A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling

Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategie

Indications for referral of Turner's syndrome cases diagnosed prenatally

We performed a retrospective study of 17 Turner's syndrome (TS) cases who were diagnosed prenatally in our Genetic Diagnostic Centre, Alsancak-Izmir, Turkey, during the period 2000-2005. The indications for prenatal diagnosis, ultra-sonographic findings and demographic data of the mothers were evaluated from patient records. The most frequent indications for prenatal diagnostic intervention were cystic hygroma (6/17) and hydrops fetalis (4/17). Other indications were advanced maternal age, abnormal triple test [alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), unconjugated estriol (Estriol)] levels in the diagnosis of Down's syndrome and fetal growth retardation. A 45,X non-mosaic karyotype (14/17) was detected in 14 of these cases, while three showed mosaicism with the following karyotypes: 45,XO/46,XX, 45,XO/46,XY and 45,XO/46,X,del (X)(q21;qter), respectively

Angiotensin Converting Enzyme Gene Polymorphisms In Male Infertility

The aim of this study was to investigate the frequency of Angiotensin Converting Enzyme (ACE) polymorphism in patients with oLigospermia or azoospermia and to compare the frequency of polymorphism with the control group which included the men who hail a child within 5 years. ACE insersion (I) / deletion (D) polymorphism was investigated at 132 men; 71 of them were diagnosed as azoospermia, 31 of them were diagnosed were oligospermia and 30 of them were healthy control. Analysis revealed that azoospermic, oligospermic and controls in terms of polymorphisms, genotype and allele frequencies, the differences were not significant and were no deviations from the Hardy-Weinberg equilibrium. The DD polymorphism ratio was found to he low (27.5%, p<0.05) in the individuals diagnosed with oligospermia in comparison to normal and azoospermic males; however, this difference was not istatistically significant and it was attributed to sampling size could have provided significant relationship

Türk populasyonunda MMP2 ve MMP9 değişimlerinin spontan abortus etiyolojisindeki rolü

Amaç: Embriyo implantasyonu ve plasental dolaşımın temel sorumlusu olan kapiller damarlardaki patolojilerin abortus etiyolojisindeki mekanizmalar üzerinde etkileri olduğu bilinmektedir. Matriks metalloproteinaz (MMP) ailesinden MMP2 ve MMP9’un ekstrasellüler matriks organizasyonunda ve trofoblast implantasyonunda önemli görevleri vardır. Bu çalışmada, fonksiyonel olduğu bilinen MMP2 735 C>T, -1306 C>T ve MMP9 -1562 C>T polimorfizmlerinin spontan abortus (SA) materyallerindeki genotip farklılıklarını belirlemek ve bu polimorfizmlerin SA etiyolojisinde rolü olup olmadığına ışık tutabilmek amaçlanmıştır. Gereç ve Yöntem: Polimorfizmlerin genotiplerinin analizinde restriksiyon fragman uzunluk polimorfizmi (RFLP) yöntemi kullanılmıştır. Çalışma grubu 80 spontan abortus örneğinden, kontrol grubu 100 sağlıklı gönüllü bireyin periferik kan örneğinden oluşmaktadır. Bulgular: MMP2 -735 C>T ve MMP9 -1562 C>T polimorfizmleri için SA örnekleri ve kontrol grubu arasında anlamlı fark saptanmadı. MMP2 -1306 C>T polimorfizminin heterozigot genotip sıklığı SA örneklerinde kontrol grubuna kıyasla 2,2 kat daha fazla bulundu (p=0.043). MMP2 genindeki normal 735 C>T ve heterozigot -1306 C>T genotiplerinin birlikte görülme sıklığı SA örneklerinde kontrol grubuna göre 3,7 kat fazla idi (p=0.021). Sonuç: MMP2 -1306 C>T fonksiyonel polimorfizmi ile SA oluşması arasında bir ilişki bulunmuştur. Daha yüksek sayılardaki SA çalışmalarındaki ileri genetik çalışmalar ve ekspresyon analizleri MMP2 ve MMP9 polimorfizmlerinin SA üzerindeki potansiyel rollerini net olarak belirlemede katkıda bulunacaktır.Aim: It is known that pathologies related to capillaries, which are responsible for maintenance of implantation and placental nutrition, have effects on mechanisms underlying abortion. Matrix metalloproteinase 2 and 9 (MMP2 and MMP9) 2, which are members of MMP family, having key roles at organization of extracellular matrix and endometrial trophoblast implantation. The aim of this study was to investigate the frequencies of functional MMP2 -735 C>T, -1306 C>T and MMP9 -1562 C>T polymorphisms in spontaneous abortion (SA) materials. Materials and Methods: Restriction fragment length polymorphism (RFLP) was used to analyze the genotypes of these polymorphisms. Study group consisted of samples collected from 80 SA specimens, and control group consisted of peripheral blood samples collected from 100 healthy subjects. Results: There was no significant difference between SA samples and control group for MMP2 -735 C>T and MMP9 -1562 C>T polymorphisms. Frequency of heterozygous MMP2 -1306 C>T genotype was 2.2-fold higher in SA samples compared to control group (p=0.043). Coexistence of normal MMP2 -735 C>T genotype and heterozygous -1306 C>T genotype was 3.7-fold higher in SA samples compared to control group (p=0.021). Conclusion: MMP2 -1306 C>T functional polymorphism have a role in spontaneous abortion. Further genetic studies on a larger number of SA samples and expression analysis of the genes may contribute to determining potential roles of MMP2 and MMP9 polymorphisms in SA