Mahmut Cerkez Ergoren

The Association between Apert Syndrome and Autistic Spectrum Disorder in a Patient of Cypriot Heritage

Apert syndrome (AS) is the most frequent form of the acrocephalosyndactyly syndromes. It has an estimated incidence of one in 100000 to 160000 newborns.A 3-year-old boy with the karyotype of 46, XY and diagnosed with AS was directed to our clinic for delay in speech acquisition. This is the first case of AS in the Cyprus Island. Due to the mutation in fibroblast growth factor receptor 2 (FGRF2) gene, he was born with the typical phenotype of AS. The Ankara Developmental Screening Inventory (ADSI) was applied to the parents, and the patient was asked some practical directives. The outcome of ADSI showed that the child could be at 13-15 months of developmental age with more than 30% of growth retardation. As per our knowledge, this is the second case of 46, XY child who was diagnosed with acrocephalosyndactyly syndrome and shows a strong association with autistic spectrum disorders.

Identification and characterization of a novel FBN1 gene variant in an extended family with variable clinical phenotype of Marfan syndrome

ABSTRACT Marfan syndrome (MFS) is a multi-systemic autosomal dominant condition caused by mutations in the gene (FBN1) coding for fibrillin-1. Mutations have been associated with a wide range of overlapping phenotypes. Here, we report on an extended family presenting with skeletal, ocular and cardiovascular clinical features. The 37-year-old male propositus, who had chest pain, dyspnea and shortness of breath, was first diagnosed based on the revised Ghent criteria and then subjected to molecular genetic analyses. FBN1 sequencing of the proband as well as available affected family members revealed the presence of a novel variant, c.7828G>C (p.Glu2610Gln), which was not present in any of the unaffected family members. In silico analyses demonstrated that the Glu2610 residue is part of the conserved DINE motif found at the beginning of each cbEGF domain of FBN1. The substitution of Glu2610 with Gln decreased fibrillin-1 production accordingly. Despite the fact that this variation appears to be primarily responsible for the etiology of MFS in the present family, our findings suggest that variable clinical expressions of the disease phenotype should be considered critically by the physicians.

Letter to the editor regarding the article “A case of hypertrophic and dilated cardiomyopathic sudden cardiac death: de novo mutation in TTN and SGCD genes”

We recently read the article entitled “A case of hypertrophic and dilated cardiomyopathic sudden cardiac death: de novo mutation in TTN and SGCD genes” by Baydar et al. (1) published in the Anatolia Journal of Cardiology in late 2016 with great interest. We commend the authors for their contribution to improving our understanding of sudden cardiac death mechanisms and suggesting potential reasons for occurrence of the condition of genetic origin. We do, however, have a number of thoughts about the study, which are outlined below. The authors mentioned de novo mutation in the sarcoglycan (SGCD) and titin (TTN) genes. The article fails to mention, however, the parent-based variant approach to analysis. In human genetic diseases, the term “de novo mutation” by definition refers to an alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell of one of the parents or in the zygote itself. It is only by analyzing the parents that their true contribution to the disease burden can be proven (2). Furthermore, in the discussion section, the authors mentioned population frequencies of 2 variants using Exome Aggregation Consortium (ExAC) browser data. If those variants are de novo, they should not be in genetic data browsers like ExAC (3). Moreover, variant TTN:c.21758T>C was previously identified by Pugh et al. (4). The team reported this variant with a different transcript (c.41249T>C, p.Ile13750Thr NM_133378.4), and it has been identified in 5 individuals with dilated cardiomyopathy (DCM) ranging in age from early infancy to mid 30s, with one individual in their 60s who has been diagnosed with hypertrophic cardiomyopathy (HCM) (4). Therefore, as these variants were already identified by other research groups, they are no longer novel, as maintained in the current report. Since only a single SGCD:c.15G>C variant with unknown significance was identified, it is not very likely that the SGCD gene is implicated in the pathology of this case. According to general variant classification assertion criteria, homozygous mutant allele of rs549319429 is classified as “likely benign” variant [December 8, 2015; GeneDx Variant Classification (06012015)] (5). Sequencing of TTN gene revealed heterozygote TTN:c. 21758T>C. Pugh et al. (4) described effect of this variant on both DCM and HCM in 2014 (4). Therefore, though SGCD:c.15G>C variant may be benign, in combination with possible pathogenic variant, such as TTN:c.21758T>C, clinical phenotype might produce an exponential effect. To understand the certain effects of these variants on gene products, parent testing and co-segregation analyses should have been conducted before mentioning pathogenicity of the variants. Unfortunately, in the current article, it appears as though the authors have not completed any of these experiments. Once again we would like to thank the authors and acknowledge their great efforts in presenting their case study. De novo mutation or pathogenicity of the variant family studies and segregation analysis should be conducted. Until these studies are completed the pathogenic effect of variants should not and cannot be mentioned. Anatol J Cardiol 2017; 17: 75-80 Letters to the Editor 76

Mesenchymal Stem Cells in Cancer Therapy

The human mesenchymal stem cells (hMSCs) are multipotent non-hematopoietic precursor cells that can generate various types of tissue cells which supports the formation of blood and fibrous connective tissue. hMSCs desirable stem cell characteristics, their ability to avoid immune rejection, and their homing ability in addition to easiness of their isolation and expansion made these cells a great therapeutic target for many diverse diseases. MSCs can be isolated from various tissues such as bone marrow, adipose tissue, dental pulp and can be expanded without greatly compromising genetic stability. Previous studies on site-directed and/or systemic administration of MSCs have revealed their ability of engraftment in a number of tissues after injury. Since the discovery that bone marrow-derived mesenchymal stem cells can be recruited to the tumor side and can home to the tumor stoma, hMSC became strong candidate for stem cell-based cancer therapy. Despite their great potential, these cells can also suffer from replicative exhaustion and acquire critically short telomeres that might increase the risk of cancer development. During transition to cancer, most often telomerase activation occurs which is highly specific to cancer and has the consequence that cancer cells maintain telomere function and thereby compensate for cell division-associated telomere attrition and facilitate crisis-bypass, which altogether promote tumor cell immortalization. The challenges and risks for cell-based therapies are multifaceted.In this current communication, the double-faced role of mesenchymal stem cells in cancer development and their therapeutic potential use in cancer therapy will be discussed. Thus, it will be focused and discussed different mechanisms that mesenchymal stem cells can show neoplastic transformation through telomere pathway and again maintain telomere homeostasis and thereby the cell’s ability to be expanded in vitro, and focus on a new therapeutic area that uses hMSCs as delivery vehicles as a potential new cancer treatment.

Near East University Genetic Mutation Database (NEU-GD): The first mutation database of Northern Cyprus.

The health care system is negatively affected by the genetic disorders that lead to an increasing rate of morbidity and neonatal deaths and affect adults as well. These create a substantial governments psychosocial and economic burden on clinicians, patients and their families with the advancement in the field of genetics. There has been a tremendous increase in the rate in which diseases associated with variant DNA sequences are being sought and identified. The goal behind the creation of Near East University Genetic Mutation Database (NEU-GD) is to map and apprehend the patterns of common genetic diversity in the human genetic makeup in order to accelerate the search for the genetic causes of human disease. NEU-GD will allow scientists to generate extraordinarily useful information such as allelic variations among population, and description of the genetic blueprint of mutations occurring in human beings. In this communication we report the construction of the first genetic mutation database for the people belonging to different ethnic groups living in North Cyprus (http://genetics-db.neu.edu.tr/). Therefore NEU-GD can serve as an important tool available online for molecular genetic testing of inherited disorder and persuade for further investigation of novel genetic disorders in North Cyprus population.