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    A case report of a patient with neurodevelopmental disorder with impaired speech and hyperkinetic movements: A biallelic variant in the ZNF142 gene
    (Wiley, 2024) Kaya, Derya; Köse, Canan Ceylan; Akcan, Mehmet Berkay; Sılan, Fatma
    Biallelic pathogenic variations in the zinc finger protein 142 (ZNF142) gene are associated with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM). This disorder is characterized by developmental delay, intellectual disability, speech delay, and movement disorders such as dystonia, tremor, ataxia, and chorea. Here, we report a patient who exhibited common neurological features and rarely reported brain MRI findings. Exome sequencing identified a novel biallelic variant in ZNF142 (c.3528_3529delTG; p.C1176fs*5 (NM_001105537.4)). NEDISHM was first described by Khan et al. (2019) and has been reported in 39 patients to date. Furthermore, upon reviewing our in-house data covering 750 individuals, we identified three different pathogenic ZNF142 variants. It appears that the frequency of ZNF142 alleles is not as low as initially thought, suggesting that this gene should be included in new generation sequencing panels for similar clinical scenarios. Our goal is to compile and expand upon the clinical features observed in NEDISHM, providing novel insights and presenting a new variant to the literature. We also aim to demonstrate that ZNF142 pathogenic variants should be considered in neurodevelopmental diseases.
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    Anemia and thrombocytopenia due to a novel BRPF1 variant in a family from canakkale with intellectual disability and dysmorphic facies: Case report and review of the literature
    (John Wiley and Sons Inc, 2023) Köse, Canan Ceylan; Kaya, Derya; Akcan, Mehmet Berkay; Sılan, Fatma
    Intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP) (MIM#617333) is an autosomal dominant disorder characterized by delayed psychomotor development, intellectual disability (ID), and dysmorphic facial features due to pathogenic variations in the Bromodomain- and PHD Finger-Containing Protein (BRPF1) (MIM#602410) gene. Herein, we report the first Turkish patients with IDDDFP. Additionally, the patients had hematopoietic disorders such as anemia and thrombocytopenia, which have not been previously described in IDDDFP patients. Genetic testing using Whole Exome Sequencing (WES) revealed a novel heterozygous c.1433G > A; p.W478* (NM_004634.3) pathogenic variant on exon 3 of the BRPF1 gene. The patients demonstrated classical features of IDDDFP such as intellectual disability, developmental delay, ptosis, micro and retrognathia, and dysmorphic facial features, in addition to the anemia and thrombocytopenia. Apart from the variant in BRPF1, no additional genomic changes were detected by WES and chromosomal microarray analysis (CMA). Hopefully, our novel report on the hematopoietic anomalies of our patients due to BRPF1 will expand upon the clinical spectrum of IDDDFP, encourage further studies about BRPF1-hematopoietic system relations, and affect the diagnostic and therapeutic schemes of hematopoietic system disorders.
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    Çanakkale örnekleminde tüm ekzom dizileme (Wes) ile elde edilen verilerden konjenital monosakkarit ve disakkarit metabolizma bozuklukları ile ilişkili genetik varyantların güncel verilerle değerlendirilmesi ve taşıyıcılık oranlarının belirlenmesi
    (Çanakkale Onsekiz Mart Üniversitesi, 2023) Akcan, Mehmet Berkay; Sılan, Fatma
    GİRİŞ VE AMAÇ: Advers gıda reaksiyonları günlük hayatta önemli bir yer kaplar ancak yetersiz olarak tanınır ve yönetilir. Konjenital monosakkarit-disakkarit metabolizma bozuklukları, karbonhidrat malabsorbiyonun alt gruplarından birisini oluşturmakta ve karın ağrısı, diare, kanama bozukluğu, ölüm gibi geniş yelpazede değişen sonuçlara sebep olmaktadır. Çalışmamızda, daha önceden tüm ekzom dizi analizi (WES) uygulanmış hastalarda, konjenital monosakkarit-disakkarit metabolizma kusurlarında rol alan bazı genlerin retrospektif olarak değerlendirilmesi, kohortumuzda taşıyıcılık frekanslarının hesaplanması ve varyant saptanan hastalarda genotip-fenotip korelasyonu kurulması amaçlanmıştır. YÖNTEM: Çalışmamızda, 15.04.2022 tarihine kadar Çanakkale Onsekiz Mart Üniversitesi Sağlık Uygulama ve Araştırma Hastanesi Tıbbi Genetik polikliniğine başvuran ve çalışmaya katılmaya onam veren 484 hastanın dataları retrospektif olarak; konjenital monosakkarit-disakkarit metabolizma bozukluklukları grubunda yer alan genlerden bir panel oluşturularak (ALDOB, FBP1, GALE, GALK1, GALM, GALT, LCT, SLC2A2, SLC5A1, SI) analiz edilmiştir. Çalışmamıza dahil edilen hastaların 107'sine segregasyon amacıyla, 377'sine çeşitli klinik bulgular sebebi ile WES analizi çalışılmıştır. WES analizi xGen Exome Research Panel v2 kiti kullanılarak Yeni Nesil Dizi Analizi (NGS) yöntemiyle çalışılmıştır. Çalışma sonucunda üretilen VCF dataları, QIAGEN Clinical Insight Interpret veritabanı ile analiz edilmiş olup hastalarda saptanan patojenik, muhtemel patojenik ve klinik önemi belirsiz (VUS) varyantlar çalışmamız kapsamına alınmıştır. BULGULAR: Çalışmamıza 244'ü kadın, 240'ı erkek olmak üzere 484 hasta dahil edilmiştir. Analizi yapılan genlerde 84/484 (%17,35) hastada 67'si farklı olmak üzere toplamda 99 tane patojenik, muhtemel patojenik ve VUS varyant saptanmıştır. Patojenik/muhtemel patojenik varyant allel frekansı 0.013 olarak, VUS varyant allel frekansı 0.088, toplam %10 olarak hesaplanmıştır. Segregasyon amaçlı WES analizi çalışılan 107 hastanın 21'inde (%19.6), çeşitli klinik bulgular sebebi ile WES analizi yapılan 377 hastanın 63'ünde (%16.7) varyant saptanmıştır. Varyant saptanan hastaların %44'ü (37/84) saptanan genotiplerle uyumlu fenotipik bulgulardan en az bir tanesini göstermiştir. En sık taşıyıcılık 1:25 ile SI, en nadir taşıyıcılık 1:968 ile GALE geninde saptanmış olup beklenen hastalık sıklığı 1:2500 ile 1: 3748000 arasında hesaplanmıştır. SONUÇ: Çalışmamızın sonuçları otozomal resesif kalıtılan hastalıklarda heterozigot taşıyıcıların da klinik bulgu sergileyebileceğini göstermiştir. Literatürde konjenital monosakkarit ve disakkarit metabolizma bozuklarına ait taşıyıcılıkların, taşıyıcıların fenotipik etkilerinin ve taşıyıcılık verilerinden tahmini hastalık prevelanslarının hesaplandığı kapsamlı bir sistematik yayın bulunmamaktadır. Çalışmamız bu alanda ulusal sağlık politikalarımızın geliştirilmesinde ve uluslararası literatürde bir öncü olma niteliği taşımaktadır.
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    DHCR24-related desmosterolosis in the first reported Turkish patient: Expanding the genotypic and phenotypic spectrum
    (Elsevier Ltd, 2026) Kose, Canan Ceylan; Erdem, Fehime; Akcan, Mehmet Berkay; Yazıcı, Havva; Cokyaman, Turgay; Canda, Ebru Erbaş; Silan, Fatma
    BACKGROUND Desmosterolosis is a ultra-rare autosomal recessive disorder caused by biallelic variants in the DHCR24 gene, which encodes 3-beta-hydroxysterol delta-24-reductase—an enzyme involved in the final step of cholesterol biosynthesis. Here, we report a 3.5-year-old female with previously unreported compound heterozygous DHCR24 variants: c.1412A>G (p.Tyr471Cys), and c.275C>T (p.Thr92Met). CASE PRESENTATION The patient presented with agenesis of the corpus callosum, hypotonia, developmental delay, and dysmorphic facial features. METHOD AND RESULTS Trio-clinical exome sequencing confirmed the trans configuration of the variants. Plasma desmosterol levels were elevated >50-fold (134 ng/L; reference ?2.5 ng/L), supporting the diagnosis. In silico 3D protein modeling demonstrated structural alterations associated with both variants. CONCLUSION A review of reported cases revealed consistent findings of corpus callosum agenesis, developmental delay, and ocular abnormalities. Our case contributes to the limited body of literature on DHCR24 -related desmosterolosis and expands the variant spectrum, emphasizing the importance of integrating clinical, biochemical, and computational approaches in diagnosing rare metabolic disorders. © © 2025. Published by Elsevier Inc.
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    Evaluating of colchicine use patterns and attack frequency of familial Mediterranean fever patients in the COVID-19 pandemic
    (John Wiley and Sons Inc, 2023) Akcan, Mehmet Berkay; Albuz, Burcu; Özdemir, Özturk; Sılan, Fatma
    Familial Mediterranean Fever (FMF) is an autosomal recessive and dominant inherited disease and is the most common autoinflamma-tory disease characterized by recurrent episodes of fever, arthritis, and polyserositis.1Colchicine is the main therapeutic agent used in FMF patients.2,3It reduces attacks, improves quality of life, and most importantly, prevents amyloidosis.3 The lifetime use of colchicine is recom-mended in individuals with M694V homozygous variant or com-pound heterozygous with other pathogenic variants.
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    Exploring and Expanding Secondary Findings Through Exome Sequencing in the Turkish Population
    (Wiley, 2025) Akcan, Mehmet Berkay; Köse, Canan Ceylan; Çelik, Kübra Müge; Tekin, Koray; Kaya, Derya; Sılan, Fatma
    Introduction Exome-sequencing (ES) methods enable accurate diagnosis in challenging cases and uncover secondary findings (SFs) potentially linked to life-threatening or preventable diseases. The American College of Medical Genetics and Genomics (ACMG) publishes a list detailing which SFs should be reported and regularly updates it. We aimed to compare results across different SF versions in patients and explore additional SFs to identify potential new recommendations for SF reporting. Methods We conducted a retrospective analysis of 724 patients to identify ACMG SFs using the QIAGEN Clinical Insight (QCI) Interpret database. Furthermore, we investigated pathogenic/likely pathogenic variants in cancer and cardiovascular disease genes not listed in ACMG SFs, as well as genes associated with common diseases prevalent in our country. Methods ACMG SF v3.2 variants were identified in 56 patients (7.7%), with no observed differences between ACMG v3.1 and v3.2. Additionally, our analysis revealed that 208 patients harbored non-ACMG SF variants. Conclusion In this study, we focused on known SFs and identified additional variants that could be considered as new recommendations. While expanding the list of SFs can pose challenges during analyses and genetic counseling, a thoughtfully curated SF list has the potential to enhance patient care and improve clinical outcomes.
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    Exploring genetic variants in congenital monosaccharide-disaccharide metabolism: Carrier ratios and phenotypic insights
    (Wiley, 2024) Akcan, Mehmet Berkay; Sılan, Fatma
    Objectives Adverse food reactions, often underestimated, encompass congenital monosaccharide-disaccharide metabolism disorders, yielding diverse outcomes such as abdominal pain, diarrhea, bleeding disorders, and even death. This study retrospectively scrutinized genetic variants linked to these disorders in a cohort subjected to whole-exome sequence analysis (WES), determining carrier frequencies and genotype-phenotype correlations. Methods Data from 484 patients, were retrospectively analyzed using a gene panel (ALDOB, FBP1, GALE, GALK1, GALM, GALT, LCT, SLC2A2, SLC5A1, SI) for congenital monosaccharide-disaccharide metabolism disorders. WES was performed on patients using the xGen Exome Research Panel v2 kit, utilizing Next Generation Sequence Analysis (NGS). The study encompassed pathogenic, likely pathogenic, and variant of uncertain significance (VUS) variants. Results Among 484 patients (244 female, 240 male), 17.35% carried 99 variants (67 distinct) in the analyzed genes. Pathogenic/likely pathogenic allele frequency stood at 0.013, while VUS allele frequency was 0.088. Notably, 44% (37/84) of patients harboring mutations manifested at least one relevant phenotype. Carriage frequencies ranged from 1:25 (SI gene) to 1:968 (GALE gene), with the estimated disease frequency spanning from 1:2500 to 1:3748000. Conclusions Our study underscores clinical manifestations in heterozygous carriers of recessive genetic disorders, addressing gaps in carrier frequencies and phenotypic effects for congenital monosaccharide-disaccharide metabolism disorders. This knowledge can improve these conditions' diagnosis and management, potentially preventing adverse food reactions and their associated complications.
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    Familial intragenic X-linked OPHN1 gene deletion in a newborn male infant with low birth weight and distinctive facial appearance that diagnosed by advanced microarray-CGH method
    (Sivas Cumhuriyet University, 2022) Aylanc, Hakan; Sılan, Fatma; Çokyaman, Turgay; Akcan, Mehmet Berkay; Özdemir, Öztürk
    The oligophrenin-1 (OPHN1) gene is localized in the Xq12 region and it encodes the rho-GTPase-activating protein which spans 500 kb in size and consists of 25 exons. Gene plays crucial role in synaptic function and dendritic morphogenesis. Here we report a 391 kb deletion in OPHN1 gene in a mother and her newborn male child with recognizable pattern of clinical and neuroradiological hallmarks. Mother has short stature, and her son has distinctive facial appearance, bilateral choroid plexus cysts and low birth weight (1600 g). After clinical evaluation, the current large intragenic gene deletion was identified by microarray-CGH and confirmed by MLPA techniques. The P106 MRX probemix kit (MRC Holland C1- 0416, Amsterdam) and Coffalyser software were used for MLPA and Agilent sure print G3 HUMAN CGH 60k Microarray platform and Agilent cytogenomics 4.0.2.21 software (Singapore) were used for advance chromosomal genotyping for mother and his son in the presented results. Presented results showed that mother with X chromosome deletion has a great risk to have a son with mental retardation due to deleted X chromosome transmission in 50% possibility. If the son has clinical findings, the genotype should be screened by using the advanced genetic methodology. Results also showed that once these cases are first diagnosed correctly, they may be candidate to IVF for preimplantation genetic diagnosis by giving appropriate genetic counseling. It is also comment that pregnant women who have the history of having X-linked mental retarded child or a mentally retarded brother need to be tested genetically for prenatal diagnosis.