DNA replication precisely duplicates the genome to ensure stable inheritance of genetic information. Impaired licensing of origins of replication during the G1 phase of the cell cycle has been ...implicated in Meier-Gorlin syndrome (MGS), a disorder defined by the triad of short stature, microtia, and a/hypoplastic patellae. Biallelic partial loss-of-function mutations in multiple components of the pre-replication complex (preRC; ORC1, ORC4, ORC6, CDT1, or CDC6) as well as de novo stabilizing mutations in the licensing inhibitor, GMNN, cause MGS. Here we report the identification of mutations in CDC45 in 15 affected individuals from 12 families with MGS and/or craniosynostosis. CDC45 encodes a component of both the pre-initiation (preIC) and CMG helicase complexes, required for initiation of DNA replication origin firing and ongoing DNA synthesis during S-phase itself, respectively, and hence is functionally distinct from previously identified MGS-associated genes. The phenotypes of affected individuals range from syndromic coronal craniosynostosis to severe growth restriction, fulfilling diagnostic criteria for Meier-Gorlin syndrome. All mutations identified were biallelic and included synonymous mutations altering splicing of physiological CDC45 transcripts, as well as amino acid substitutions expected to result in partial loss of function. Functionally, mutations reduce levels of full-length transcripts and protein in subject cells, consistent with partial loss of CDC45 function and a predicted limited rate of DNA replication and cell proliferation. Our findings therefore implicate the preIC as an additional protein complex involved in the etiology of MGS and connect the core cellular machinery of genome replication with growth, chondrogenesis, and cranial suture homeostasis.
Generally, infertility is defined as the inability of couples who have had unprotected and regular intercourse for at least 12 months or longer to conceive naturally. When all societies in the world ...are examined, infertility is an important health problem affecting approximately 48 million couples, and it also has socio-cultural, economic, and psychological effects. While 8-12% of reproductive age couples have infertility problems, when gender-related reasons are examined, 20-30% of these reasons are male, 20-30% are female, and 25-40% are together with couples. While the etiology of 60% of male infertility causes has not been clarified yet, congenital urogenital anomalies are the most common causes, and genetic causes are the second most common cause among the known causes. While investigating genetic etiology in patients, chromosomal anomalies and Y microdeletions are at the forefront; however, the importance of monogenic causes has increased as some known genes have been associated with infertility because of familial segregation studies and the whole exome analyses with the development of new generation sequencing technologies. In this review, genetic causes of male infertility, diagnosis, and treatment approaches for genetic causes were examined by the current literature, and the importance of providing the proper genetic counseling to infertility patients was mentioned.
Genel olarak infertilite, en az 12 ay veya daha uzun süre korunmasız ve düzenli cinsel ilişki yaşayan çiftlerin doğal yollarla gebe kalamaması olarak tanımlanmaktadır. Dünyadaki tüm toplumlar incelendiğinde, infertilite yaklaşık olarak 48 milyon çifti etkileyen önemli bir sağlık sorunu olmanın yanı sıra, sosyo-kültürel, ekonomik ve psikolojik etkileri de bulunmaktadır. Üreme çağındaki çiftlerin %8-12’si infertilite problemi yaşarken, cinsiyete bağlı sebepler incelendiğinde, bu nedenlerin %20-30’unu erkek cinsiyet, %20-30’unu kadın cinsiyet ve %25-40’ını çiftler beraber oluşturmaktadır. Erkek cinsiyet kaynaklı infertilite nedenlerinin %60’ının etiyolojisi henüz aydınlatılmamışken, bilinen nedenler arasında doğumsal ürogenital anomaliler en sık nedenler ve genetik nedenler ise ikinci sıklıktaki nedenlerdir. Hastalarda genetik etiyoloji araştırılırken kromozomal anomalileri ve Y mikrodelesyonları ön planda izlenmektedir, ancak, yeni nesil dizileme teknolojilerinin gelişmesiyle birlikte yapılan ailesel segregasyon çalışmaları ve tüm ekzom analizleri sonucunda bilinen bazı genlerin infertilite ile ilişkilendirilmesiyle monogenik nedenlerin önemi artmıştır. Bu derlemede, erkek infertilitesinin genetik nedenleri, genetik nedenlere yönelik tanı ve tedavi yaklaşımları güncel literatürle uyumlu bir şekilde incelenmiş ve infertilite hastalarına doğru genetik danışmanlığın sağlanmasının öneminden bahsedilmiştir.
Sayın Editör,
Tüm ekzom dizileme analizi (Whole-exome-sequencing-WES) genetik etiyolojisinde heterojenite gösteren hastalıkların tanısında etkili bir yöntemdir1. Ancak, çok sık görülen ve klinik ...etkisi bilinmeyen varyantların analizi veya genotip–fenotip korelasyonunun kısıtlı olduğu olgularda ileri düzeyde klinik yorumlama gerektirmektedir. Ekzom sekanslamanın uygulanmaya ve varyant analizinin etkin yapılmaya başlanmasından sonra daha önceden moleküler tanı konamamış veya klinik tanı sonrasında yapılan hedef moleküler test sonuçları normal bulunmuş birçok hastaya tanı konabilmiştir2. Bu yazıda, genotipleme ve fenotiplemenin önemini vurgulamak amacıyla 3 olgu sunulmaktadır.
To date, studies in all populations showed that mutations in the gene of Gap junction protein beta 2 (GJB2) play an important role in non-syndromic autosomal recessive congenital hearing loss. The ...aim of this study was to evaluate GJB2 gene of patients with hearing loss in our region using deoxyribonucleic acid (DNA) sequencing method and to demonstrate region-specific mutation and polymorphism distribution.
Patients who had bilateral severe sensorineural non-syndromic hearing loss identified by audiologic evaluation were included. Peripheral blood samples were collected and the GJB2 gene exon1 and exon 2 regions were amplified by polymerase chain reaction (PCR). Obtained PCR products were sequenced by the DNA sequence analysis method (SeqFinder Sequencing System; ABI 3130; Foster City, CA, USA) and analyzed using the SeqScape software.
Of the 77 patients, 16 had homozygous or heterozygous mutation.
The mutation of 35delG, which is known as the most frequent mutation of GJB2 gene, was also the most frequently seen mutation at a ratio of 5.5% in patients with hearing loss in our region; this was followed by the V27I mutation. As this is the first study conducted by sequence analysis in our region, it was worth to be presented in terms of showing the distribution of mutation.
Amaç: Çalışmamızda epilepsi ve anlıksal yetiyitimlerinde ilk basamak tanı testi olarak moleküler karyotipleme yapmayı ve bu hastalıklar ile ilişkisini ortaya koymayı amaçladık.
Gereç ve Yöntem: ...Çukurova Üniversitesi Balcalı Hastanesi Tıbbi Genetik Polikliniği'ne başvuran ve geniş bir klinik problem yelpazesi sergileyen 580 hastaya Affymetrix CytoScan platform aracılı moleküler karyotipleme yapıldı.
Bulgular: Moleküler karyotipleme sonucunda anlıksal yetiyitimi olan hastaların %41’inde mikrodelesyon, %32’sinde duplikasyon ve %50’sinde hem delesyon hem de duplikasyon tespit edildi. Epilepsi hastalarının %16’sında mikrodelesyon, %34’ünde duplikasyon ve %50’sinde delesyon ve duplikasyon; anlıksal yetiyitiminin eşlik ettiği epileptik hastalarda %33,3 mikrodelesyon, %44,4 duplikasyon ve %22,2 hem delesyonlar hem de duplikasyon bulundu. Ayrıca, bu çalışmada bir epileptik hastada uniparental dizomi ve 2 hastada marker kromozom saptandı.
Sonuç: Elde edilen sonuçlar, moleküler karyotipleme tekniğinin klinik rutinde uygulanmasının ve elde edilen verilerin tıbbi genetik uzmanı tarafından yorumlanmasının kromozom düzeyindeki anomalilerin veya sendromların tanınmasında faydalı olduğunu göstermektedir. Özellikle epilepsi ve anlıksal yetiyitimi olan hastaların tanısında ilk basamak tanı testi olarak moleküler karyotipleme tercih edilebilir.
BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis ...and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands’ primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands’ fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social skills and communication with repetitive behaviors. Etiology is still unclear although it is ...thought to develop with interaction of genes and environmental factors. Oxytocin has extensive effects on intrauterine brain development. Vitamin D, affects neural development and differentiation and contributes to the regulation of around 900 genes including oxytocin receptor gene. In the present study, the contribution of D vitamin receptor and oxytocin receptor gene polymorphisms in the development of ASD in Turkish community was investigated. To our knowledge, this is the first study examining these two associated genes together in the literature.
Eighty-five patients diagnosed with ASD according to DSM-5 who were referred to outpatient clinics of Child and Adolescent Psychiatry of Başkent University and Mersin University and 52 healthy, age and gender-matched controls were included in the present study. Vitamin D receptor gene rs731236 (Taq1), rs2228570 (Fok1), rs1544410 (Bsm1), rs7975232 (Apa1) polymorphisms and oxytocin receptor gene rs1042778 and rs2268493 polymorphisms were investigated using real time polymerase chain reaction method.
No significant difference between groups in terms of distribution of genotype and alleles in each of polymorphisms for these genes could be found.
Knowledge of genes and polymorphisms associated with the development of ASD may be beneficial for early diagnosis and future treatment. Further studies with larger populations are required to demonstrate molecular pathways which may play part in the development of ASD in Turkey.
To look over the distribution of the mutations in a large series from Adana province, Southern Turkey, and determine the genotype-phenotype correlation of the frequent mutations. Among the 2500 ...individuals with mild or moderate anemia, microcytosis, and normal iron levels that were referred to our Genetic Diagnosis Center, a population consisting of 539 individuals were included in the study and tested for alpha-thalassemia mutations by using reverse dot blot hybridization technique. Twelve different mutations were detected in 539 patients. Among the 12 different mutations found, the most frequent mutations were the –α
3.7
(63.3 %), --
MED
(11.7 %), --
20.5
(10.7 %), α2
IVS1(−5nt)
(3.9 %), and α2
polyA−2
(3.5 %). The most frequent genotypes were –α
3.7
/αα (35.8 %), –α
3.7
/-α
3.7
(18.9 %), –
20.5
/αα (11.5 %), and --
MED
/αα (10.4 %), respectively. There were statistically significant differences in hematological findings between –α
3.7
/–α
3.7
and --
MED
/αα, even though both have two mutated genes in the genotype. Our results show that alpha-thalassemia mutations are highly heterogeneous as well as deletional and –α
3.7
single gene deletion is particularly prevalent at Adana province in agreement to other studies from Turkey.
The associations between the gene polymorphisms and erectile dysfunction (ED) are limited.
To examine a potential association between variable number of tandem repeats (intron 4 VNTR), G894T ...polymorphisms, and ED in Turkish men.
Sixty-four men with ED and 82 healthy men as a control group were included in the study. The patients were evaluated by medical history, International Index of Erectile Function (IIEF), serum glucose, and lipid profiles. VNTR and G894T polymorphism were assessed by isolated DNA blood samples obtained from the patient group with ED and controls.
Assesment of IIEF and VNTR and G894T polymorphism in the isolated DNA blood samples.
Genotype distributions of endothelial nitric oxide syntase (eNOS) gene intron 4 VNTR polymorphisms in the patient group were similar to those in the healthy group (P > 0.05). The frequency of the eNOS gene intron 4 genotype was found as bb: 55 (67.1%), ab: 26 (31.7%), and aa: 1 (1.2%) in the controls and bb: 43 (67.2%), ab: 19 (29.7%), and aa: 2 (3.1%) in the patient group. The frequency of the G894T was found as gg: 61 (74.4%), gt: 21 (25.6%), and tt: 0 (0.0%) in the controls and gg: 32 (50.0%), gt: 27 (42.1%), and tt: 5 (7.8%) in the patient group (P = 0.002). The frequencies of the “t” allele were 21 (12.8%) in the control group and 37 (28.9%) in the patient group (P = 0.001). Logistic regression analysis showed that G894T polymorphism was an independent risk factor for ED.
We found significant differences in allelic and genotypic frequencies between patients and controls for the G894T eNOS polymorphisms. The presence of 894T allele in carriers increased the risk of ED. No association was found between VNTR polymorphism and in patients with ED. Erol B, Bozdogan G, Akduman B, Dursun A, Bozdogan S, Onem K, and Mungan A. eNOS gene intron 4 VNTR and exon 7-G894T polymorphisms in Turkish men with erectile dysfunction: A case control study. J Sex Med 2009;6:1423–1429.
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