 34 Ayşe Nur COŞKUN OLGU 35 İpek DOKUREL ÇETİN OLGU 36 Sevim TÜRAY OLGU 37 Mutluay ARSLAN OLGU 38 Selen HAS ÖZHAN OLGU 39 Hilal AYDIN OLGU 40 Gül YÜCEL OLGU 41 Esra ÜLGEN TEMEL OLGU 42 İlknur CANKURT OLGU 43 Beyza Belde DOĞAN OLGU 44 Çağatay GÜNAY OLGU 45 Aliye GÜLBAHÇE OLGU 46 Dilek GÜNEŞ OLGU 47 Asburce OLGAC OLGU 48 Mehtap KAĞNICI OLGU 49 Nazlı Balcan KARACA OLGU 50 Halil ÇELİK OLGU 51 Esra SARIGEÇİLİ OLGU 52 Serap BİLGE OLGU 53 Hakan ERÇELEBİ OLGU 54 Gül YÜCEL OLGU 55 Asburce OLGAC OLGU 56 Emine Gülben YURDAGÜL OLGU 57 Berrak BİLGİNER GÜRBÜZ, Habibe KOÇ UÇAR OLGU 58 Fatih Mehmet Akif ÖZDEMİR OLGU 59 Özge TOPTAŞ DEDEOĞLU OLGU 60 Fatih Mehmet Akif ÖZDEMİR OLGU 61 Şeyma Nur KARATAŞ OLGU 62 Sevil DORUM, Cengiz HAVALI OLGU 63 Gamze AYVAZOĞLU Nörometabolik Hastalıklar ve Karaciğer Nilüfer ÜLKÜ ŞAHİN OLGU 64 Didem SOYDEMİR

Background: Wilson's disease (WD) is a copper metabolism disorder caused by ATP7B gene mutations and shows an autosomal recessive pattern of inheritance. We aimed to contribute to the mutation profile of ATP7B and show demographic and phenotypic differences in this study. Materials and methods: The clinical and demographic characteristics of patients who underwent ATP7B gene sequence analysis using next-generation sequencing were evaluated to improve genotype-phenotype correlation in WD. Results: An uncertain significance (D563N) and seven likely pathogenic (Y532D, Y715Y, T977K, K1028*, E1086K, A1227Pfs*103, and E1242K) variants were identified as associated with WD. Uniparental disomy was detected in one case. Conclusion: Our work expanded the ATP7B variant spectrum and pointed to clinical heterogeneity in ATP7B variants among patients with WD. All symptomatic patients had hepatic involvement and were clinically and/or genetically diagnosed with WD in the pediatric period. T977K, A1003V, H1069Q, E1086K, and N1270S variants were associated with hepatic failure.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) is the most common hereditary form of cerebral small vessel disease. It is clinically, radiologically, and genetically heterogeneous and is caused by NOTCH3 mutations. Methods: In this study, we analyzed NOTCH3 in 368 patients with suspected CADASIL using next-generation sequencing. The significant variants detected were reported along with the clinical and radiological features of the patients. Results: Heterozygous NOTCH3 changes, mostly missense mutations, were detected in 44 of the 368 patients (~12%). Conclusions: In this single-center study conducted on a large patient group, 30 different variants were detected, 17 of which were novel. CADASIL, which can result in mortality, has a heterogeneous phenotype among individuals in terms of clinical, demographic, and radiological findings regardless of the NOTCH3 variant.

Clinical exome sequencing (CES) is important for the diagnosis of Mendelian diseases, which are clinically and etiologically heterogeneous. Sharing of large amounts of CES data associated with clinical findings will increase the accuracy of variant interpretation. We performed a retrospective study to state the diagnostic yield of CES in 1589 patients with a wide phenotypic spectrum. CES was performed using the Sophia Clinical Exome Sequencing Kit with 4493 genes, followed by sequencing on a NextSeq 500 system. The diagnosis rate was 36.8% when only pathogenic and likely pathogenic variants were included. Consanguineous unions and positive family history were associated with a high diagnostic yield. The neurological disease group had the highest number of patients. The groups with high diagnosis rates were ear, eye, and muscle disease groups. Seven candidate genes (EFHC2, HSPB3, FAAH2, ITGB1, GYG2, CD177, and CSTF2T) that are not yet associated with human diseases were identified. Owing to the high diagnostic yield of CES compared with that of other genetic tests, it can be used as a standard diagnostic test in patients with rare genetic disorders that require a wide differential diagnosis, especially in laboratories with limited resources.

Deficiency of adenosine deaminase 2 (DADA2) is a childhood-onset disease known with pleiotropic clinical manifestations due to a monogenic form of systemic vasculopathy. Although the clinical spectrum of DADA2, linked to biallelic mutations in the ADA2 gene, has significantly expanded since 2014, approximately 200 cases have been reported thus far. In this report, two siblings are presented to draw attention to an unreported mutation of DADA2 and different phenotypic features of the same missense type homozygous mutation, p.Ser50Leu (c.149C>T). Next-generation sequencing demonstrated an autosomal recessive inherited missense type p.Ser50Leu (c.149C>T) variant homozygous mutation in the ADA-2 gene. The index patient is a 10-year-old Iraqi citizen boy who was referred to us with a complaint of anemia. The patient still needed blood transfusions after 2 hematopoietic stem cell transplantations. His older brother was an 11-year-old boy who presented to the emergency with a history of recurrent lung infections since 7 years of age. Considering the genotype-phenotype relationship from literature data, although vasculitis and low ADA2 activity are defined in cases with missense mutations, immuno-hematological manifestations are remarkable in our patients rather than vasculitic manifestations. While bone marrow failure findings e.g., anemia, neutropenia, etc. are reported to be seen in the 5th and 6th decades of life, those were predominant clinical features in our patients despite their younger age. DADA2 should also be kept in mind in cases of otherwise unexplained cytopenia, especially when associated with panhypogammaglobulinaemia and bone marrow hypocellularity, irrespective of the age of the patient at presentation.

Introduction: The coexistence of progressive familial intrahepatic cholestasis type 2, failure to thrive due to an LPIN3 mutation, and stigmata of neonatal neurofibromatosis represents a complex diagnostic challenge. Case report: We present a child with cholestasis requiring hepatic transplantation, explained by the progressive familial intrahepatic cholestasis type 2, failure to thrive could be contributed to by the LPIN3 mutation, and skin findings along with the family history of the patient was due to neurofibromatosis type 1. Conclusion: Our case illustrates the complexities of multiple genetic mutations in a child.

Amaç: Yeni nesil dizileme (Next generation sequencing-NGS) testlerinin kullanım alanlarının genişlemesi, birçok alanda olduğu gibi kardiyoloji alanında da tanı değerlerinin artmasına imkan sunmuştur. Bu çalışmada kardiyak semptomlar açısından değerlendirilen hastalara uygulanan NGS testleri sonucunda tespit edilen varyantların sunulması amaçlanmıştır. Yöntemler: Bursa Yüksek İhtisas Eğitim ve Araştırma Hastanesi Tıbbi Genetik Birimi’nde, 2015-2019 tarihleri arasında, özellikle aritmi ile kardiyomiyopati (KMP) açısından değerlendirilen ve 128 farklı geni kapsayan bir kardiyak panel uygulanan hastalar, retrospektif olarak taranmış ve çalışmaya dahil edilmiştir. Sonuç: Çalışmaya alınan 42 hastanın 23’ünde klinik bulgular açısından anlamlı varyantlar tespit edilmiştir. Hastalardan birinde iki farklı, diğerlerinde ise birer anlamlı varyant saptandığı için toplamda 24 farklı varyant tespit ettik ve bunlardan 14'ü literatürde daha önce bildirilmemişti. Tartışma: Bu çalışma ile kardiyolojik açıdan toplumda nadir olarak gözlenen varyantlar hastaların klinik ve demografik özellikleri ile birlikte sunulmuştur. Sonuç olarak literatürde aritmi ve KMP ile ilişkilendirilmiş olan genlerin mutasyon spektrumuna katkı sağlanmıştır.

Thrombocytopenia is often seen as a laboratory finding during childhood. A supposed idiopathic thrombocytopenic purpura patient who was later diagnosed as Wiskott-Aldrich syndrome (WAS) and developed acquired thrombotic thrombocytopenic purpura (aTTP). Although autoimmune manifestations in WAS described, aTTP was reported just once. Five-year-old-boy was initially brought with cough, bloody stool (diarrhea), oral mucosal bleeding at 12th months of age. Following diagnosed with idiopathic thrombocytopenic purpura and receiving intravenous immunoglobulin, platelet count raised from 20,000 to 50,000/µL. One year after WAS diagnosis by mutation analysis, he presented with complaints of resistant fever, epistaxis, and melena. Hemoglobin decreased from 10 to 5.9 g/dL. Schistocytes in peripheral blood smear and high anti-ADAMTS-13 antibody level indicated development of aTTP.

Mutations in ANO3 have recently been identified as an autosomal dominant cause of dystonia (dystonia-24). Since then, the phenotypic spectrum has also been extended in children. Here, we reported a case of a 10-year-old Turkish girl child patient with a novel variant (NM_001313726: c.221dupA, p.Tyr74*), who exhibited tremor with mild dystonia. This report expands the phenotype caused by ANO3 variants and reveals an essential clinical aspect for patients and medical staff.

Objective: 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is a rare metabolic disease of valine metabolism. Only 22 cases of HIBCH deficiency have been reported in the literature. Our algorithm could help in the diagnosis of this disease. Methods: HIBCH gene analysis was performed in all cases. Results: The common features of our five patients from the same family with a developmental delay, seizures, and neurological regression were the elevation of 3-hydroxy-isobutyryl-carnitine and Leigh-like abnormalities. Unlike other patients in the literature, our patients were diagnosed with HIBCH gene analysis, rather than whole exome sequencing (WES). In all our cases, a missense c.452C>T, p. Ser151Leu homozygous novel pathogenic mutation was detected in the HIBCH gene. Conclusion: In cases where HIBCH deficiency is considered in our differential diagnosis algorithm, HIBCH gene analysis, which is cost-effective, should be performed instead of WES, and the number of cases should be increased in the literature.

Objective: The programmed cell death 1 (PD-1) receptor is an immune checkpoint receptor expressed by activated T cells. PD-1 inhibits the immune system by binding to its ligands expressed on tumor cells. Nivolumab and pembrolizumab are some of the monoclonal antibodies that inhibit the PD-1. We present our experience with eight cases which were treated with nivolumab for different malignant diseases in our clinic. Methodology: A total of eight patients (5 girls, 3 boys) aged between 4 and 16 years were treated with nivolumab at 3mg/kg/dose approximately twice a week in Erciyes University Pediatric Hematology clinic between 2019-2021. Nivolumab treatments of seven patients were given median 11 (4-32) doses and discontinued due to progression at a median 6 months (2-17 months). Results: Four patients were diagnosed with miss match repair syndrome in addition to their malignant disease. Non-Hodgkin lymphoma (two with T-cell and one with histiocyte-rich B-cell) in three patients, brain tumor (pons glioma, midline glioma, glioblastoma multiforme) in three patients, germ cell tumor (yolk salk, immature teratoma) in two patients, one patient had colon adenocarcinoma in addition to brain tumor. Except for nausea in a patient, no drug-related side effect was observed in patients. Conclusion: Nivolumab was well tolerated in patients with CMMRD syndrome with some transient partial responses. There is a risk of developing secondary cancer in patients with CMMRD syndrome. Further studies are needed due to the limited use in children.

The genetic defect of MYO5B is usually associated with microvillus inclusion disease (MVID). MYO5B mutations are one of the rare causes of progressive familial intrahepatic cholestasis (PFIC) with normal/low gamma-glutamyl transferase (GGT). In this report, we discuss the case of a nine-month-old girl with low-GGT cholestasis whose next-generation sequencing (NGS) showed a homozygous splicing variation (c.3045+3A>T) on the MYO5B (NM_001080467) gene, which was a novel mutation. We identified that this mutation had a disease-causing effect in silico analysis.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by deficiency of sterol 27-hydroxylase enzyme encoded by CYP27A1 gene. This multicenter, cross-sectional descriptive study aimed to document clinical characteristics of CTX patients of different ages, clinical presentations of early-diagnosed patients, and responses to short-term chenodeoxycholic acid (CDCA) treatment. Seven of 11 CTX patients were diagnosed in childhood. Three patients (27%) had neonatal cholestasis, seven (63%) patients had a history of frequent watery defecation started in infantile period, and eight (72.7%) patients had juvenile cataract. Four patients in the adult age group had pyramidal signs and parkinsonism symptoms. The mean Mignarri score at diagnosis was significantly lower in the pediatric patients (267.8 ± 51.4) than in the adult patients (450.0 ± 64.0, p = 0.001). No significant difference was determined between pediatric patients and adult patients regarding plasma cholestanol concentration at diagnosis (p = 0.482). The frequency of defecation decreased with treatment in six children, who had diarrhea at admission. Compared to pretreatment values, patients' body weight and standardized body mass index significantly increased at the 12th month of treatment. In conclusion, Mignarri scores are lower in the pediatric patients than in adult patients since the most determinative signs of the CTX disease are not apparent yet in the childhood. The disease is frequently overlooked in routine practice as the disease presents itself with different clinical combinations both in adults and in children. CTX is potentially a treatable disease; thereby, enhanced awareness is critically important for early diagnosis particularly in children.