Z. Oya Uyguner

Romano-Ward sendromunda KCNQ1 geninde bir duplikasyon mutasyonu

Long QT syndrome (LQTS), a rare congenital cardiac condition associated with life‐threatening ventricular arrhythmias is characterized by a prolonged QT interval on electrocardiograph corrected for heart rate [corrected QT (QTc)]. LQTS has been historically categorized into the autosomal dominant Romano–Ward syndrome (RWS) and the autosomal recessive Jervell and Lange‐Nielsen syndrome (JLNS). JLNS is associated with prelingual sensorineural deafness. Both types of LQTS can be caused by mutations in channel genes (e.g. KCNQ1) responsible for potassium homeostasis in cardiac myocytes and cochlea. Autosomal dominant mutations often cause the RWS phenotype and homozygous or compound heterozygous mutations contribute to JLNS. Two First Nations communities in northern British Columbia are affected disproportionately with LQTS largely due to the V205M mutation in KCNQ1, however, the pathology and phenotypic expression for those V205M homozygous has been unknown. Here, we show that four V205M homozygous individuals have a significantly higher ‘peak’ QTc, and a more severe cardiac phenotype compared with 41 V205M heterozygous carriers and 57 first to third degree relatives without mutations. Given the lack of prelingual deafness the homozygous V205M LQTS patients present with a phenotype more typical of RWS than JLNS.

Molecular genetic screening of MBS1 locus on chromosome 13 for microdeletions and exclusion of FGF9, GSH1 and CDX2 as causative genes in patients with Moebius syndrome.

Moebius syndrome is a rare disorder primarily characterized by congenital facial palsy, frequently accompanied by ocular abduction anomalies, and occasionally associated with orofacial, limb and musculoskeletal malformations. Abnormal development of cranial nerves V through XII underlines the disease pathogenesis. Although some investigations suggested that a causative gene may lie on 13q12.2-q13, there have been no molecular studies targeting possible microdeletions in this region to date. In the present study, we performed microdeletion analyses on 13q12.11-q13 in nine patients, and sequenced three candidate genes in nineteen patients for functional relevance and further resolution of our screening. We ruled out microdeletions on the critical region as a common cause of Moebius syndrome and excluded FGF9, GSH1 and CDX2 genes.

Cleidocranial dysplasia: Clinical, endocrinologic and molecular findings in 15 patients from 11 families

Cleidocranial dysplasia (CCD) is an autosomal dominant disorder characterized by skeletal anomalies such as delayed closure of the cranial sutures, underdeveloped or absent clavicles, multiple dental abnormalities, short stature and osteoporosis. RUNX2, encoding Runt DNA-binding domain protein important in osteoblast differentiation, is the only known gene related to the disease and identified as responsible in 70% of the cases. Our clinical evaluations revealed that short stature present at a rate of 28.6%, osteoporosis at a rate of 57.1% and osteopenia at 21.4%. In this study, RUNX2 sequencing revealed nine different variations in 11 families, eight being pathogenic of which one was novel gross insertion (c.1271_1272ins20) and one other being predicted benign in frame gross deletion (c.241_258del).

Eyelid myoclonic status epilepticus: A rare phenotype in spinal muscular atrophy with progressive myoclonic epilepsy associated with ASAH1 gene mutation

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a rare autosomal recessive disease associated with mutations of ASAH1 gene, which encodes N-acylsphingosine amidohydrolase 1 [1]. It is characterized by progressive proximal muscle weakness due to anterior horn cell degeneration, followed by myoclonic seizures and cognitive decline [1]. Age of onset can range from childhood to adolescence [1,2]. In addition to myoclonic seizures, absence, atonic, and rare generalized tonic–clonic seizures have been described [1,2]. Abnormal eye movements and eyelid flutter have also been described but without an epileptiform EEG correlate [1,2]. Herein, we report an unusual clinical manifestation of SMAPME syndrome, eyelid myoclonic status epilepticus (SE), which has not been previously reported and needed particular attention for the use of appropriate anti-epileptic drug treatments.

A novel homozygous COL11A2 deletion causes a C-terminal protein truncation with incomplete mRNA decay in a Turkish patient†

Recessive mutations in COL11A2 (collagen, type XI, alpha 2), are responsible for otospondylomegaepiphyseal dysplasia (OSMED) and non‐syndromic hearing loss while dominant mutations are associated with Stickler type III, isolated cleft palate, Robin sequence, non‐ophthalmic Stickler syndrome, early onset osteoarthritis and autosomal dominant hearing loss. We describe here the clinical findings of two Turkish cousins with OSMED carrying a novel homozygous truncating mutation in exon 38 of COL11A2 gene, c.2763delT, identified on cDNA and confirmed at gDNA. This mutation is located on triple helix repeat domain of the collagen alpha‐2(XI) chain, where the majority of the previously identified mutations are located. Real‐time RT‐PCR experiment provided that mutated transcript does not decay completely. Although our analysis displays the partial survival of the mutant transcript from blood tissue, not from cartilage, we propose that this mechanism may play an important role on the variable expressivity of the heterozygous COL11A2 gene mutations.

Mutational screening of BASP1 and transcribed processed pseudogene TPΨg-BASP1 in patients with Möbius syndrome

Möbius syndrome is a rare disorder primarily characterized by congenital facial palsy, frequently accompanied by ocular abduction anomalies and occasionally associated with orofacial, limb and musculoskeletal malformations. Abnormal development of cranial nerves V through XII underlines the disease pathogenesis. Although a genetic etiology for Möbius syndrome was proposed, molecular genetic studies to identify the causative gene(s) are scarce. In this study, we selected two candidate genes. One is BASP1 residing in a human chromosome 5p15.1-p15.2, syntenic to mouse chromosome 15qA2-qB2, to which a mouse model with facial nerve anomalies was mapped. The other is transcribed processed pseudogene TPPsig-BASP1, which is located on chromosome 13q flanking the putative locus for Möbius syndrome and might be involved in the regulation of the transcripts encoded by BASP1. Mutation analyses in nineteen patients excluded these genes as being candidates for Möbius syndrome.

Colorectal Cancer-Associated Genes Are Associated with Tooth Agenesis and May Have a Role in Tooth Development

Previously reported co-occurrence of colorectal cancer (CRC) and tooth agenesis (TA) and the overlap in disease-associated gene variants suggest involvement of similar molecular pathways. Here, we took an unbiased approach and tested genome-wide significant CRC-associated variants for association with isolated TA. Thirty single nucleotide variants (SNVs) in CRC-predisposing genes/loci were genotyped in a discovery dataset composed of 440 individuals with and without isolated TA. Genome-wide significant associations were found between TA and ATF1 rs11169552 (P = 4.36 × 10−10) and DUSP10 rs6687758 (P = 1.25 × 10−9), and positive association found with CASC8 rs10505477 (P = 8.2 × 10−5). Additional CRC marker haplotypes were also significantly associated with TA. Genotyping an independent dataset consisting of 52 cases with TA and 427 controls confirmed the association with CASC8. Atf1 and Dusp10 expression was detected in the mouse developing teeth from early bud stages to the formation of the complete tooth, suggesting a potential role for these genes and their encoded proteins in tooth development. While their individual contributions in tooth development remain to be elucidated, these genes may be considered candidates to be tested in additional populations.

Multiple synostoses syndrome in three members of a family displaying a novel mutation in NOGGIN gene

Multiple synostoses syndrome (MSS) is an autosomal dominant developmental disorder, characterized by a variable degree of proximal symphalangism of the fingers and/or toes often associated with fusion of carpal and tarsal bones. Fusions of midphalangeal joints are clinically detectable by the absence of flexion creases over the distal (DIP) and proximal (PIP) interphalangeal joints. Other features can include cutaneous syndactyly, humeroradial synostosis, subluxation of the radial head, and occasionally, ankylosis of cervical vertebrae. The joint fusions are progressive. The PIP joints are the first to be affected. This is usually evident at birth or by early childhood. Patients may exhibit dysmorphic features such as narrow facies, hypoplastic alae nasi, a thin vermilion border of the upper lip and short philtrum, as well as progressive conductive hearing loss due to ankylosis of the auditory ossicles following adolescence. Dominant mutations in the NOGGIN [MIM *602991] gene on 17q22 have been shown to be responsible for MSS1 [SYNS1, MIM #186500]. We report here on three members of a family with MSS, in which a novel missense mutation in NOGGIN gene were shown. A three-year-old boy, the first-born to nonconsanguineous parents, was referred due to marked rigidity of his fingers and elbows. He had brachydactylic

Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis

Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in TSPEAR, associated with syndromic and isolated TA in one family each; a variant in LAMB3 associated with syndromic TA in one family; and a variant in BCOR plus a disease-associated WNT10A variant in one family with syndromic TA. With the notable exception of WNT10A (Tooth agenesis, selective, 4, MIM #150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes: TSPEAR (Deafness, autosomal recessive 98, MIM #614861), LAMB3 (Amelogenesis imperfecta, type IA, MIM #104530; Epidermolysis bullosa, junctional, MIMs #226700 and #226650), and BCOR (Microphthalmia, syndromic 2, MIM #300166). We provide evidence supporting the candidacy of these genes with TA, and propose TSPEAR as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the BCOR and WNT10A loci, underscoring the complexity of the genotype–phenotype relationship in the common complex trait of TA.

GG Polymorphism of Platelet ITGA2B Gene Increases the Magnitude of Interleukin-6 Release after Cardiopulmonary Bypass

Objective: Cardiopulmonary bypass (CPB) induces a systemic inflammatory response which is thought to be a significant cause of postoperative organ dysfunction and mortality. In this study we aimed to investigate the effect of ITGA2B (integrin alpha 2b, platelet glycoprotein IIb of IIb/IIIa complex) gene polymorphism on the magnitude of inflammatory response after CPB