Ozgur Cogulu

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 strategies.

SMOC1 is essential for ocular and limb development in humans and mice.

Microphthalmia with limb anomalies (MLA) is a rare autosomal-recessive disorder, presenting with anophthalmia or microphthalmia and hand and/or foot malformation. We mapped the MLA locus to 14q24 and successfully identified three homozygous (one nonsense and two splice site) mutations in the SPARC (secreted protein acidic and rich in cysteine)-related modular calcium binding 1 (SMOC1) in three families. Smoc1 is expressed in the developing optic stalk, ventral optic cup, and limbs of mouse embryos. Smoc1 null mice recapitulated MLA phenotypes, including aplasia or hypoplasia of optic nerves, hypoplastic fibula and bowed tibia, and syndactyly in limbs. A thinned and irregular ganglion cell layer and atrophy of the anteroventral part of the retina were also observed. Soft tissue syndactyly, resulting from inhibited apoptosis, was related to disturbed expression of genes involved in BMP signaling in the interdigital mesenchyme. Our findings indicate that SMOC1/Smoc1 is essential for ocular and limb development in both humans and mice.

The missing “link”: an autosomal recessive short stature syndrome caused by a hypofunctional XYLT1 mutation

Proteoglycan (PG) synthesis begins with the sequential addition of a “linker chain”, made up of four sugar residues, to a specific region of a core protein. Defects in the enzymes catalyzing steps two to four of the linker chain synthesis have been shown to cause autosomal recessive human phenotypes while no mutation has yet been reported in humans for the xylosyltransferases 1 and 2 (XT1 and XT2), the initiating enzymes in the linker chain formation. Here, we present a consanguineous Turkish family with two affected individuals presenting with short stature, distinct facial features, alterations of fat distribution, and moderate intellectual disability. X-rays showed only mild skeletal changes in the form of a short femoral neck, stocky and plump long bones and thickened ribs. Using a combination of whole-exome sequencing (WES), determination of homozygous stretches by WES variants, and classical linkage analysis, we identified the homozygous missense mutation c.C1441T in XYLT1, encoding XT1, within a large homozygous stretch on chromosome 16p13.12-p12.1. The mutation co-segregated with the phenotype in the family, is not found in over 13,000 alleles in the exome variant server and is predicted to change a highly conserved arginine at position 481 (p.R481W) located in the putative catalytical domain. Immunostaining of primary patient fibroblasts showed a loss of predominance of Golgi localization in mutant cells. Moreover, western blot analysis of decorin in cell culture supernatant demonstrated glycosylation differences between patient and control cells. Our data provide evidence that functional alterations of XT1 cause an autosomal recessive short stature syndrome associated with intellectual disability.

Cytogenetic abnormalities in 179 cases with male infertility in Western Region of Turkey: Report and review

PurposeIn this study we aimed to evaluate the postnatally screened karyotype results in couples who were referred because of primary infertility between 2000 and 2006 in Izmir.MethodsThe records of a total of 179 cases were evaluated retrospectively.ResultsA total of 21 cases (11.74%) showed chromosomal alteration. Thirteen (7.26%) were 47,XXY; three (1.68%) were pericentric inversion of chromosome 9; one (0.56%) 46,XY/45,XO; one (0.56%) 46,XY/47,XXY/48,XXXY; one (0.56%) 46,XY,t(X;1); one (0.56%) 46,XY/46,XY,del(Y)(q11.2) and one (0.56%) 46,XX.ConclusionsThe rate of gonosomal chromosomal abnormalities was nearly three times higher in our region than the rate in the literature. Chromosomal analysis is strongly suggested particularly in those who suffer fertility problems.

Evaluation of 80 children with prolonged fever

Background : Several studies have been published regarding the etiology and evaluation of a child with prolonged fever, however, the reasons for the prolonged fever have changed during the years. The present study aims to determine the causes of prolonged fever, to investigate the relationship of fever using some basic laboratory tests, and to establish guidelines for the approach in those children.

Pontocerebellar hypoplasia type III (CLAM): Extended phenotype and novel molecular findings

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by abnormally small cerebellum and brainstem. Recently a rare, novel form of PCH has been reported called cerebellar atrophy with progressive microcephaly (CLAM). Here we report a second family of CLAM with additional phenotypic features and novel molecular findings. Three-year old index patient had severe developmental delay and presented with short stature and microcephaly. Her cranial magnetic resonance imaging revealed hypoplasia of the cerebellum, brainstem and cerebrum associated with hypoplasia of the corpus callosum. Brainstem auditory evoked potentials revealed hearing loss and visual evoked potentials confirmed the optic atrophy. She also had seizures with two posterior epileptic foci on electroencephalogram. Molecular analysis revealed a homozygous haplotype between the markers D7S802 and D7S630 within the originally linked region, narrowing the critical region from 20 Mb to 7 Mb. Two highly relevant candidate genes, CROT and SLC25A40 located in this region were sequenced, but no causative mutations identified. Our case provides additional clinical characteristics on the previously described features of this new entity, and reducing the critical region will now allow systematic positional cloning efforts to identify the causative gene.

Celiac disease in children with Down syndrome : Importance of follow-up and serologic screening

Background : Celiac disease, also known as gluten‐sensitive enteropathy, is a chronic inflammation disease of the small intestinal mucosa. Detection of Ig‐A antigliadin antibodies (AGA) and antiendomysial antibodies (EMA) in serum is important in the diagnosis and screening for celiac disease. Antiendomysial antibodies have greater sensitivity compared to antigliadin antibodies. It has been reported that the prevalence of celiac disease is higher in children with Down syndrome than the other autoimmune conditions. The aim of the present study was to investigate the incidence of celiac disease in children with Down syndrome, to assess the availability of Ig‐A AGA and EMA for serologic screening, and to highlight the importance of follow‐up for children with Down syndrome.

Prospective Evaluation of Whole Genome MicroRNA Expression Profiling in Childhood Acute Lymphoblastic Leukemia

Dysregulation of microRNA (miRNA) expression contributes to the pathogenesis of several clinical conditions. The aim of this study is to evaluate the associations between miRNAs and childhood acute lymphoblastic leukemia (ALL) to discover their role in the course of the disease. Forty-three children with ALL and 14 age-matched healthy controls were included in the study. MicroRNA microarray expression profiling was used for peripheral blood and bone marrow samples. Aberrant miRNA expressions associated with the diagnosis and outcome were prospectively evaluated. Confirmation analysis was performed by real time RT-PCR. miR-128, miR-146a, miR-155, miR-181a, and miR-195 were significantly dysregulated in ALL patients at day 0. Following a six-month treatment period, the change in miRNA levels was determined by real time RT-PCR and expression of miR-146a, miR-155, miR-181a, and miR-195 significantly decreased. To conclude, these miRNAs not only may be used as biomarkers in diagnosis of ALL and monitoring the disease but also provide new insights into the potential roles of them in leukemogenesis.

A Severe α Thalassemia Case Compound Heterozygous for Hb Adana in α1 Gene and 20.5 kb Double Gene Deletion

We report a 6-year-old boy diagnosed as transfusion dependent chronic nonspherocytic hemolytic anemia since 40 days old. Hemoglobin H inclusions were detected with brilliant cresyl blue preparation. His parents were found to be normal on physical examination. His mother had hemoglobin level of 9.34 g/dL, accompanied by typical thalassemic changes of the red cells, and inclusion bodies were also detected with brilliant cresyl blue staining. His father had normal hemoglobin level and borderline red cell indices. Mutation analysis using strip assay capable of detecting 22 mutations within the alpha genes was performed for the proband and the parents which revealed that the case was compound heterozygous for Hb Adana in alpha1 gene and 20.5 kb double gene deletion. The father was found to be heterozygous for Hb Adana alpha1 gene whereas the mother was found to be compound heterozygous for 20.5 kb double gene deletion and 3.7 kb single gene deletion. It is well known that non deletional forms of HbH disease are more severe than the deletional forms. This case represents another example of the nondeletional mutation underlying Hb Adana, which is rarely seen in alpha1 gene, and illustrates the distinctive phenotypes of both the deletional and nondeletional forms of hemoglobin H disease within the same family.

Role of angiotensin-converting enzyme gene polymorphisms in children with sepsis and septic shock

Background: Sepsis is characterized by a systemic inflammatory response. Its development and outcome are associated with host defense, pathogenicity of the microorganism and genetic polymorphisms. Genetic polymorphisms of the immune system genes have been shown to have a close relationship with the clinical outcomes of sepsis. Angiotensin‐converting enzyme (ACE) plays a major role in the host defense against invading pathogens. It is therefore likely that polymorphisms in the ACE gene may have an important effect on determining the development and the outcome of sepsis.