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Schaaf-Yang syndrome (SHFYNG) is a rare pleiotropic disorder, characterized by hypotonia, joint contractures, autism spectrum disorders (ASD), and developmental delay/intellectual disability. Although it shares some common features with Prader-Willi Syndrome, joint contractures, and ASD were more commonly detected in in this syndrome. Recently, it was shown that truncating variants in the paternal allele of the MAGEL2 gene cause SHFYNG. Here, we present two patients diagnosed with SHFYNG syndrome having two different novel truncating variants in the MAGEL2 gene, one paternally inherited and one de novo. One patient had obesity, brachydactyly and dysmorphic features, and the other patient presented with contractures, severe hypotonia and early death. This is the first report of Turkish SHFYNG syndrome cases presented to emphasize the phenotypic diversity of the syndrome.

Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin (FII) and Factor V Leiden (FVL) genotypes to the severity of COVID-19 disease and the development of thrombosis.This study investigated FII and FVL alleles in a cohort of 9508 patients (2606 male and 6902 female) with thrombophilia. It was observed that 930 of these patients had been infected by SARS-CoV-2 causing COVID-19. The demographic characteristics of the patients and their COVID-19 medical history were recorded. Detailed clinical manifestations were analyzed in a subset of cases (n=4092). This subgroup was age and gender matched. FII and FVL frequency data of healthy populations without thrombophilia risk were obtained from Bursa Uludag University Medical Genetic Department's Exome Databank.The ratio of males (31.08%; 27.01%) and the mean age (36.85±15.20; 33.89±14.14) were higher among COVID-19 patients compared to non-COVID-19 patients. The prevalence of FVL and computerized tomography (CT) positivity in COVID-19 patients was statistically significant in the thrombotic subgroup (p0.05). FVL prevalence, CT positivity rate, history of thrombosis, and Pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p0.05). Disease severity was mainly affected by Factor V Leiden and not related to genotypes at the Prothrombin mutations.Overall, disease severity and development of thrombosis in COVID-19 are mainly affected by the variation within the FVL gene. Possible FVL mutation should be investigated in COVID-19 patients and appropriate treatment should be started earlier in FVL-positive patients. This article is protected by copyright. All rights reserved.

PURPOSE: Premature ovarian insufficiency (POI) is a heterogeneous disorder characterized by the cessation of menstrual cycles before the age of 40 years due to the depletion or dysfunction of the ovarian follicles. POI is a highly heterogeneous disease in terms of etiology. The aim of this study is to reveal the genetic etiology in POI patients. METHODS: A total of 35 patients (mean age: 27.2 years) from 28 different families diagnosed with POI were included in the study. Karyotype, FMR1 premutation analysis, single nucleotide polymorphism (SNP) array, and whole-exome sequencing (WES) were conducted to determine the genetic etiology of patients. RESULTS: A total of 35 patients with POI were first evaluated by karyotype analysis, and chromosomal anomaly was detected in three (8.5%) and FMR1 premutation was detected in six patients (17%) from two different families. A total of 29 patients without FMR1 premutation were included in the SNP array analysis, and one patient had a 337-kb deletion in the chromosome 6q26 region including PARK2 gene, which was thought to be associated with POI. Twenty-nine cases included in SNP array analysis were evaluated simultaneously with WES analysis, and genetic variant was detected in 55.1% (16/29). CONCLUSION: In the present study, rare novel variants were identified in genes known to be associated with POI, which contribute to the mutation spectrum. The effects of detected novel genes and variations on different pathways such as gonadal development, meiosis and DNA repair, or metabolism need to be investigated by experimental studies. Molecular etiology allows accurate genetic counseling to the patient and family as well as fertility planning.

Konjenital kalp hastalığı (KKH), doğumsal anomalilerin en sık görülen şeklidir. Yenidoğanda yaklaşık %1 sıklıktadır ve doğumsal anomaliler içinde çocuk ölümlerinin en sık sebebidir. KKH etyolojisi çoğu vakada tam belirlenememiştir. Embriyogenezde anormal kalp gelişimindeki biyolojik süreç heterojen ve komplekstir, hem çevresel ve hem de genetik risk faktörlerini içerdiği düşünülmektedir. Bu çalışmada KKHda moleküler etiyolojiyi aydınlatmak için NKX2- 5 genindeki varyantların DNA dizi analizi ile saptanması hedeflenmiştir. Çalışmamızda KKH tanısı alan 80 hasta ve 50 kontrol grubu incelenmiştir. Kromozom anomalisi, Digeorge sendromu ve multipl konjenital anomalileri olan hastalar dahil edilmemiştir. Hastalarda ventriküler septal defekt (VSD) %23, atrial septal defekt (ASD) %20, Fallot tetralojisi (TOF) %11, atrioventriküler septal defekt, pulmoner atrezi ve aort quarktasyonu %10 oranında mevcuttu. Sırasıyla ASD ve patent foramen ovale saptanan hastalarda missense tanımlı heterozigot p.C270Y ve p.R161P varyantları saptandı. p.C270Y olası benign, VUS (Variant of unknown significance) ve p.R161P KKH’nın eşlik edebileceği konjenital hipotiroidi ile ilişkili patojenik varyant olarak tanımlıdır. Segregasyon analizi için yapılan ebeveyn taramasında taşıyıcılık saptanmıştır. Türk toplumunda KKH patogenezinde varyantların saptanması, dünya çapında bu zamana kadar tespit edilen varyantlar ile kıyaslanması ile etnik kökene göre varyant farklılığının etkisi belirlenebilecektir. Böylelikle KKH tedavisine yönelik çalışmaların ilerlemesine katkı sağlanarak morbidite ve mortalite azalacaktır. Bu çalışma Marmara Üniversitesi, Bilimsel Araştırma Projeleri Birimi tarafından desteklenmiştir. Proje Kodu: SAG-B -070317- 0085 Anahtar Kelimeler: Konjenital kalp hastalığı, NKX2-5 geni, kardiyak transkripsiyon faktörü

Neurodevelopmental disorders (NDD5) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDD5 is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDD5; however, the majority of NDD5 remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDD5. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROH5) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey. United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Human Genome Research Institute (NHGRI) ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) ; International Rett Syndrome Foundation (IRSF

© 2022 American College of Medical Genetics and GenomicsPurpose: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified. Methods: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. Results: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect. Conclusion: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.

Background: Meckel–Gruber syndrome (MKS; OMIM No. 249000) is a rare, in utero lethal disease characterized by occipital encephalocele, polycystic kidneys, and polydactyly. Methodology and Results: ...

Context Developmental disorders of the pituitary gland leading to congenital hypopituitarism can either be isolated or associated with extrapituitary abnormalities (syndromic hypopituitarism). A large number of syndromic hypopituitarism cases are linked to mutations in transcription factors. The forkhead box A2 (FOXA2) is a transcription factor that plays a key role in the central nervous system, foregut, and pancreatic development. Objective This work aims to characterize 2 patients with syndromic hypopituitarism due to FOXA2 gene defects. Results We report a novel heterozygous nonsense c.616C > T(p.Q206X) variant that leads to a truncated protein that lacks part of the DNA-binding domain of FOXA2, resulting in impaired transcriptional activation of the glucose transporter type 2 (GLUT2)-luciferase reporter. The patient is the sixth patient described in the literature with a FOXA2 mutation, and the first patient exhibiting pancreatic hypoplasia. We also report a second patient with a novel de novo 8.53 Mb deletion of 20p11.2 that encompasses FOXA2, who developed diabetes mellitus that responded to sulfonylurea treatment. Conclusion Our 2 cases broaden the molecular and clinical spectrum of FOXA2-related disease, reporting the first nonsense mutation and the first case of pancreatic dysgenesis.

Polycystic kidney disease (PKD) is a life-threatening condition resulting in end-stage renal disease. Two major forms of PKD are defined according to the inheritance pattern. Autosomal dominant PKD (ADPKD) is characterized by renal cysts, where nearly half of the patients suffers from renal failure in the 7th decade of life. Autosomal recessive PKD (ARPKD) is a rarer and more severe form presenting in childhood. Whole-exome sequencing (WES) analyses was performed to investigate molecular causes of the disease in the fetus. In this study, we present 2 fetuses prenatally diagnosed with PKD in a consanguineous family. WES analysis of the second fetus revealed a homozygous variant (c.740+1G>A) in DNAJB11 which is related to ADPKD. This study reveals that DNAJB11 biallelic mutations may cause an antenatal severe form of ARPKD and contributes to understanding the DNAJB11-related ADPKD phenotype. The possibility of ARPKD due to biallelic mutations in ADPKD genes should be considered in genetic counseling.

Background The human INHA gene encodes the inhibin subunit alpha protein, which is common to both inhibin A and B. The functional importance of inhibins in male sex development, sexual function, and reproduction remain largely unknown. Objective We report for the first time two male siblings with homozygous INHAmutations. Methods The medical files were examined for clinical, biochemical, and imaging data. Genetic analysis was performed using next-generation and Sanger sequencing methods. Results Two brothers complained of gynecomastia, testicular pain, and had a history of hypospadias. Biochemistry revealed low serum testosterone, high gonadotropin and anti-Mullerian hormone, and very low/undetectable inhibin concentrations, where available. Both patients had azoospermia in the spermiogram. We have identified a homozygous 2 bp deletion (c.208_209delAG, R70Gfs*3) variant, which leads to a truncated INHA protein in both patients, and confirmed heterozygosity in the parents. The external genital development, pubertal onset and progression, reproductive functions, serum gonadotropins, and sex hormones of mother and father, who were heterozygous carriers of the identified mutation, were normal. Conclusion Homozygosity for INHA mutations causes decreased prenatal and postnatal testosterone production and infertility in males, while the heterozygous female and male carriers of INHA mutations do not have any abnormality in sex development and reproduction.

© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder with recurrent fever, abdominal pain, serositis, articular manifestations, erysipelas-like erythema, and renal complications as its main features. Caused by the mutations in the MEditerranean FeVer (MEFV) gene, it mainly affects people of Mediterranean descent with a higher incidence in the Turkish, Jewish, Arabic, and Armenian populations. As our understanding of FMF improves, it becomes clearer that we are facing with a more complex picture of FMF with respect to its pathogenesis, penetrance, variant type (gain-of-function vs. loss-of-function), and inheritance. In this study, MEFV gene analysis results and clinical findings of 27,504 patients from 35 universities and institutions in Turkey and Northern Cyprus are combined in an effort to provide a better insight into the genotype-phenotype correlation and how a specific variant contributes to certain clinical findings in FMF patients. Our results may help better understand this complex disease and how the genotype may sometimes contribute to phenotype. Unlike many studies in the literature, our study investigated a broader symptomatic spectrum and the relationship between the genotype and phenotype data. In this sense, we aimed to guide all clinicians and academicians who work in this field to better establish a comprehensive data set for the patients. One of the biggest messages of our study is that lack of uniformity in some clinical and demographic data of participants may become an obstacle in approaching FMF patients and understanding this complex disease.

Giriş: Lynch Sendromu, diğer adıyla Herediter Nonpolipozis Kolon Kanseri (HNPCC), kolorektal kanserler başta olmak üzere gastrointestinal sistem kanserleri, endometrium kanseri, meme kanseri gibi kanserlerle karşımıza çıkan kalıtımsal bir kanser yatkınlık sendromudur. Hatalı eşleşme tamir genlerindeki (MMR genleri: MLH1, MSH2, MSH6, PMS2 ve EPCAM) mutasyonlar Lynch Sendromuna neden olmaktadır. Olgu: Tarafımıza endometrium kanseri tanısı ile yönlendirilen 69 yaşında kadın olgu polikliniğimizde değerlendirildi. Olgunun 3 yıl önce kolon kanseri tanısı nedeniyle yapılan rutin takiplerinde endometrial kitle saptanması üzerine yapılan total abdominal histerektomi öyküsü mevcuttu. Pedigri analizinde kanser öyküsü bulunmayan hasta izole vaka olarak değerlendirildi. Patolojik değerlendirmesinde endometrial kanser tanısı alan hastanın tümör dokusunda yüksek mikrosatellit instabilitesi ve PMS2 ekspresyon kaybı saptandı, MLH1 hipermetilasyonu ve BRAF V600E mutasyonu saptanmadı. Periferik kandan DNA izolasyonu (QIAamp DNA Mini Kit, QIAGEN Germantown, MD USA) sonrası MLH1 ve PMS2 genleri Illumina MiSeq platformunda, HNPCC MASTR Plus (Multiplicom, Agilent,CA,USA) kiti kullanılarak yeni nesil dizi analizi yöntemiyle değerlendirildi. MLH1 geninde mutasyon saptanmayan olguda PMS2 geni ekzon 11’de heterozigot 47bç bir duplikasyon saptandı (c.1362_1407dup; p.Pro470Valfs*3). Mutasyon veri tabanlarında tanımlı değildi, çerçeve kaymasına yol açarak erken stop kodonuna sebep olması beklendiğinden patojenik bir varyant olarak değerlendirildi. Ancak pseödogen nedeniyle tahmin ettiğimiz gibi kopya sayı analizinde ekzon 11’in 4 kopya olduğu görünmekteydi. Amplikon değerlendirildiğinde bu bölgede PMS2CL ile PMS2 arasında kısmen düşük bir homoloji olduğu dikkat çekiciydi (%96). Farklı olan nükleotidlerin değerlendirilmesi ile yapılan haplotip analizinde insersiyonun olduğu okumaların tamamıyla PMS2 genine ait olduğu ortaya koyuldu. Sonuç: Psödogenler moleküler tanıyı zorlaştıran bir problem olarak karşımıza çıkmaktadır. Gen ile psödogenleri arasındaki minimal farklılıkları kullanarak saptanan mutasyonun gen veya psödogen üzerinde olduğunu belirlemek ek yöntemler gerektirmektedir. Bu durum tanıda gecikmelere yol açması ve ek olanaklar gerektirmesi bakımından klinik pratikte zorluklara yol açmaktadır. Bu çalışmada yeni nesil dizileme yönteminin tek bir DNA ipliğine ait diziyi ortaya koyma avantajı kullanılarak amplikondaki tek nükleotid varyasyonları (SNVs) analiz edilmiş ve amplikonun kopyalandığı DNA molekülünün tamamıyla PMS2 genine ait olduğu gösterilmiştir. Varyasyonun psödogene ait olduğundan şüphelenildiğinde amplikonun bilgi verici SNV’ler açısından değerlendirilmesi ek tetkik gereksinimini ortadan kaldırarak zaman kazandıracak ve gereksiz harcamaları da azaltacaktır.

Ghosal hematodiafizer displazi, uzun kemiklerin metadiafizyal displazisi ve kemik iliğinin fibrozisi veya sklerozuna bağlı inefektif hematopoez ile karakterize, nadir görülen otozomal resesif kalıtılan bir sendromdur. Endoplazmik retikulum membran proteini olan Tromboksan A Sentaz 1 enzimini kodlayan TBXAS1 genindeki mutasyonlar bu sendroma neden olmaktadır. Hastalarda görülen anemi ve kan tranfüzyonu ihtiyacı kortikosteroidler ile etkili şekilde tedavi edilebildiğinden diğer sklerozan kemik hastalıklarından ayırt edilmesi önemlidir. TBXAS1 geninde homozigot mutasyon saptanarak Ghosal Hematodiyafizer Displazi tanısı konulan hastanın klinik bulgularının genetik analiz sonuçları eşliğinde sunulması amaçlanmıştır. Periferik kandan DNA izolasyonu sonrası genomda kodlama yapan tüm gen bölgeleri Clinical Exome Sequencing (CES) kiti Agilent SureSelect V5 kullanılarak İllumina NextSeq Platformunda dizilenmiştir. Elde edilen veriler Sophia DDM veri analizi platformu aracılığı ile analiz edilmiştir. Saptanan mutasyon Sanger dizi analizi konfirme edilmiş ve aile bireylerinden segregasyon yapılmıştır. Tarafımıza yönlendirilen bir yaşında erkek hasta insidental saptanan hemoglobin ve trombosit düşüklüğü nedeniyle takibe alındı. Eritrosit replasman ihtiyacının olması üzerine kemik iliği aspirasyonu yapılan hastada normosellüler kemik iliği, normoblastik eritroid matürasyon, kesintisiz rölatif azalmış myelopoez ve nadir megakaryosit varlığı gözlendi. Periferik yaymada ise anizositoz, hipokromi, poikilositoz, polikromazi, yer yer şistozit ve gözyaşı hücreleri izlendi. Bu bulgulara eşlik eden displazi ve malign hücreler saptanmadı. Hastanın fizik muayenesi ve görüntülemelerinde hepatosplenomegali ve lenfadenopati saptanmadı. Hastada hemolitik aneminin eşlik edebileceği Atipik Hemolitik Üremik Sendrom, Konjenital Trombositopenik Purpura ve Proksismal Noktürnal Hemoglobinüri ön tanıları düşünüldü. Hastanın Tıbbi Genetik poliklinik değerlendirmesinde hemolitik anemiye eşlik eden kemik grafilerinde epifizyal diyafizyer düzensizlikler, kortikal hiperostozis ve mild mental retardasyon izlendi. Tanıya yönelik Yeni Nesil Dizileme (NGS) yöntemi ile klinik ekzom dizileme planlandı. Klinik ekzom dizilemede hemolitik anemi ile ilişkilendirilmiş genlerden kliniği açıklayabilecek bir varyasyon saptanmamış, TBXAS1 geninde homozigot c.1238 G>A p.(Arg413Gln) varyasyonu saptanmıştır. Literatürde steroid tedavisi sonrası aneminin gerilediği bildirildiğinden hastaya tedavi başlanmış olumlu yanıt alınmıştır. Ortak bulgularla seyreden farklı grup hastalıkların tanısında masif paralel dizileme teknolojileri hızlı tanı koymayı sağlamakta ve tedavi açısından yol gösterici olmaktadır. Bu çalışma TBXAS1 geninde saptanan novel varyasyon ile literatüre katkı sağlaması ve bir çok moleküler mekanizmayla ilişkili olabilecek hastalıklarda masif paralel dizilemenin önemini vurgulamak amacıyla sunulmaktadır. Anahtar Kelimeler: Ghosal hematodiafizer displazi, Hipoplastik anemi, TBXAS1

Polycystic kidney disease (PKD) is a life-threatening condition resulting in end-stage renal disease. Two major forms of PKD are defined according to the inheritance pattern. Autosomal dominant PKD (ADPKD) is characterized by renal cysts, where nearly half of the patients suffers from renal failure in the 7th decade of life. Autosomal recessive PKD (ARPKD) is a rarer and more severe form presenting in childhood. Whole-exome sequencing (WES) analyses was performed to investigate molecular causes of the disease in the fetus. In this study, we present 2 fetuses prenatally diagnosed with PKD in a consanguineous family. WES analysis of the second fetus revealed a homozygous variant (c.740+1G>A) in DNAJB11 which is related to ADPKD. This study reveals that DNAJB11 biallelic mutations may cause an antenatal severe form of ARPKD and contributes to understanding the DNAJB11-related ADPKD phenotype. The possibility of ARPKD due to biallelic mutations in ADPKD genes should be considered in genetic counseling.