Prediction of molecular phenotypes for novel SCN1A variants from a Turkish genetic epilepsy syndromes cohort and report of two new patients with recessive Dravet syndrome

Abstract Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+) are both epilepsy syndromes that can be attributed to deleterious mutations occurring in SCN1A, the gene encoding the pore‐forming α‐subunit of the NaV1.1 voltage‐gated sodium channel predominantly expressed in the central nervous system. In this research endeavor, our goal is to expand our prior cohort of Turkish patients affected by SCN1A‐positive genetic epilepsy disorders. This will be accomplished by incorporating two recently discovered and infrequent index cases who possess a novel biallelic (homozygous) SCN1A missense variant, namely E158G, associated with Dravet syndrome. Furthermore, our intention is to use computational techniques to predict the molecular phenotypes of each distinct SCN1A variant that has been detected to date within our center. The correlation between genotype and phenotype in Dravet syndrome/GEFS+ is intricate and necessitates meticulous clinical investigation as well as advanced scientific exploration. Broadened mechanistic and structural insights into NaV1.1 dysfunction offer significant promise in facilitating the development of targeted and effective therapies, which will ultimately enhance clinical outcomes in the treatment of epilepsy

Are diagnostic magnetic resonance patterns life-saving in children with biotin-thiamine-responsive basal ganglia disease?

WOS: 000455065100029PubMed ID: 30054086Background: Biotin-thiamine responsive basal ganglia disease (BTBGD) is an autosomal recessive disorder caused by mutations in the SLC19A3 gene and characterized by recurrent sub-acute episodes of encephalopathy that typically starts in early childhood. This study describes characteristic clinical and magnetic resonance imaging (MRI) findings of six cases of BTBGD diagnosed with newly identified mutations and genetically confirmed, with very early and different presentations compared to cases in the previous literature. Methods: Six patients referred from different centers with similar clinical findings were diagnosed with BTBGD with newly identified mutations in the SLC19A3 gene. Two novel mutations in the SLC19A3 gene were identified in two patients at whole exome sequencing analysis. The clinical characteristics, responses to treatment, and electroencephalography (EEG) and MRI findings of these patients were examined. The other four patients presented with similar clinical and cranial MRI findings. These patients were therefore started on high-dose biotin and thiamine therapy, and mutation analysis concerning the SLC19A3 gene was performed. Responses to treatment, clinical courses, EEG findings and follow-up MRI were recorded for all these patients. Results: Age at onset of symptoms ranged from 1 to 3 months. The first symptoms were generally persistent crying and restlessness. Seizures occurred in five of the six patients. Cranial magnetic resonance imaging revealed involvement in the basal ganglia, brain stem, and the parietal and frontal regions in general. The first two patients were siblings, and both exhibited a novel mutation of the SLC19A3 gene. The third and fourth patients were also siblings and also exhibited a similar novel mutation of the SLC19A3 gene. The fifth and sixth patients were not related, and a newly identified mutation was detected in both these subjects. Three novel mutations were thus detected in six patients. Conclusion: BTBGD is a progressive disease that can lead to severe disability and death. Early diagnosis of treatable diseases such as BTBGD is important in order to prevent long-term complications and disability.Karadeniz Technical University Scientific Research Projects UnitThis study was funded by Karadeniz Technical University Scientific Research Projects Unit. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The requisite permissions were received from patients'families before the genetic tests

Interleukin-6 and interleukin-17 gene polymorphism association with celiac disease in children

Background/Aims: This study aimed to investigate polymorphisms in the genes responsible for encoding cytokines interleukin-6 (IL-6) (-572G/C) (rs1800796) and IL-17 (-197A/G) (rs2275913) in patients with celiac disease (CD). We further aimed to investigate the relationship between CD symptoms and histopathological findings and the relationship between these polymorphisms

Constitutional Mismatch Repair Gene Defect Syndrome Presenting With Adenomatous Polyposis and Cafe au Lait Spots: A Case Report

Introduction: Adenomatous polyps in the gastrointestinal system rarely occur in childhood and are accompanied by syndromes such as Familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MUTYH-associated polyposis, Gardner and Turcot syndrome, and also mismatch repair (MMR) gene defects. In this article, we want to present a rare patient who had adenomatous polyposis and in situ carcinoma and was detected biallelic MMR gene defect. Case: A 16-year-old female patient admitted with painless rectal bleeding, chronic abdominal pain, and anorexia for 1 year. Her physical examination was notable for multiple cafe au lait spots. The colonoscopic and histopathologic examination revealed multiple adenomatous polyps that one of them contains low-high grade dysplasia and in situ carsinoma. Genetic analysis revealed a homozygous mutation in the PMS2 gene [c.1164delT (p.H388Qfs*10) (p.His388GInfsTer10)] and she was diagnosed with constitutional MMR gene defect syndrome. Polypectomy was performed 4 times in 2 years period. Then, the patient's last colonoscopic examination revealed a large broad polyp in the rectum and multiple polyps in the other colon segments, and she underwent colectomy because of high risk of colorectal cancer. Conclusions: Adenomatous polyps are very important in childhood because of rarity. In particular, the presence of cafe au lait spots and a history of malignancy detected in relatives at an early age must be considered for CMMRD

Early onset congenital diarrheas; single center experience

Background: Congenital diarrheal disorders (CDDs) are a rare group of enteropathies that typically present in the early few months of life and pose a diagnostic challenge. We aimed to analyze the clinical findings and outcome of infants with CDDs and share experience about genetic testing. Methods: Demographic, clinical and genetic findings, and outcome of the patients (n = 24) with CDDs were recorded from hospital files. Results: The onset of diarrhea was within the neonatal period in 45.8% of the patients. The most frequent causes of CDDs were defects in digestion, absorption and transport of nutrients and electrolytes (DATN) (n = 11, 45.8%) and defects in intestinal immune-related homeostasis (IIH) (n = 6, 25%). Fat malabsorption (n = 6) was the leading cause of defects in DATN. Extra intestinal manifestations including neurological involvement (25%) and renal involvement (20.8%) were common among the patients. Genetic analyses were performed for 16 patients (targeted gene analysis in 9, congenital diarrhea panel in 3, immune deficiency panel in 1 and whole-exome sequencing in 3 patients). Genetic diagnosis was achieved in 14 of 16 patients (87.5%) with therapeutic consequences in 8 of 16 patients (50%). During the followup, 6 patients (25%) died. Conclusion: The percentage of undefined etiology decreased, and treatment of the patients improved with the increased number of genetic testing in patients with CDDs. Copyright (c) 2021, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/)

Structural Characteristics in the gamma Chain Variants Associated with Fibrinogen Storage Disease Suggest the Underlying Pathogenic Mechanism

Particular fibrinogen gamma chain mutations occurring in the gamma-module induce changes that hamper gamma-gamma dimerization and provoke intracellular aggregation of the mutant fibrinogen, defective export and plasma deficiency. The hepatic storage predisposes to the development of liver disease. This condition has been termed hereditary hypofibrinogenemia with hepatic storage (HHHS). So far, seven of such mutations in the fibrinogen gamma chain have been detected. We are reporting on an additional mutation occurring in a 3.5-year-old Turkish child undergoing a needle liver biopsy because of the concomitance of transaminase elevation of unknown origin and low plasma fibrinogen level. The liver biopsy showed an intra-hepatocytic storage of fibrinogen. The molecular analysis of the three fibrinogen genes revealed a mutation (Fibrinogen Trabzon Thr371Ile) at exon 9 of the gamma chain in the child and his father, while the mother and the brother were normal. Fibrinogen Trabzon represents a new fibrinogen gamma chain mutation fulfilling the criteria for HHHS. Its occurrence in a Turkish child confirms that HHHS can present in early childhood and provides relevant epidemiological information on the worldwide distribution of the fibrinogen gamma chain mutations causing this disease. By analyzing fibrinogen crystal structures and calculating the folding free energy change (Delta Delta G) to infer how the variants can affect the conformation and function, we propose a mechanism for the intracellular aggregation of Fibrinogen Trabzon and other gamma-module mutations causing HHHS

Karaciğer fibrokistik hastalıklarının değerlendirilmesi tek merkez deneyimi

Amaç: Karaciğerin fibrokistik hastalığı (KFKH), intrauterin dönemden adölesan yaşa kadar geniş bir yaş aralığındagörülebilen, multisistemik bir hastalıktır. Çalışmadaki amacımız kliniğimizde KHFK olan hastaların, başvuru semptomları,klinik-laboratuvar bulguları, tedavi yaklaşımı ve takip sonuçlarını değerlendirmektir.Gereç ve Yöntemler: Ocak 2008-Aralık 2019 yılları arasında, Çocuk Gastroenteroloji, Hepatoloji ve Beslenmepolikliniğinde KFKH nedeniyle takipli olan hastaların demografik özellikleri, klinik-laboratuar bulguları, tedavi yaklaşımlarıve son durumları geriye dönük olarak incelendi.Bulgular: Otuz dokuz hastanın (56.4 erkek, ortanca yaş 5 yıl 3 ay, yaş aralığı: 10 gün-6.8 yıl) sekizinde (20.5) Carolihastalığı (CH), 16’sında (41) konjenital hepatik fibrozis (KHF), 15’inde koledok kisti tespit edildi. En sık başvuru şikayetisarılık (n=8, 20.5), kronik karın ağrısı (n=6, 15.4) ve splenomegali (n=4, 10.3)’dü. Hastaların sekizi (20.5) böbrektekist tespit edildikten sonra yapılan incelemelerde, yedisi (17.9) intrauterin dönemde, ikisi (5.1) insidental olarak tespitedilmişti. Otozomal resesif polikistik böbrek hastalığı (ORPBH) olan altı hastada PKHD1 gen mutasyonu saptandı. On sekizhasta (46.2) opere edildi (karaciğer nakli, sol lob segmental hepatektomi, mezokavalşant, böbrek nakli, kistektomi).Yirmi beş hastada (64.1) ekstrahepatik tutulum mevcuttu [ORPBH (n=18), mental motor retardasyon (n=2, birindemetokromatik lökodistrofi, diğerinde Arnold Chiari malformasyonu), nefrokalsinozis (n=1), juvenil nefronofitizis (n=1),akut pankreatit (n=1), pulmoner hipoplazimetakarpal distal falanks hipoplazisi (n=1) ve medüler sünger böbrekpinealkist (n=1)]. Takip edilen 39 hastanın altısında portal hipertansiyon, beşinde kronik böbrek yetmezliği (12.8), dördündekompanse kronik karaciğer hastalığı (10.3) gelişmiş olup iki hastaya dekompanse siroz nedeniyle karaciğer nakli, birhastaya son dönem böbrek yetmezliği nedeniyle böbrek nakli yapıldı.Sonuç: Karaciğerin fibrokistik hastalıklarında, morbidite ve komplikasyon riskinin yüksek olması nedeniyle erken tanı,düzenli takip ve tedavi önemlidi

Secondary findings in 622 Turkish clinical exome sequencing data

CES (Clinical Exome Sequencing) is a method that we use to diagnose rare diseases with nonspesific clinical features. Besides primary indication for testing genetic information may be detected about diseases which have not yet emerged. ACMG guidelines recommend to report pathogenic variations in medically actionable 59 genes. In this study we evaluated CES data of 622 cases which were tested for various indications. According to ACMG recommendations 59 genes were screened for reportable variations. The detected variations were reviewed using distinct databases and ACMG variation classification guidelines. Among 622 cases 13 (2.1%) had reportable variations including oncogenetic, cardiogenetic disorders, and malignant hyperthermia susceptibility-related genes. In 15 cases (2.4%) heterozygous pathogenic and likely pathogenic variations were detected in genes showing autosomal recessive inheritance. Ten novel variations causing truncated protein or splicing defect were reported. We detected 11 variations having conflicting interpretations in databases and 30 novel variations, predicted as likely pathogenic via insilico analysis tools which further evaluations are needed. As to our knowledge this is the first study investigating secondary findings in Turkish population. To extract the information that may lead to prevent severe morbidities and mortalities from big data is a valuable and lifesaving effort. Results of this study will contrbute to existing knowledge about secondary findings in exome sequencing and will be a pioneer for studies in Turkish population