JAKCalc: A machine-learning approach to rationalized JAK2 testing in patients with elevated hemoglobin levels.

The demand for Janus Kinase-2 (JAK2) testing has been disproportionate to the low yield of positive results, which highlights the need for more discerning test strategies. The aim of this study is to introduce an artificial intelligence application as a more rational approach for testing JAK2 mutations in cases of erythrocytosis. Test results were sourced from samples sent to a tertiary hospital's genetic laboratory between 2017 and 2023, meeting 2016 World Health Organization criteria for JAK2V617F mutation testing. The JAK2 Somatic Mutation Screening Kit was used for genetic testing. Machine learning models were trained and tested using Python programming language. Out of 458 cases, JAK2V617F mutation was identified in 13.3%. There were significant differences in complete blood count parameters between mutation carriers and non-carriers. Various models were trained with data, with the random forest (RF) model demonstrating superior precision, recall, F1-score, accuracy, and area under the receiver operating characteristic, all reaching 100%. Gradient boosting (GB) model also showed high scores. When compared with existing algorithms, the RF and GB models displayed superior performance. The RF and GB models outperformed other methods in accurately identifying and classifying erythrocytosis cases, offering potential reductions in unnecessary testing and costs.

Association between fetal fraction of cell-free DNA and adverse pregnancy outcomes.

PURPOSE: To determine the association between fetal fraction (FF) levels in cell-free fetal DNA (cffDNA) testing and adverse pregnancy outcomes. METHODS: This retrospective cohort study, conducted at a single center, involved 2063 pregnant women with normal 1st and 2nd trimester non-invasive prenatal test (NIPT) results between 2016 and 2021. Pregnancy outcomes were examined by determining the < 4% and < 5th percentile (3.6%) cut-off values for low fetal fraction (LFF). Pregnancy outcomes were also examined by dividing the FF into population-based quartiles. Adverse pregnancy outcomes were pregnancy-induced hypertensive diseases (PIHD), gestational diabetes mellitus (GDM), spontaneous preterm birth (PTB), intrahepatic cholestasis of pregnancy (ICP), small for gestational age (SGA), large for gestational age (LGA), low birth weight (LBW), macrosomia, and 1st and 5th minutes low APGAR scores (< 7). RESULTS: PIHD was significantly higher in LFF (< 4% and < 5th percentile) cases (p = 0.015 and p < 0.001, respectively). However, in population-based quartiles of FF, PIHD did not differ significantly between groups. Composite adverse maternal outcomes were significantly higher in the FF < 4% group (p = 0.042). When analyzes were adjusted for maternal age, BMI, and gestational age at NIPT, significance was maintained at < 4%, < 5th percentile LFF for PIHD, and < 4% LFF for composite adverse maternal outcomes. However, there was no significant relationship between LFF with GDM, ICP and PTB. Additionally, there was no significant association between low APGAR scores, SGA, LGA, LBW, macrosomia, and LFF concerning neonatal outcomes. CONCLUSION: Our study showed that LFF in pregnant women with normal NIPT results may be a predictor of subsequent PIHD.

Prognostic and predictive role of liquid biopsy in lung cancer patients.

Introduction: Lung cancer (LC) is a leading cause of cancer-related mortality worldwide. Approximately 80% of LC cases are of the non-small cell lung cancer (NSCLC) type, and approximately two-thirds of these cases are diagnosed in advanced stages. Only systemic treatment methods can be applied to patients in the advanced stages when there is no chance of surgical treatment. Identification of mutations that cause LC is of vital importance in determining appropriate treatment methods. New noninvasive methods are needed to repeat and monitor these molecular analyses. In this regard, liquid biopsy (LB) is the most promising method. This study aimed to determine the effectiveness of LB in detecting EGFR executive gene mutations that cause LC. Methods: One hundred forty-six patients in stages IIIB and IV diagnosed with non-squamous cell non-small cell LC were included. Liquid biopsy was performed as a routine procedure in cases where no mutation was detected in solid tissue or in cases with progression after targeted therapy. Liquid biopsy samples were also obtained for the second time from 10 patients who showed progression under the applied treatment. Mutation analyses were performed using the Cobas® EGFR Test, a real-time PCR test designed to detect mutations in exons 18, 20, and 21 and changes in exon 19 of the EGFR gene. Results: Mutation positivity in paraffin blocks was 21.9%, whereas it was 32.2% in LB. Solids and LB were compatible in 16 patients. Additionally, while no mutation was found in solid tissue in the evaluation of 27 cases, it was detected in LB. It has been observed that new mutations can be detected not only at the time of diagnosis, but also in LB samples taken during the follow-up period, leading to the determination of targeted therapy. Discussion: The results showed that "liquid biopsy" is a successful and alternative non-invasive method for detecting cancer-causing executive mutations, given the limitations of conventional biopsies.

Gilbert Syndrome and Genetic Findings in Children: A Tertiary-Center Experience from Turkey.

OBJECTIVE: Gilbert syndrome (GS) is a disease characterized by mildly elevated indirect serum bilirubin levels due to mutation in the promoter of the UGT1A1 gene, which causes a decrease in uridine diphosphate glucuronyltransferase enzyme activity. Gilbert syndrome should be considered based on clinical and laboratory findings in differential diagnosis, which can be supported by genetic analysis. This study aimed to evaluate the clinical findings and UGT1A1 mutations of children with Gilbert syndrome. MATERIALS AND METHODS: Patients who were admitted to the pediatric gastroenterology clinic and who were considered to have Gilbert syndrome based on clinical and laboratory findings were included in the study. The UGT1A1 analysis was performed by Sanger sequence analysis. RESULTS: A total of 56 children were included in the study. A(TA)7TAA, A(TA)6TAA, and (TA)6/7 allele promoter polymorphism was detected in 75.5%, 22.5%, and 2% of the patients, respectively. Other than these, in 3 patients, 3 different sequence variants associated with GS [c.880_893delinsA (p.Tyr294MetfsTer69) and c.1091C>T(p.Pro365Leu)] were detected. CONCLUSION: We detected 7 TA repeats in the majority of our patients. A mild bilirubin elevation was determined in cases with 6 repetitions that were not considered risky for Gilbert syndrome. We concluded that the c.880_893delinsA (p.Tyr294MetfsTer69) variant, previously shown to be associated with Crigler-Najjar syndrome type I, may also be associated with partial enzyme deficiency leading to the Gilbert syndrome phenotype.

The utility of next-generation sequencing technologies in diagnosis of Mendelian mitochondrial diseases and reflections on clinical spectrum.

OBJECTIVES: Diagnostic process of mitochondrial disorders (MD) is challenging because of the clinical variability and genetic heterogeneity of these conditions. Next-Generation Sequencing (NGS) technology offers a high-throughput platform for nuclear MD. METHODS: We included 59 of 72 patients that undergone WES and targeted exome sequencing panel suspected to have potential PMDs. Patients who were included in the analysis considering the possible PMD were reviewed retrospectively and scored according to the Mitochondrial Disease Criteria Scale. RESULTS: Sixty-one percent of the patients were diagnosed with whole-exome sequencing (WES) (36/59) and 15% with targeted exome sequencing (TES) (9/59). Patients with MD-related gene defects were included in the mito group, patients without MD-related gene defects were included in the nonmito group, and patients in whom no etiological cause could be identified were included in the unknown etiology group. In 11 out of 36 patients diagnosed with WES, a TES panel was applied prior to WES. In 47 probands in 39 genes (SURF1, SDHAF1, MTO1, FBXL4, SLC25A12, GLRX5, C19oRF12, NDUFAF6, DARS2, BOLA3, SLC19A3, SCO1, HIBCH, PDHA1, PDHAX, PC, ETFA, TRMU, TUFM, NDUFS6, WWOX, UBCD TREX1, ATL1, VAC14, GFAP, PLA2G6, TPRKB, ATP8A2, PEX13, IGHMBP2, LAMB2, LPIN1, GFPT1, CLN5, DOLK) (20 mito group, 19 nonmito group) 59 variants (31 mito group, 18 nonmito group) were detected. Seven novel variants in the mito group (SLC25A12, GLRX5, DARS2, SCO1, PC, ETFA, NDUFS6), nine novel variants in the nonmito group (IVD, GCDH, COG4, VAC14, GFAP, PLA2G6, ATP8A2, PEX13, LPIN1) were detected. CONCLUSIONS: We explored the feasibility of identifying pathogenic alleles using WES and TES in MD. Our results show that WES is the primary method of choice in the diagnosis of MD until at least all genes responsible for PMD are found and are highly effective in facilitating the diagnosis process.

Neuronal ceroid lipofuscinosis: genetic and phenotypic spectrum of 14 patients from Turkey.

INTRODUCTION AND PURPOSE: Neuronal ceroid lipofuscinoses (NCLs) is a group of congenital metabolic diseases where the neurodegenerative process with the accumulation of ceroid and lipofuscin autofluorescent storage materials is at the forefront. According to the age of presentation, NCLs are classified as congenital, infantile (INCL), late infantile (LINCL), juvenile (JNCL), and adult (ANCL) NCLs. In our study, it was aimed to discuss the clinical and molecular characteristics of our patients diagnosed with NCL. MATERIAL AND METHOD: This is a descriptive cross-sectional study which was conducted in 14 patients from 10 unrelated families who were diagnosed with different types of NCL based on clinical presentation, neuroimaging, biochemical measurements, and molecular analyses, at the department of pediatric metabolism between June 2015 and June 2020. RESULTS: A total of 14 patients were diagnosed with different types of NCL. Of those, 4 patients were diagnosed with NCL7 (4/14; 30%), 3/14 (23%) with NCL1, 3/14 (23%) with NCL2, 2/14 (14.2%) with NCL13, and 1/14 (7.1%) with NCL10. Eleven pathogenic variants were detected, 5 of which are novel (c.721G>T [p.Gly241Ter] and c.301G>C [p.Ala146Pro] in MFDS8 gene; c.316C>T [p.Gln106Ter] in PPT1 gene; c.341C>T [p.Ala114Val] in TPP1 gene; c.686A>T [p.Glu229Val] in CTSD gene) CONCLUSION: This study is one of the pioneer comprehensive researches from Turkey that provides information about disease-causing variants and clinical presentation of different and rare types of NCLs. The identification of novel variants and phenotypic expansion is important for genetic counselling in Turkey and expected to improve understanding of NCLs.

The relation between distant metastasis and genetic change type in stage IV lung adenocarcinoma patients at diagnosis.

INTRODUCTION: Brain metastasis prevalence is higher in patients with positive epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) and C-ROS oncogene 1 (ROS-1) fusion change in lung adenocarcinoma. OBJECTIVES: The purpose of our study is to investigate the relation between the genetic change type and the initial distant metastasis in stage IV lung adenocarcinoma patients with genetic changes. METHODS: The study was conducted between January 2007 and December 2018 in a retrospective fashion with patients who had lung cancer diagnosed as stage IV adenocarcinoma. The relation between genetic mutation change (EGFR, ALK or ROS-1) and distant metastasis was analysed. RESULTS: A total of 845 patients were included in the study. The median age was 62 (28-88). It was determined that lung and pleura metastases were more frequent at a significant level in patients with positive EGFR mutation (P = 0.032, P = 0.004, respectively). In patients with positive ALK fusion change, pleura metastasis was determined to be more frequent (P = 0.001). Multiple metastases were determined to be significantly more in patients with positive ALK fusion change than single metastasis (P = 0.02). CONCLUSION: In patients with EGFR mutant lung adenocarcinoma, lung and pleura metastasis is more frequent and pleura metastasis is more frequent in ALK positive adenocarcinoma. Additionally, multiple organ metastases are higher in ALK positive lung adenocarcinoma.

SURF1 related Leigh syndrome: Clinical and molecular findings of 16 patients from Turkey.

INTRODUCTION: Pathogenic variants in SURF1, a nuclear-encoded gene encoding a mitochondrial chaperone involved in COX assembly, are one of the most common causes of Leigh syndrome (LS). MATERIAL-METHODS: Sixteen patients diagnosed to have SURF1-related LS between 2012 and 2020 were included in the study. Their clinical, biochemical and molecular findings were recorded. 10/16 patients were diagnosed using whole-exome sequencing (WES), 4/16 by Sanger sequencing of SURF1, 1/16 via targeted exome sequencing and 1/16 patient with whole-genome sequencing (WGS). The pathogenicity of SURF1 variants was evaluated by phylogenetic studies and modelling on the 3D structure of the SURF1 protein. RESULTS: We identified 16 patients from 14 unrelated families who were either homozygous or compound heterozygous for SURF1 pathogenic variants. Nine different SURF1 variants were detected The c.769G > A was the most common variant with an allelic frequency of 42.8% (12/28), c.870dupT [(p.Lys291*); (8/28 28.5%)], c.169delG [(p.Glu57Lysfs*15), (2/24; 7.1%)], c.532 T > A [(p.Tyr178Asn); (2/28, 7.1%)], c.653_654delCT [(p.Pro218Argfs*29); (4/28, 14.2%)] c.595_597delGGA [(p.Gly199del); (1/28, 3.5%)], c.751 + 1G > A (2/28, 4.1%), c.356C > T [(p.Pro119Leu); (2/28, 3.5%)] were the other detected variants. Two pathogenic variants, C.595_597delGGA and c.356C > T, were detected for the first time. The c.769 G > A variant detected in 6 patients from 5 families was evaluated in terms of phenotype-genotype correlation. There was no definite genotype - phenotype correlation. CONCLUSIONS: To date, more than 120 patients of LS with SURF1 pathogenic variants have been reported. We shared the clinical, molecular data and natural course of 16 new SURF1 defect patients from our country. This study is the first comprehensive research from Turkey that provides information about disease-causing variants in the SURF1 gene. The identification of common variants and phenotype of the SURF1 gene is important for understanding SURF1 related LS. SYNOPSIS: SURF1 gene defects are one of the most important causes of LS; patients have a homogeneous clinical and biochemical phenotype.

Topiramate-Responsive Tremor in a Novel Pathogenic Variant of SPG15 Patient.

Hereditary spastic paraplegia (HSP) is group of a rare neurodegenerative disorder with both genetically and clinically diverse neurologic features. Indeed, disease progression is varying greatly within the different forms and current treatment modalities are exclusively symptomatic for HSP. Tremor in HSP patients is only mentioned with rare case reports, so treatment option is lack in clinical ground. We reported a case of a HSP-15 girl with a previously reported novel mutation of SPG15 complained of a life disturbing tremor and topiramate as a drug therapy for tremor in our HSP patient.

Can fetal fractions in the cell-free DNA test predict the onset of fetal growth restriction?

Objective To investigate the possible predictive value of fetal fraction in the cell-free DNA (cfDNA) test in pregnancies with early- and late-onset fetal growth restriction (FGR). Methods This retrospective study comprised 247 women who were screened using the cfDNA test for aneuploidies during the first or second trimester and had deliveries at our institution from January 2016 to December 2019. The fetal fractions of women with early- (n = 14) and late-onset (n = 83) FGR and those with uncomplicated pregnancies (n = 150) were compared. Results The median fetal fractions for the early-onset FGR, late-onset FGR, and control groups were 5.7 [interquartile range (IQR) 2.65], 7 (IQR 5), and 7.35 (IQR 3.65), respectively. The fetal fractions were significantly lower in the early-onset FGR group than in the late-onset FGR and control groups (P = 0.047 and P = 0.037, respectively). There was no difference in fetal fractions between the late-onset FGR and control groups (P = 1.00). Conclusion As a placenta-related disease, early-onset FGR had lower fetal fractions in the cfDNA test than uncomplicated pregnancies. For clinical use, lower fetal fractions can contribute as a biomarker for screening asymptomatic women for possible placenta-related diseases, such as early-onset FGR. However, more studies are needed to define the "lower" limit.

Evaluation of chromosomal abnormalities and Y-chromosome microdeletions in 1696 Turkish cases with primary male infertility: A single-center study.

OBJECTIVE: The aim of this study was to determine the frequencies of chromosomal abnormalities and Y-chromosome microdeletions in Turkish cases with primary male infertility in a single center. MATERIAL AND METHODS: Chromosomal abnormalities and Y-chromosome microdeletions were investigated in 1696 cases with primary male infertility between 2012 and 2017. Karyotype analyzes and Y-chromosome microdeletions analyzes [azoospermia factor (AZF) regions] were performed in all cases by using standard cytogenetic methods and the multiplex polymerase chain reaction method, respectively. RESULTS: Chromosomal abnormalities were found in 142 cases (8.4%; 142/1696). Y-chromosome microdeletions were detected in 46 cases (2.7%; 46/1696). Y-chromosome microdeletions in the AZFc region were found in 20 of 46 cases (43%). CONCLUSION: This study is one of the few were a large number of cases was studied in Turkey. It indicates that cytogenetic and Y-chromosome microdeletion studies should be conducted in cases with primary male infertility prior to selecting assisted reproductive techniques.

First-Line Molecular Genetic Evaluation of Autosomal Recessive Non-Syndromic Hearing Loss.

OBJECTIVE: The aim of this study is to investigate the efficiency of a first-line molecular genetic evaluation approach, in children with deafness. METHODS: Patients who were found to have sensorineural hearing loss by age-appropriate audiological tests were selected for the molecular genetic evaluation. The molecular genetic evaluation was carried out with GJB2 gene sequence analysis and mtDNA m.1555A>G mutation Restriction Fragment Length Polymorphism (RFLP) analysis. Additionally, in a small group of patients, hearing loss Multiplex Ligation-dependent Probe Amplification (MLPA) analysis was done out to identify the possible role of copy number changes. RESULTS: In this Turkish cohort, which included 104 index patients and 78 relatives, 33 (31.7%) had Pathogenic/Likely Pathogenic variants. One or more GJB2 sequence variants were identified in 46 (44.1%) of the 104 index patients. The homozygous c.35delG mutation by itself explained the etiology in 24% of our ARSNHL group. In one (5%) of the 20 patients of MLPA group, a hemizygous deletion in POU3F4 gene was detected. CONCLUSION: In our Turkish cohort, we applied a first-line molecular genetic evaluation approach using GJB2 gene sequence analysis and mtDNA m.1555A>G RFLP analysis. This approach revealed the genetic etiology of 44.1% of our index patients. Additionaly, the results of hearing loss MLPA analysis revealed the limited role of copy number changes in this patient group. Furthermore, with a detailed genotype-phenotype association workup, 2 rare cases of Deafness with Palmoplantar Hyperkeratosis and Keratitis-Ichthyosis-Deafness syndrome were reported.

A case of spastic paraplegia-15 with a novel pathogenic variant in ZFYVE26 gene.

Hereditary spastic paraplegia (HSP) is a group of rare neurodegenerative disorder with genetic and clinical heterogeneity. It has autosomal dominant (AD), autosomal recessive (AR) and X-linked forms. HSPs are clinically classified into 'pure' and 'complicated' (complex) forms. SPG11 (KIAA1840) and SPG15 (ZFYVE26) are the most common ARHSPs with thin corpus callosum (TCC). They typically present with early cognitive impairment in childhood followed by gait impairment and spasticity in the second and third decades of life. Here, we present a patient girl, born to a couple who were first cousins, was admitted to the pediatric neurology outpatient clinic at 14 years of age because of walking with help, dysarthria and forgetfulness. Her examination revealed a motor mental retardation, bilateral leg spasticity, increased deep tendon reflexes in lower limbs, bilateral pigmentary retinopathy; TCC and white matter hyperintensities on brain MRI, sensorimotor axonal polyneuropathy findings in lower limbs on electromyography. Based on the clinical features and the imaging studies, the diagnosis of HSP was suspected. Targeted next generation sequencing (NGS) was performed using Inherited NGS Panel that consists of 579 gene associated with Mendelian disorders. Analysis of the patient revealed a c.6398_6401delGGGA(p.Arg2133Asnfs*15)(Exon35) homozygous novel change in ZFYVE26 gene. Genotype-phenotype correlation of HSP is complicated due to heterogeneity. The clinical similarity of HSP types increases the importance of genetic diagnosis. There are few reports about pathogenic variants in ZFYVE26 gene in the literature. This case report is one of the few studies that revealed a novel pathogenic variant in ZFYVE26 gene using NGS.

cfDNA in exhaled breath condensate (EBC) and contamination by ambient air: toward volatile biopsies.

Exhaled breath is a source of volatile and nonvolatile biomarkers in the body that can be accessed non-invasively and used for monitoring. The collection of lung secretions by conventional methods such as bronchoalveolar lavage, induced sputum collection, and core biopsies is limited by the invasive nature of these methods. Non-invasive collection of exhaled breath condensate (EBC) provides fluid samples that are representative of airway lining fluids. Various volatile and nonvolatile biomarkers can be detected in volatile condensates, such as H2O2, nitric oxide, lipid mediators, cytokines, chemokines, DNA, and microRNAs. Studies have examined cell-free DNA (cfDNA) in plasma samples from non-small-cell lung cancer patients, offering to new insights and fostering development of the liquid biopsy. However, few studies have examined cfDNA in EBC samples. This study examined whether EBC is an appropriate source of cfDNA using housekeeping-gene-specific primer probes and quantitative real-time polymerase chain reaction in healthy subjects. Ambient (room) air is contaminated with DNA, so caution is needed. Preliminary studies indicated that volatile biopsies are becoming an important diagnostic tool in lung cancer.

A novel thyroid hormone receptor alpha gene mutation, clinic characteristics, and follow-up findings in a patient with thyroid hormone resistance.

Thyroid hormone receptor alpha (THRA) gene mutation is a thyroid hormone resistance syndrome characterized by near-normal thyroid function tests and tissue-specific hypothyroidism. In this case study, we report a novel de novo p.G291S heterozygous mutation in the THRA gene was detected at mutation analysis. A 4-year-old male patient was admitted due to short stature, motor-mental retardation, and constipation. At physical examination, coarse facial appearance, eyelid edema, pallor, and umbilical hernia were observed. Primary thyroid hormone resistance should be considered in patients with phenotypically hypothyroid features. Laboratory analysis found moderate elevation in free triiodothyronine (T3) levels, normochromic normocytic anemia, and elevated creatine kinase levels. In conclusion, THRA gene mutation should be considered in patients with clinical hypothyroid findings and increased/moderately elevated free T3, decreased/ normal free thyroxine, normal thyroid-stimulating hormone levels, and increased muscle enzymes.

The clinical and molecular features of three Turkish patients with a rare genetic disorder: 2q37 deletion syndrome.

Gürsoy S, Kutbay YB, Özdemir TR, Hazan F. The clinical and molecular features of three Turkish patients with a rare genetic disorder: 2q37 deletion syndrome. Turk J Pediatr 2019; 61: 589-593. Chromosome 2q37 deletion syndrome is a rare chromosomal disorder which is characterized by mild-moderate intellectual disability, brachymetaphalangy of digits 3-5, short stature, obesity, hypotonia and characteristic facial appearance. Here, we report three Turkish patients who have 2q37 deletion in aCGH analysis with various sizes (9.08 Mb, 2.3 Mb and 2.021 Mb, respectively). HDAC4 gene, which is a class II histone deacetylase, has been considered to be associated with most of the features including brachymetaphalangy and intellectual disability. The deletion region included HDAC4 gene in the two patients. However, all of the patients had intellectual disability, especially with a cheerful mood. Some autistic features were detected in one of our patients. Although two patients had some skeletal findings, the deletion region did not contain HDAC4 gene in one of the patients. We suggest that our findings support understanding and updating knowledge on the phenotype-genotype correlation in patients with 2q37 deletion syndrome.

Targeted Next-Generation Sequencing of MLH1, MSH2, and MSH6 Genes in Patients with Endometrial Carcinoma under 50 Years of Age

Background: Lynch syndrome is an inherited cancer disorder that causes an increased lifetime risk of various types of cancers. Endometrial cancer is the most common extracolonic cancer in Lynch syndrome. Guidelines recommend that patients with endometrial cancer younger than 50 years of age should be evaluated for Lynch syndrome. Molecular analysis of the mismatch repair genes and EPCAM gene is required for a definitive diagnosis of Lynch syndrome. Aims: To report the mutation analysis of mismatch repair genes using targeted next-generation sequencing in endometrial cancer diagnosed patients <50 years of age. Study Design: Retrospective cross-sectional study. Methods: Seventy-nine endometrial cancer diagnosed patients <50 years of age underwent genetic counseling. They were selected among 1094 consecutive endometrial cancer patients between 2006 and 2017. Molecular analysis of MLH1, MSH2, and MSH6 genes was performed in 79 patients by using next-generation sequencing. Deletion/duplication analysis of mismatch repair genes and EPCAM gene was also performed in 79 patients by using the multiplex ligation-dependent probe amplification method. Results: Germline testing of mismatch repair genes was performed in 79 endometrial cancer patients. Lynch syndrome was confirmed in 4 patients (5%; 4/79). A total of 14 variants (6 in MSH2, 5 in MLH1, 3 in MSH6 genes) were found in 14 patients. Four variants were assessed as pathogenic/likely pathogenic, and 10 variants were assessed as variants of uncertain significance. Conclusion: Lynch syndrome should be investigated in patients diagnosed with endometrial cancer that are less than 50 years of age due to the increased lifetime risk of developing cancer.

The first pediatric case of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) from Turkey.

Çavusoglu D, Olgaç-Dündar N, Öztekin Ö, Özdemir TR, Arican P, Gençpinar P. The first pediatric case of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) from Turkey. Turk J Pediatr 2018; 60: 216-220. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is defined as an autosomal recessive inheritance disorder characterized by slowly progressive cerebellar, pyramidal and dorsal column dysfunction. The diagnosis is based on specific magnetic resonance imaging abnormalities (MRI) in the cerebral and cerebellar white matter and selective involvement of white matter tracts in the brain stem and spinal cord. LBSL is caused by mutations in the DARS2 gene which encodes the mitochondrial aspartyl-tRNA synthetase. Herein, we report the first pediatric case from Turkey with a typical MRI course of LBSL associated with a compound heterozygous mutation in DARS2 gene.

A Novel Homozygous Selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2, SBP2) Gene Mutation in a Turkish Boy.

SECISBP2 is an essential factor in selenoprotein synthesis, and its mutations result in a multiorgan syndrome, including abnormal thyroid hormone metabolism. A 10-year-old obese Turkish boy born to consanguineous parents presented with high thyroxine, low triiodothyronine, high reverse triiodothyronine, and normal or slightly elevated thyrotropin. He also had attention-deficit disorder and muscle weakness but no delay in growth or bone age. Sequencing of genomic DNA revealed a novel c.800_801insA, p.K267Kfs*2 mutation, homozygous in the proband and heterozygous in both parents and his brother. Studies showed reduction in several selenoproteins in serum and fibroblasts.