Evaluation of clinical, laboratory, and molecular genetic features of patients with biotinidase deficiency.

Biotinidase deficiency (BD) is an autosomal recessive inherited metabolic disorder which results from the inability of biotin-dependent carboxylase enzymes to function due to the release and absorption of biotin, leading to neurological and cutaneous findings. In the present study, evaluation of demographic characteristics, clinical findings, laboratory results, molecular genetic characteristics, and genotype-phenotype correlations of cases with BD. Two hundred forty-seven cases were included in the study who were admitted to the Department of Pediatric Metabolism of Ankara Bilkent City Hospital after being identified with potential BD through the Newborn Screening Program (NBS), during family screening or based on suspicious clinical findings, or following the detection of a pathogenic variant in a BTD genetic analysis during the period of October 2020 and February 2022. The medical files of the cases were reviewed retrospectively. An analysis of the admission routes of all cases to our clinic revealed 89.5% NBS, 5.7% family screening, and 4.9% suspicious clinical findings suggestive of BD. Complete enzyme deficiency was identified in 19.8%, partial enzyme deficiency in 55.1%, and heterogenous enzyme deficiency in 9.7%. The most common pathogenic variants were c.1270G > C (p.Asp424His), c.410G > A (p.Arg137His), and c.38_44delGCGCTGinsTCC (p.Cys13Phefs*36) in BTD gene. The c.1270G > C variant was most common in patients with cutaneous symptoms. The c.410G > A and c.38_44delGCGCTGinsTCC variants were more common in the patients with neurological symptoms. The mean activity level in patients with the c.1270G > C homozygous variant was statistically significantly higher than the mean activity level in the c.1270G > C compound heterozygous patients and the activity level of patients without the c.1270G > C variant. The mean activity level in c.410G > A homozygous patients was statistically significantly lower than the mean activity level of the c.410G > A compound heterozygous patients and the activity level of patients without the c.410G > A variant. In the course of our study, four new pathogenic variants were detected, namely: c.190G > A (p.Glu64Lys), c.249 + 5G > T, c.228delA (p.Val77*), and c.682A > G (p.Ile228Val).     Conclusions: The present study has determined the clinical and genetic spectrum of a large group of patients with BD in a single center. The frequent mutations in our study were similar to those reported in literature, and four novel variants were also described. What is Known: • Biotinidase deficiency is an autosomal recessive, treatable inborn error of metabolism. Two hundred ninety-four pathogenic variants in the BTD gene have been identified and the c.1270G > C variant is the most frequent BTD gene mutation in both Turkey and around the world. What is New: • Four new pathogenic variants (c.190G > A, p.Glu64Lys; c.249 + 5G > T; c.228delA, p.Val77*; and c.682A > G, p.Ile228Val) have been identified. It is believed that the c.38_44delGCGGCTGinsTCC variant is more commonly seen in individuals with ocular issues; however, further genotype-phenotype correlations are needed.

Contribution of Inherited Variants to Hereditary Cancer Syndrome Predisposition.

Cancer is a clonal disease that develops as a result of the changes on the genetic material by various factors in micro/macro environment. It has a multi-step development process. In some cancer types, genetic factors allow this multi-step process to proceed easily. These cancer types are also called hereditary cancer syndromes. Targeted gene panels are important diagnostic methods in hereditary cancer syndromes to detect the causative variants associated with these hereditary cancer syndromes. We reviewed the data of 94 patients who applied to Ankara City Hospital Genetic Diseases Evaluation Center from March 2019 to July 2021. Qiagen familial cancer susceptibility gene panel kit was used for next generation sequencing to detect the single nucleotide variants for the targeted genes. Sixty-one genes which are associated with increased cancer risk or well characterized hereditary cancer syndromes were included to this panel. Twenty five patients (27%), including 8 males and 17 females, had pathogenic/likely pathogenic variants in 13 of the 61 genes analyzed. Forty patients (43%) had variants which were assessed as variant of unknown significant. In our study, targeted multi-gene panel was diagnostic in nearly one third of the patients with personal/familial cancer syndromes. Molecular diagnosis in familial cancer syndromes is important in terms of predictive diagnosis and family screening, as well as patient follow-up and early prophylactic surgery. The predisposition for hereditary cancer syndromes can be determined according to pre-test evaluation, figuring out the inheritance type with pedigree analysis, cancer type and the genetic analysis for appropriate susceptibility genes.

Are angiotensin converting enzyme (ACE1/ACE2) gene variants associated with the clinical severity of COVID-19 pneumonia? A single-center cohort study.

OBJECTIVE: The impact of the coronavirus disease 2019 (COVID-19) pandemic has been unceasingly ongoing worldwide. Recent bioinformatics analysis and epidemiologic studies have highlighted that the functional polymorphisms on the angiotensin converting enzyme (ACE) gene may have an impact on the clinical progress of COVID-19. In this study, we aimed to determine the impact of the ACE1 gene I/D polymorphism and ACE2 peptidase-2 domain variants on disease severity. METHODS: Hundred patients with confirmed COVID-19 related pneumonia [50 patients with severe disease in intensive care unit (ICU) and 50 patients not in ICU] were compared on the basis of genetic and clinical characteristics. Genomic DNA was purified from peripheral blood lymphocytes with an automated QIA symphony DSP DNA Mini-Kit. The Sanger sequencing analysis was performed. The frequencies of ACE1 gene polymorphism and ACE2 PD variants were compared in patients hospitalized in ICU and those not in ICU. The Statistical Package for Social Sciences version 22.0 was used for statistical analysis. RESULTS: The sequencing analysis of the ACE2 gene exon 1 and 2 revealed none of the polymorphisms investigated or any other variants in the present cohort. The frequencies of the ACE1 ID, DD, and II genotypes were 51%, 31%, and 18%, respectively. The frequency of the D allele was similar between the ICU and non-ICU groups (50.4% versus 49.6%). Older age and the presence of advanced stage radiologic abnormalities on admission were detected as independent predictors of ICU requirement. CONCLUSION: No effect of any ACE1 gene polymorphism on predicting ICU requirement was detected. To the best of our knowledge, this is the first study investigating the impact of ACE gene polymorphisms on clinical severity of COVID-19 in a Turkish cohort.

Clinical and Demographic Characteristics of Cutaneous Mastocytosis in Childhood: Single-center Experience.

INTRODUCTION: Mastocytosis is a rare and heterogenous disease, and in children it is generally limited to the skin and tends to regress spontaneously in adolescence. AIM: In this study, demographic, clinical, and laboratory characteristics of pediatric patients with mastocytosis, and also coexisting diseases were investigated. RESULTS: A total of 61 pediatric patients were included in the study. The male-to-female ratio was 2.2, the median age was 2 years (range, 0.25 to 19 y), and the median follow-up period was 2.0 years (range, 0.25 to 19 y). Types of clinical presentation at diagnosis consisted of mainly urticaria pigmentosa (45.9%). Seven patients were further investigated with suspicion of systemic mastocytosis, they were followed up, median of 9 years (range, 2.5 to 16 y), and none of them developed systemic disease. Coexisting allergic diseases were recorded in total 5 patients (8.2%). Three patients had immunoglobulin A deficiency, 1 patient had elevated immunoglobulin E level. A patient developed mature B-cell lymphoma with a heterozygous mutation in c-KIT exon 11. DISCUSSION: Cutaneous mastocytosis in children may present as a complex disease with different clinical signs and symptoms. Standardized clinical criteria and guidelines for the follow-up of children with mastocytosis are required.