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    Clinical exome sequencing reveals an important role for clinical diagnosis of intellectual disability with definition of seven novel variants
    (Asean Neurological Assoc, 2023) Yalcintepe, Sinem; Gorker, Isik; Bozatli, Leyla; Guler, Hazal Sezginer; Zhuri, Drenushe; Demir, Selma; Atli, Emine Ikbal
    Intellectual disability can be defined as a significantly below-average general mental function, accompanied by environmental adaptation and behavioural deterioration. Patient files of 87 children with intellectual disability were evaluated in this study. After clinical exclusion criterias, clinical exome sequencing was performed for 25 of 87 intellectual disability cases with a massively parallel targeted sequencing method. Seventeen variants in the genes MBOAT7, KDM5C, TUBB3, MAN1B1, GFAP, CACNA1A, BCOR, LMNA, LBR, ALS2, ENPP1, UBE3A, TRAPPC9, HSPG2, AFF2, NLGN4, and SOX10 were identified in 14 of 25 patients (56%). Seven of the 17 variants (41.1%) were novel in the genes KDM5C, BCOR, UBE3A, TRAPPC9, AFF2, NLGN4, and SOX10. Seven cases (7/25, 28%) had a definite diagnosis of intellectual disability with their pathogenic variants. The high rate of variant detection (56%) in the current study shows that multiple gene analysis plays an essential role in diagnosing the uncertain etiology of intellectual disability. This study also presents seven novel variants, which are first reported.
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    Germline Pathogenic Variants Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma
    (Codon Publications, 2021) Yalcintepe, Sinem; Gurkan, Hakan; Korkmaz, Fatma Nur; Demir, Selma; Atli, Engin; Eker, Damla; Guler, Hazal Sezginer
    The aim of this study was to evaluate germline variant frequencies of pheochromocytoma and paraganglioma targeted susceptibility genes with next-generation sequencing method. Germline DNA from 75 cases were evaluated with targeted next-generation sequencing on an Illumina NextSeq550 instrument. KIF1B. RET, SDHB, SDHD, TMEM127, and VHL genes were included in the study, and Sanger sequencing was used for verifying the variants. The pathogenic/likely pathogenic variants were in the VHL, RET, SDHB, and SDHD genes, and the diagnosis rate was 24% in this study. Three different novel pathogenic variants were determined in five cases. This is the first study from Turkey, evaluating germline susceptibility genes of pheochromocytoma and paraganglioma with a detection rate of 24% and three novel variants. All patients with pheochromocytoma and paraganglioma need clinical genetic testing with expanded targeted gene panels for higher diagnosis rates.
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    Homozygous Paternally Inherited ASPA Variant in a Patient with Canavan Disease
    (Karger, 2024) Yalcintepe, Sinem; Maras, Tuba; Kizilyar, Ilke; Guler, Hazal Sezginer; Zhuri, Drenushe; Atli, Engin; Ozen, Yasemin
    Introduction: Canavan disease is an autosomal recessive disorder that causes accumulation of N-acetyl ASPArtic acid in the brain due to ASPArtoacylase deficiency with homozygous or compound heterozygous pathogenic variants in the ASPA gene located on the short arm of chromosome 17. Clinical findings are hypotonia, progressive macrocephaly, deafness, nystagmus, blindness, and brain atrophy. Case Presentation: A one-year-old female case was evaluated in our medical genetics clinic for hypotonia, nystagmus, and strabismus. Chromosome analysis and array-comparative genomic hybridization showed no pathology. Clinical exome sequencing by next-generation sequencing was performed and a homozygous likely pathogenic variant NM_000049.4(ASPA):c.857C > A p.(Ala286Asp) was identified. Sanger sequencing of the parents showed that the index case had a homozygous genotype, the father was heterozygous and the mother had a wild genotype for the identified variant in ASPA. A single nucleotide polymorphism (SNP) array test was planned for the family to explain this homozygosity and a loss of maternal heterozygosity was determined in the 17p13.3-p13.2 region of the ASPA gene. Conclusion: In this report, we aimed to present the first case of Canavan disease with maternal loss of heterozygosity in the ASPA gene. (c) 2024 S. Karger AG, Basel
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    Identification of a Novel KIF11 Variant p.(Leu804Thrfs Ter13) in a Case with Isolated Microcephaly
    (Wolters Kluwer Medknow Publications, 2022) Yalcintepe, Sinem; Guler, Hazal Sezginer; Zhuri, Drenushe; Eker, Damla; Gurkan, Hakan
    Microcephaly is a rare neurological condition, and it is characterized by a smaller head than other children of the same age and sex. Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MLCRD) is a syndrome with a varying spectrum that occurs as a result of variants of KIF11 gene. A 3-year-old girl was presented to our clinic with microcephaly; she had no motor or growth retardation except microcephaly. After obtaining a normal karyotype and microarray result, Trusight One-Expanded Panel analysis showed NM_004523.4 (KIF11): c. 2409dupA (p. Leu804Thrfs Ter13) heterozygous pathogenic novel variant. Patients who have KIF11 mutation often also have different clinical features; in our case, the motor development is consistent with its peers and has a history of prenatal and postnatal microcephaly. Microcephaly can be caused by a variety of genetic mutations. In our case, firstly we identify the association of a novel de novo KIF11 gene duplication variant related to isolated microcephaly.
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    A Study of FoxO1, mTOR, miR-21, miR-29b, and miR-98 Expression Levels Regarding Metabolic Syndrome in Acne Vulgaris Patients
    (Springernature, 2024) Akdag, Nazan; Atli, Engin; Zhuri, Drenushe; Guler, Hazal Sezginer; Urun, Yildiz Gursel
    Background: Acne vulgaris (AV) is an inflammatory skin disease caused by the mechanistic target of rapamycin complex 1 (mTORC1). forkhead box protein (Fox) O1 is known to regulate the relationship between the mTORC1 signaling pathway and insulin resistance (IR). Increased mTORC1 signaling is known to predispose one to diseases such as insulin resistance (IR), obesity, and diabetes mellitus. One of the major components of mTORC1 is mTOR. FoxO1 and mTOR play key roles in the onset and progression of metabolic syndrome (MetS). In this study, we aimed to elucidate the relationship between AV and MetS through FoxO1 and mTOR signaling pathways and microRNAs (miRs) associated with these signaling pathways. Methods: We examined 20 AV patients without MetS, 16 AV patients with MetS, and 20 healthy controls. The demographic characteristics of the patients, MetS parameters, clinical severity of AV (Global Acne Grading System, GAGS), and the homeostasis model assessment (HOMA) values were compared between the groups. In addition, the expression levels of FoxO1 and mTOR genes, along with the expression levels of miR-21, miR-29b, and miR-98, were assessed in skin biopsy samples from all groups using real-time polymerase chain reaction methods. FoxO1, mTOR, and miRNA expression levels were recorded as fold change. Results: The mean age of patients with AV without MetS was statistically lower. In AV patients with MetS, those with moderate GAGS scores had statistically significantly higher HOMA values than those with mild GAGS scores. FoxO1 expression was significantly lower in AV patients compared to controls. The mTOR expression levels of AV patients with MetS were significantly higher than the other two groups. The expression levels of miR-21 and miR-29b were significantly increased in the group of AV patients with MetS compared to the group of AV patients without MetS. Conclusions: These results suggested that the mTOR pathway may play an important role in explaining the relationship between AV and MetS in acne pathogenesis. They also suggested that miR-21 and miR-29b play a role in the inflammatory process of AV.