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    Clinical and molecular findings in a Turkish family with an ultra-rare condition, ELP2-related neurodevelopmental disorder
    (Springer, 2021) Dogan, Mustafa; Terali, Kerem; Eroz, Recep; Demirci, Huseyin; Kocabay, Kenan
    Elongator is a multi-subunit protein complex bearing six different protein subunits, Elp1 to -6, that are highly conserved among eukaryotes. Elp2 is the second major subunit of Elongator and, together with Elp1 and Elp3, form the catalytic core of this essential complex. Pathogenic variants that affect the structure and function of the Elongator complex may cause neurodevelopmental disorders. Here, we report on a new family with three children affected with a severe form of intellectual disability along with spastic tetraparesis, choreoathetosis, and self injury. Molecular genetic analyses reveal a homozygous missense variant in the ELP2 gene (NM_018255.4 (ELP2): c.1385G > A (p.Arg462Gln)), while in silico studies suggest a loss of electrostatic interactions that may contribute to the overall stability of the encoded protein. We also include a comparison of the patients with ELP2-related neurodevelopmental disorder to those previously reported in the literature. Apart from being affected with intellectual disability, we have extremely limited clinical knowledge about patients harboring ELP2 variants. Besides providing support to the causal role of p.Arg462Gln in ELP2-related neurodevelopmental disorder, we add self-injurious behavior to the clinical phenotypic repertoire of the disease.
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    Clinical, radiological and computational studies on two novel GNPTG variants causing mucolipidosis III gamma phenotypes with varying severity
    (Springer, 2021) Dogan, Mustafa; Eroz, Recep; Terali, Kerem; Gezdirici, Alper; Bolu, Semih
    Mucolipidosis III gamma (ML III gamma) is a slowly progressive disorder that affects multiple parts of the body such as the skeleton, joints, and connective tissue structures. It is caused by pathogenic variants in the GNPTG gene that provides instructions for producing the gamma subunit of GlcNAc-1-phosphotransferase. In this study we aim to characterize clinical findings and biological insights on two novel GNPTG variants causing ML III gamma phenotypes with varying severity. We report on two siblings with ML III gamma bearing the previously undescribed c.477C > G (p.Y159*) nonsense variant in a homozygous state as well as a patient with ML III gamma bearing the novel c.110 + 19_111-17del variant in a homozygous state. These variants were revealed by whole-exome sequencing and Sanger sequencing, respectively. Their parents, who are heterozygotes for the same mutation, are healthy. The clinical and radiographic presentation of ML III gamma in our patients who had c.477C > G (p.Y159*) variant is consistent with a relatively severe form of the disease, which is further supported by a working three-dimensional model of the GlcNAc-1-phosphotransferase gamma subunit. On the other hand, it is seen that our patient who carries the c.110 + 19_111-17del variant has a milder phenotype. Our findings help broaden the spectrum of GNPTG variants causing ML III gamma and offer structural and mechanistic insights into loss of GlcNAc-1-phosphotransferase gamma subunit function.
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    An integrated clinical and molecular study of a cohort of Turkish patients with Marfan syndrome harboring known and novel FBN1 variants
    (Springernature, 2021) Gezdirici, Alper; Terali, Kerem; Gulec, Elif Yilmaz; Bornaun, Helen; Dogan, Mustafa; Eroz, Recep
    Marfan syndrome (MFS) is an autosomal dominant genetic condition that mainly affects connective tissue in many parts of the body. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. The diagnosis of MFS relies on the revised Ghent criteria, outlined by international expert opinion to facilitate accurate recognition of this syndrome as well as to improve patient management and counseling. However, it may not always be possible to make a definitive diagnosis according to these criteria in each patient and thus molecular confirmation is necessary in subjects with suspected MFS. This debilitating, if not fatal, disorder is caused by mutations in FBN1, which encodes a major constitutive element of extracellular microfibrils. Here, we present a detailed clinical and molecular analysis of 76 Turkish patients with definitive or suspected MFS diagnosed at our center between 2014 and 2019. We were able to identify a total of 51 different FBN1 variants in our cohort, 31 of which have previously been reported in the relevant scientific literature. The remaining 20 variants have not been documented to date. In one patient, we detected a large deletion including the entire FBN1 gene using the array CGH approach. Currently, there are very few studies on the genotype-phenotype correlation of patients with MFS, and no clear genotype-phenotype maps for MFS have been constructed so far, except for some cases. We believe that our findings will make a rich and peculiar contribution to the elusive genotype-phenotype relationship in MFS, especially in this large and populous ethnic group.
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    Study of ten causal genes in Turkish patients with clinically suspected maturity-onset diabetes of the young (MODY) using a targeted next-generation sequencing panel
    (Springer, 2022) Doğan, Mustafa; Eröz, Recep; Bolu, Semih; Yüce, Hüseyin; Gezdirici, Alper; Arslanoğlu, İlknur; Terali, Kerem
    Background Maturity-onset diabetes of the young (MODY), which is the most common cause of monogenic diabetes, has an autosomal dominant pattern of inheritance and exhibits marked clinical and genetic heterogeneity. The aim of the current study was to investigate molecular defects in patients with clinically suspected MODY using a next-generation sequencing (NGS)-based targeted gene panel. Methods Candidate patients with clinical suspicion of MODY and their parents were included in the study. Molecular genetic analyses were performed on genomic DNA by using NGS. A panel of ten MODY-causal genes involving GCK, HNF1A, HNF1B, HNF4A, ABCC8, CEL, INS, KCNJ11, NEUROD1, PDX1 was designed and subsequently implemented to screen 40 patients for genetic variants. Results Ten different pathogenic or likely pathogenic variants were identified in MODY-suspected patients, with a diagnostic rate of 25%. Three variants of uncertain significance were also detected in the same screen. A novel pathogenic variant in the gene HNF1A (c.505_506delAA [p.Lys169AlafsTer18]) was described for the first time in this report. Intriguingly, we were able to detect variants associated with rare forms of MODY in our study population. Conclusions Our results suggest that in heterogenous diseases such as MODY, NGS analysis enables accurate identification of underlying molecular defects in a timely and cost-effective manner. Although MODY accounts for 2-5% of all diabetic cases, molecular genetic diagnosis of MODY is necessary for optimal long-term treatment and prognosis as well as for effective genetic counseling.