Publications by authors named "Gozde Yesil"

69 Publications

Natural history of facial and skeletal features from neonatal period to adulthood in a 3M syndrome cohort with biallelic CUL7 or OBSL1 variants.

Eur J Med Genet 2021 Sep 28;64(12):104346. Epub 2021 Sep 28.

Department of Pediatric Endocrinology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey.

3M syndrome is characterized by severe pre- and post-natal growth restriction, typical face, slender tubular bones, tall vertebral bodies, prominent heels and normal intelligence. It is caused by biallelic variants of CUL7, OBSL1 and, more rarely, CCDC8. The aim of this study is to evaluate facial and skeletal findings in 3M patients from neonatal period to adulthood. A total of 19 patients with a median age of diagnosis of 9.2 months were included in this study and were followed for two to 20 years. CUL7 and OBSL1 variants were found in 57.9% and 42.1% of patients, respectively, five of which are novel. Most of patients had triangular face, frontal bossing, short fleshy nose, full fleshy lower lip, transverse groove of rib cage, hyperlordosis and prominent heels. Three new early-diagnostic signs were observed in infants; two were infraorbital swelling of the lower lid and facial infantile hemangioma, both of which became less pronounced with aging. The third was the central tubercle of the upper lip that became more prominent with in time. While slender long bones did not change with aging, the tall vertebral bodies became more prominent radiologically. The mean birth length in patients was -4.3 SDS. Eight patients reached a mean final height of -4.9 SDS. Despite described growth hormone (GH) insensitivity in 3M syndrome, 12 patients either with GH deficiency or with normal GH levels were treated with GH; seven patients responded with an increase in height SDS. This study not only provided early diagnostic signs of the syndrome, but also presented important follow-up findings.
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http://dx.doi.org/10.1016/j.ejmg.2021.104346DOI Listing
September 2021

Evaluation of the parents' anxiety levels before and after the diagnosis of their child with a rare genetic disease: the necessity of psychological support.

Orphanet J Rare Dis 2021 09 28;16(1):402. Epub 2021 Sep 28.

Department of of Medical Genetics, Istanbul University Faculty of Medicine, Istanbul, Turkey.

Background: The diagnosis of the rare genetic diseases has great importance in treating multisystemic conditions, preventing potential complications, and estimating disease risk for family members. The duration of obtaining genetic test results is varies. The demand to learn the diagnosis of a possible untreatable illness involves a struggle between uncertainty and a lifetime chronic disease. The current uncertainty of their child's condition and the long wait for a diagnosis may increase the parents' anxiety level and cause difficulties in the continuation of diagnostic procedures in some families. This study aimed to investigate the prediagnosis and postdiagnosis anxiety levels of parents who have a child with a rare genetic disease.

Method: The parents in this study, mothers or fathers, admitted their children to the Bezmialem Vakıf University Medical Genetics Clinic due to a suspected rare genetic disease (n = 40). Researchers created "The Sociodemographic Questionnaire" and used it to analyze the parents' sociodemographic status. In addition, they used the State-Trait Anxiety Inventory (STAI) to determine the anxiety levels of the parents.

Results: The state anxiety levels of parents decreased significantly after learning the diagnosis. However, there was no statistically significant decrease observed in trait anxiety levels.

Conclusion: Data from this study revealed that informing parents about their child's disease and properly explaining to them the expected difficulties might help to reduce their anxiety levels. Psychological support for parents is necessary to reduce their long-term stress, thus increasing the patient's compliance with treatment.
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http://dx.doi.org/10.1186/s13023-021-02046-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480067PMC
September 2021

High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population.

Am J Hum Genet 2021 Oct 28;108(10):1981-2005. Epub 2021 Sep 28.

Department of Medical Genetics, Adana City Training and Research Hospital, Adana 01170, Turkey.

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs 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 NDDs; however, the majority of NDDs 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 NDDs. 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 (ROHs) - 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.
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http://dx.doi.org/10.1016/j.ajhg.2021.08.009DOI Listing
October 2021

Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.

Allergy 2021 Jul 20. Epub 2021 Jul 20.

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.

Background: Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations.

Methods: The presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cT ) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape.

Results: Mean age at disease onset was 38 ± 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4 T cells, Treg, and cT cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3-17 years).

Conclusion: This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.
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http://dx.doi.org/10.1111/all.15010DOI Listing
July 2021

Expanding the clinical phenotype of RASopathies in 38 Turkish patients, including the rare LZTR1, RAF1, RIT1 variants, and large deletion in NF1.

Am J Med Genet A 2021 Jun 29. Epub 2021 Jun 29.

Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey.

RASopathies are a group of disorders caused by pathogenic variants in the genes encoding Ras/mitogen-activated protein kinase pathway and share overlapping clinical and molecular features. This study is aimed to describe the clinical and molecular features of 38 patients with RASopathies. Sanger or targeted next-generation sequencing of related genes and multiplex ligation-dependent-probe amplification analysis for NF1 were performed. The pathogenic variant detection rate was 94.4%. While PTPN11 was responsible for 50% of 18 patients with Noonan syndrome (NS), SOS1, LZTR1, RIT1, and RAF1 were responsible for the remaining 27.8%, 11.1%, 5.5%, and 5.5%, respectively. Three variants in LZTR1 were novel, of which two were identified in the compound heterozygous state in a patient with intellectual disability and hypertrophic cardiomyopathy, whereas the third variant was found in the heterozygous state in a patient with pulmonary stenosis and normal intelligence. We described pyloric stenosis, knee dislocation, and cleft palate in patients with SOS1, RIT1, and RAF1 variants, respectively, that was not previously reported. We detected a PTPN11 variant in three patients from same family with NS with multiple lentigines. BRAF and MAP2K2 variants were found in eight patients with Cardiofaciocutaneous syndrome. Two variants in HRAS were detected in two Costello syndrome patients, one with a mild and the other with a severe phenotype. While large NF1 deletions were identified in four Neurofibromatosis-NS patients with intellectual disability, intelligence was normal in one patient with missense variant. In conclusion, this study provided three novel variants in LZTR1 and expanded the clinical phenotype of rare RASopathies.
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http://dx.doi.org/10.1002/ajmg.a.62410DOI Listing
June 2021

A novel mutation in the gene: Diagnostic approach from relatively common skeletal dysplasias to an extremely rare Odontochondrodysplasia.

J Clin Res Pediatr Endocrinol 2021 Jun 11. Epub 2021 Jun 11.

Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey.

Odontochondrodysplasia (ODCD, OMIM #184260) is a quite rare non-lethal skeletal dysplasia characterized by involvement of the spine and metaphyseal regions of the long bones, pulmonary hypoplasia, short stature, joint hypermobility, and dentinogenesis imperfecta. ODCD is inherited in an autosomal recessive fashion with an unknown frequency caused by mutations of the thyroid hormone receptor interactor 11 gene (TRIP11; OMIM *604505). TRIP11 gene encodes the Golgi microtubule-associated protein 210 (GMAP-210), which is an indispensable protein for the function of the Golgi apparatus. Mutations of the TRIP11 gene also cause achondrogenesis type 1A (ACG1A). Null mutations of TRIP11 lead to ACG1A, also known as a lethal skeletal dysplasia, while hypomorphic mutations cause ODCD. Here we report a male child diagnosed as ODCD with a novel compound heterozygote mutation who presented with skeletal changes, short stature, dentinogenesis imperfecta, and facial dysmorphism resembling Achondroplasia (ACH) and Hypochondroplasia (HCH).
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http://dx.doi.org/10.4274/jcrpe.galenos.2021.2021.0099DOI Listing
June 2021

Cause of recurrent rhabdomyolysis, carnitine palmitoyltransferase II deficiency and novel pathogenic mutation.

Ideggyogy Sz 2021 Mar;74(3-4):135-138

Department of Medical Genetics, Bezmialem Vakif University Istanbul, Turkey.

Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal inherited metabolic disorder in which the β-oxidation of the long chain fatty acids is defective. The clinical presentation may be in various forms; it presents itself in the severe form during neonatal and infantile periods and as the less severe myopathic form in the school age and adolescence. While the severity of the rhabdomyolysis attacks varies, occasionally the clinical course may be complicated with acute renal failure. Acylcarnitine analysis may help in the diagnosis of CPT II, but its normality does not indicate the absence of the disease. If there is strong suspicion, genetic analysis should be performed on the cases. In this article, we present a 15-year-old male patient who had two rhabdomyolysis attacks triggered by infection and starvation. Acylcarnitine analysis of the case was normal, CPT II deficiency was considered when the history was evaluated, and CPT II gene c.137A>G (p.Gln46Arg) homozygous novel pathogenic mutation was detected. CPT II deficiency is one of the most common causes of metabolic rhabdomyolysis in patients with recurrent episodes of rhabdomyolysis.
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http://dx.doi.org/10.18071/isz.74.0135DOI Listing
March 2021

Neurofibromatosis type 1: Expanded variant spectrum with multiplex ligation-dependent probe amplification and genotype-phenotype correlation in 138 Turkish patients.

Ann Hum Genet 2021 Sep 20;85(5):155-165. Epub 2021 Apr 20.

Cerrahpaşa Medical Faculty, Department of Pediatric Genetics, Istanbul University-Cerrahpaşa, Istanbul, Turkey.

Objective: To investigate the variant spectrum and genotype-phenotype correlations in a Turkish cohort with Neurofibromatosis Type-1 (NF1).

Materials And Methods:  We retrospectively investigated the clinical and molecular data of 138 NF1 patients from 129 families who had been followed-up for a median of 3.9 (1.25-18.5) years.

Results: NF1 sequencing revealed 73 different intragenic variants, 19 of which were novel. Seven large deletions were detected by multiplex ligation-dependent probe amplification (MLPA) analyses. The total detection rate of pathogenic NF1 variants was found to be 87.1%. Comparing age groups, cutaneous neurofibromas, freckling, and Lisch nodules were more prevalent in patients older than 12 years (p > .05). Optic glioma detected in 17.3% of the patients and was significantly more common before the age of 6 (p > .001). Other solid tumors developed in 5% of the patients. There was no genotype-phenotype correlation between patients with truncating and nontruncating variants. However, six out of seven patients with large deletions had significant developmental delay, one patient with the c.2970_2972delAAT (p.Met992del) variant had only typical pigmentary features, and another patient with the c.4267A > G (p.Lys1423Glu) variant had CALMs, freckling, neurofibromas, and Noonan-like phenotype.

Conclusions: We described 19 novel variants and seven large deletions in NF1. Applying MLPA assay in NF1 is useful in expanding the molecular diagnosis. Although very limited genotype-phenotype correlation has been reported in NF1, the fact that specific phenotypic findings were observed in our patients with large deletions and two intragenic variants supports the studies published recently.
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http://dx.doi.org/10.1111/ahg.12422DOI Listing
September 2021

Investigation of (epi)genotype causes and follow-up manifestations in the patients with classical and atypical phenotype of Beckwith-Wiedemann spectrum.

Am J Med Genet A 2021 06 11;185(6):1721-1731. Epub 2021 Mar 11.

Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Department of Neonatology, Istanbul, Turkey.

Beckwith-Wiedemann syndrome (BWS) is a genomic imprinting disorder, characterized by macroglossia, abdominal wall defects, lateralized overgrowth, and predisposition to embryonal tumors. It is caused by the defect of imprinted genes on chromosome 11p15.5, regulated by imprinting control (IC) domains, IC1, and IC2. Rarely, CDKN1C and chromosomal changes can be detected. The aim of this study is to retrospectively evaluate 55 patients with BWS using the new diagnostic criteria developed by the BWS consensus, and to investigate (epi)genetic changes and follow-up findings in classic and atypical phenotypes. Loss of methylation in IC2 region (IC2-LoM), 11p15.5 paternal uniparental disomy (pUPD11), and methylation gain in IC1 region (IC1-GoM) are detected in 31, eight, and five patients, respectively. Eleven patients have had no molecular defects. Thirty-five patients are classified as classical and 20 as atypical phenotype. Patients with classical phenotype are more frequent in the IC2-LoM (25/31), while patients with atypical phenotype are common in the pUPD11 group (5/8). Malignant tumors have developed in six patients (10.9%); three of these patients have IC1-GoM, two pUPD11, one IC2-LoM genotype, and four an atypical phenotype. We observed that the face was round in the infantile period and elongated as the child grew-up, developing prognathism and becoming asymmetrical if hemi-macroglossia was present in the classical phenotype. These findings were mild in the atypical phenotype. These results support the importance of using the new diagnostic criteria to facilitate the diagnosis of patients with atypical phenotype who have higher tumors risk. This study also provides important information about facial gestalt.
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http://dx.doi.org/10.1002/ajmg.a.62158DOI Listing
June 2021

Strong mesangial IgA staining-does it always refer to IgA nephropathy in a patient with proteinuria and hematuria? Answers.

Pediatr Nephrol 2021 Jul 18;36(7):2043-2045. Epub 2021 Jan 18.

Department of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.

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http://dx.doi.org/10.1007/s00467-020-04899-4DOI Listing
July 2021

Strong mesangial IgA staining-does it always refer to IgA nephropathy in a patient with proteinuria and hematuria? Questions.

Pediatr Nephrol 2021 Jul 18;36(7):2039-2041. Epub 2021 Jan 18.

Department of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34098, Istanbul, Turkey.

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http://dx.doi.org/10.1007/s00467-020-04886-9DOI Listing
July 2021

Two patients with chronic mucocutaneous candidiasis caused by TRAF3IP2 deficiency.

J Allergy Clin Immunol 2021 07 22;148(1):256-261.e2. Epub 2021 Jan 22.

Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address:

Background: TRAF3 interacting protein 2 (TRAF3IP2) (Act1) is an adapter protein that interacts with IL-17R via its similar expression to fibroblast growth factor genes and IL-17R domain and coordinates 2 separate proinflammatory pathways following IL-17 cytokine stimulation.

Objective: We sought to elucidate the immunologic consequences of TRAF3IP2 homozygous mutations to improve treatments for immunodeficiency patients with chronic mucocutaneous candidiasis.

Methods: We describe 2 patients presenting with chronic mucocutaneous candidiasis who harbor biallelic nonsense mutations in TRAF3IP2. The cellular and molecular features of this genetic defect were assessed using in vitro cytokine assays and protein analysis.

Results: We show that the homozygous mutation causes complete loss of protein expression. We also show that the absence of TRAF3IP2 was associated with a defective response to combined IL-2/IL-25 (IL-17E) stimulation.

Conclusions: Failure to initiate normal signaling downstream of IL-17R engagement likely contributes to the patients' recurrent fungal infections. These findings add to our molecular understanding of genetic defects affecting this critical pathway of antifungal immunity.
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http://dx.doi.org/10.1016/j.jaci.2020.12.629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273085PMC
July 2021

Evaluation of clinical, neuroradiologic, and genotypic features of patients with L-2-hydroxyglutaric aciduria.

Turk Pediatri Ars 2020 23;55(3):290-298. Epub 2020 Sep 23.

Division of Pediatric Nutrition and Metabolism, Department of Pediatrics, İstanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, İstanbul, Turkey.

Aim: L-2-hydroxyglutaric aciduria is a slowly progressive neurometabolic disorder caused by an enzymatic deficiency of L-2-hydroxyglutarate dehydrogenase. Here, we aimed to evaluate the clinical, neuroradiologic, and genotypic characteristics of patients with L-2-hydroxyglutaric aciduria who were followed in our outpatient clinic.

Material And Methods: Twenty-five patients with L-2-hydroxyglutaric aciduria were enrolled in the study. Data regarding demographic, clinical, and neuroradiologic findings and molecular analysis were evaluated retrospectively.

Results: The mean age of patients at the time of diagnosis was 12.09±8.02 years, whereas the mean age at the time of the first symptoms was 39.47±29.96 months. Diagnostic delay was found as 9.95±7.78 years. Developmental delay, decrease in school success, and seizures were the most common initial symptoms; however, behavioral problems and seizures became more prominent in the disease course. At the time of diagnosis, mental retardation and at least one pathologic cerebellar finding were detected in all symptomatic patients. Three patients developed brain tumors. The most common neuroimaging findings were subcortical white matter changes and cerebellar dentate nucleus involvement. In one patient, there was only isolated basal ganglia involvement without white matter lesions. Patients with similar genotypic features exhibited different clinical and radiologic findings.

Conclusion: Although clinical symptoms appear early in L-2-hydroxyglutaric aciduria, there is approximately a ten-year delay in diagnosis. In subjects in whom brain tumor is detected in early childhood, L-2-hydroxyglutaric aciduria should be considered in the differential diagnosis in the presence of mental retardation accompanied by developmental delay, cerebellar and pyramidal findings, and behavior disorders in a wide spectrum ranging from autism spectrum disorder to psychosis. In patients with L-2-hydroxyglutaric aciduria, incipient headache, tinnitus, altered consciousness, and seizures can be indicative of brain tumors.
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http://dx.doi.org/10.14744/TurkPediatriArs.2019.06926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536460PMC
September 2020

Parents of ataxia-telangiectasia patients display a distinct cellular immune phenotype mimicking ATM-mutated patients.

Pediatr Allergy Immunol 2021 02 19;32(2):349-357. Epub 2020 Oct 19.

Division of Pediatric Allergy-Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey.

Background: Heterozygous relatives of ataxia-telangiectasia (AT) patients are at an increased risk for certain AT-related manifestations. We also show that there is an increase of infection frequency in parents of AT patients. Thus, we hypothesized that the parents might exhibit immune alterations similar to their affected children.

Methods: Lymphocyte phenotyping to enumerate T- and B-cell subsets was performed. Functional analyses included in vitro quantified γ-H2AX, poly (ADP-ribose) polymerase (PARP) and caspase-9 proteins. Chromosomal instability was determined by comet assay.

Results: We analyzed 20 AT patients (14F/6M), 31 parents (16F/15M), and 35 age-matched healthy controls. The AT patients' parents exhibited low frequency of naive CD4 T- (n = 14, 45%) and recent thymic emigrants (n = 11, 35%) in comparison with the age-matched healthy donors. Interestingly, parents with low naive T cells also demonstrated high rate of recurrent infections (9/14, 64%). In comparison with age-matched controls, parents who had recurrent infections and low naive T cells showed significantly higher baseline γ-H2AX levels and H O -induced DNA damage as well as increased cleaved caspase-9 and PARP proteins.

Conclusion: Parents of AT patients could present with recurrent infections and display cellular defects that mimic AT patients. The observed immunological changes could be associated with increased DNA double-strand breaks.
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http://dx.doi.org/10.1111/pai.13387DOI Listing
February 2021

Diagnostic Modalities Based on Flow Cytometry for Chronic Granulomatous Disease: A Multicenter Study in a Well-Defined Cohort.

J Allergy Clin Immunol Pract 2020 Nov - Dec;8(10):3525-3534.e1. Epub 2020 Jul 28.

Faculty of Medicine, Pediatric Allergy-Immunology, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey. Electronic address:

Background: Chronic granulomatous disease (CGD) is characterized by defective microbial killing due to mutations affecting subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Definitive genetic identification of disease subtypes may be delayed or not readily available.

Objective: Sought to investigate the role of intracellular staining of NADPH oxidase enzyme subunits in predicting the respective genetic defects in patients with CGD and carriers.

Methods: Thirty-four patients with genetically inherited CGD, including 12 patients with X-linked CGD (gp91 deficiency due to cytochrome b-245, beta polypeptide [CYBB] mutations) and 22 patients with autosomal-recessive CGD (p22, p47, and p67 deficiency due to cytochrome b-245, alpha polypeptide [CYBA], neutrophil cytosolic factor 1 [NCF1] and NCF2 mutations, respectively) were recruited from different immunology centers and followed up prospectively. Dihydrorhodamine testing and NADPH oxidase subunit expression in white blood cells were determined by flow cytometry.

Results: gp91 and p22 defects, which result in simultaneous loss of both proteins due to their complex formation, were differentiated only by comparative analysis of patients' and mothers' intracellular staining. p47 and p67 protein expression was almost undetectable in patients compared with carrier mothers and healthy controls. The expression values of the respective subunits were found to be significantly higher in all controls as compared with carrier mothers, which in turn were higher than those of patients.

Conclusions: Analysis of NADPH oxidase enzyme subunits by flow cytometry in patients and carriers is useful in the rapid prediction of the genetic defect of patients with CGD, thus guiding targeted sequencing and aiding in their early diagnosis.
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http://dx.doi.org/10.1016/j.jaip.2020.07.030DOI Listing
May 2021

Early-onset rapidly progressive myoclonic epilepsy associated with G392R likely pathogenic variant in SERPINI1.

Seizure 2020 08 16;80:181-182. Epub 2020 Jun 16.

İstanbul Bezm-i Alem University, Department of Medical Genetics, İstanbul, Turkey.

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http://dx.doi.org/10.1016/j.seizure.2020.06.022DOI Listing
August 2020

Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.

Eur J Hum Genet 2020 09 6;28(9):1243-1264. Epub 2020 May 6.

Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA.

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.
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http://dx.doi.org/10.1038/s41431-020-0632-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608441PMC
September 2020

Expanding Clinical Phenotype of TRAPPC12-Related Childhood Encephalopathy: Two Cases and Review of Literature.

Neuropediatrics 2020 12 5;51(6):430-434. Epub 2020 May 5.

Department of Medical Genetics, Faculty of Medicine, Bezmialem Vakıf University, Istanbul, Turkey.

Biallelic mutations in the gene are responsible for early-onset progressive encephalopathy with brain atrophy and spasticity (PEBAS). To date, three different allelic variants have been reported. Next-generation sequencing allowed discovery of unique alternations in this gene with different phenotypes. We report two patients carrying TRAPPC12 variants, one previously reported and one unknown mutation, with severe neurodevelopmental delay and brain atrophy. Standard clinical examination and cranial imaging studies were performed in these two unrelated patients. In addition, whole-exome sequencing was performed, followed by Sanger sequencing for verification. The first patient, a 2-year-old boy, was found to be homozygous for the previously reported c.1880C > T (p.Ala627Val) mutation. He presented with a phenotype including severe progressive cortical atrophy, moderate cerebellar atrophy, epilepsy, and microcephaly, very similar to the previously reported cases. The second case, a 9-year-old boy, carried a novel homozygous c.679T > G (p.Phe227Val) variant and presented with mild cortical atrophy, severe cerebellar atrophy, and neither clinically manifest epilepsy nor microcephaly, which were previously considered typical findings in PEBAS with TRAPPC12 mutations. Our findings suggest that clinical and brain imaging findings might be more variable than previously anticipated; however, a larger number of observations would benefit for broader phenotypic spectrum.
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http://dx.doi.org/10.1055/s-0040-1710526DOI Listing
December 2020

A Rare Cause of Adrenal Insufficiency - Isolated ACTH Deficiency Due to TBX19 Mutation: Long-Term Follow-Up of Two Cases and Review of the Literature.

Horm Res Paediatr 2019 28;92(6):395-403. Epub 2020 Apr 28.

Department of Pediatric Endocrinology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Introduction: Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rare cause of adrenal insufficiency and T-box pituitary restricted transcription factor (TBX19) mutations are responsible for two-thirds of the neonatal onset form of the disease. IAD presents with hypoglycemia and prolonged jaundice in the neonatal period. TBX19 is important for both pro-opiomelanocortin (POMC) gene transcription and differentiation of POMC-expressing cells. We describe 2 patients, 1 with a reported and 1 with a novel TBX19 mutation, and present information about the long-term follow-up of these patients.

Case Presentation: Both patients had critical illnesses, recurrent hypoglycemia, convulsions, and neonatal hyperbilirubinemia. They also had low cortisol and ACTH levels, while other pituitary hormones were within the normal range. Pituitary imaging was normal. After hydrocortisone treatment, there was resolution of the hypoglycemia and the convulsions were controlled. Genetic studies of the patients revealed both had inherited a homozygous mutation of the TBX19 gene. The first patient had an alteration of NM_005149.3:c.856C>T (p.R286*) and the second patient had a novel NM_005149.3:c.584C>T (p.T195I) mutation, analyzed by next-generation sequencing. The noteworthy findings of the patients at follow-up were: short stature, microcephaly, and decreased pubic hair in the first, and dysmorphic features, Chiari type 1 malformation, tall stature, and low bone mineral density (BMD) in the second.

Conclusion: Congenital IAD can be life-threatening if it is not recognized and treated early. TBX19 mutations should be considered in the differential diagnosis of IAD. Further cases or functional analyses are needed for genotype-phenotype correlations. Low BMD, dysmorphic features, Chiari type 1 malformation, and sparse pubic hair are some of the important features in these patients.
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http://dx.doi.org/10.1159/000506740DOI Listing
July 2020

Correlation Between DTI Findings and Volume of Corpus Callosum in Children with AUTISM.

Curr Med Imaging Rev 2019;15(9):895-899

Department of Radiology, School of Medicine, Bezmialem Vakif University, Istanbul, Turkey.

Background: Autism Spectrum Disorder (ASD) is a complex developmental disorder in which neurological basis is largely unknown. The Corpus Callosum (CC) is the main commissure that connects the cerebral hemispheres. Previous evidence suggests the involvement of the CC in the pathophysiology of autism.

Aim: The aim of our study is to assess whether there were any changes in Corpus Callosum (CC) area and volume and to reveal the relationship between Diffusion Tensor Imaging (DTI) features in genu and splenium of corpus callosum in children with ASD.

Methods: Eighteen patient and 15 controls were recruited. The volumetric sagittal TI images were used to provide measurements of midsagittal corpus callosum surface area while FA, MD, RD, and ADC values were extracted from genu and splenium of corpus callosum after which the correlation in the area and volume in ASD children was examined.

Results: CC area and volume in children with ASD were decreased than controls. FA values obtained from the genu and splenum of CC were significantly lower and RD values were significantly higher. A positive correlation was observed between the FA of the genu and splenium and area and volume of the CC. There was a negative correlation between ADC, MD and RD of CC and area and volume measurements.

Conclusion: The conclusions in the interrelations of morphometric and DTI data may demonstrate a likelihood of damages in the axons and cortical neurons. The results showed that there existed microstructural damages from the DTI findings. Furthermore, the decrease in FA could be a representation of the reduction in the myelination in nerve pathways, impaired integrity, reduced axonal density, and organization. Indeed, the changes in volumetric and microstructural of CC could be useful in evaluating underlying pathophysiology in children with autism.
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http://dx.doi.org/10.2174/1573405614666181005114315DOI Listing
October 2020

A rare cause of hypertension in childhood: Answers.

Pediatr Nephrol 2020 01 20;35(1):79-82. Epub 2019 Sep 20.

Department of Pediatric Endocrinology and Diabetes, Marmara University, School of Medicine, Fevzi Çakmak Mahallesi, Muhsin Yazıcıoğlu Caddesi, No: 10 34899 Pendik, Istanbul, Turkey.

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http://dx.doi.org/10.1007/s00467-019-04329-0DOI Listing
January 2020

A rare cause of hypertension in childhood: Questions.

Pediatr Nephrol 2020 01 20;35(1):77-78. Epub 2019 Sep 20.

Department of Pediatric Endocrinology and Diabetes, Marmara University, School of Medicine, Fevzi Çakmak Mahallesi, Muhsin Yazıcıoğlu Caddesi, No:10 34899 Pendik, Istanbul, Turkey.

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http://dx.doi.org/10.1007/s00467-019-04326-3DOI Listing
January 2020

Rare cause of severe hypertension in an adolescent boy presenting with short stature: Answers.

Pediatr Nephrol 2020 03 16;35(3):405-407. Epub 2019 Sep 16.

School of Medicine, Department of Pediatric Endocrinology and Diabetes, Marmara University, Fevzi Çakmak Mahallesi, Muhsin Yazıcıoğlu Caddesi, No:10 34899 Pendik, Istanbul, Turkey.

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http://dx.doi.org/10.1007/s00467-019-04352-1DOI Listing
March 2020

Rare cause of severe hypertension in an adolescent boy presenting with short stature: Questions.

Pediatr Nephrol 2020 03 16;35(3):403-404. Epub 2019 Sep 16.

School of Medicine, Department of Pediatric Endocrinology and Diabetes, Marmara University, Fevzi Çakmak Mahallesi, Muhsin Yazıcıoğlu Caddesi, No:10 34899 Pendik, Istanbul, Turkey.

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http://dx.doi.org/10.1007/s00467-019-04351-2DOI Listing
March 2020

Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities.

Am J Med Genet A 2019 10 13;179(10):2056-2066. Epub 2019 Aug 13.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Co-occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < -3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier-Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel-like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral-Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel-like phenotype and FFS, the last of which has not been associated with any disease gene to date.
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http://dx.doi.org/10.1002/ajmg.a.61315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936249PMC
October 2019

Vanishing white matter disease with different faces.

Childs Nerv Syst 2020 02 5;36(2):353-361. Epub 2019 Aug 5.

Department of Pediatric Neurology, Marash Life Hospital, Kahramanmaraş, Turkey.

Purpose: The goal of this study was to better understand vanishing white matter (VWM) disease, which is one of the most common hereditary white matter disorders, and its relationship to radiologic features, genetic analyses, and clinical findings.

Methods: We performed a study on 11 patients to describe the clinical and neuroimaging features of VWM. Patients were grouped into "infantile," "early childhood," and "juvenile" based on their onset age. EIF2B1-5 genes encoding five subunits of eukaryotic translation initiation factor 2B (eIF2B) were analyzed in all patients with clinically suspected VWM disease.

Results: In brain magnetic resonance imaging (MRI), all patients showed white matter abnormalities with various degrees. The initial clinical presentation in five of patients was ataxia, with severe refractory epilepsy in three patients. In children with infantile-onset VWM, a rapid deterioration of motor function was detected, and the frequency of epilepsy was higher. Two patients showed manifestations of end-stage VWM disease, and one of them had chronic subdural hematoma. One of our patients and his father were diagnosed with Brugada syndrome. Sequencing of the exons and exon-intron boundaries of the EIF2B1-5 genes revealed mutations in the genes EIF2B5 (5 cases), EIF2B3 (3 cases), and EIF2B4 (2 cases). We also found a novel mutation in one patient: c.323_325delGAA in the EIF2B1 gene.

Conclusions: In this study, in addition to classical clinical and radiological findings, we wanted to emphasize that we may be confronted with refractory epilepsy (early infancy), cardiac problems, and intracranial complications that may occur in advanced stages.
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http://dx.doi.org/10.1007/s00381-019-04334-6DOI Listing
February 2020

Novel Gene Mutation in a Patient with Gorlin-Goltz Syndrome.

Ann Dermatol 2019 Aug 1;31(Suppl):S10-S11. Epub 2019 Jul 1.

Department of Dermatology, Istanbul Medeniyet University School of Medicine, Istanbul, Turkey.

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http://dx.doi.org/10.5021/ad.2019.31.S.S10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997056PMC
August 2019

The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.

Am J Hum Genet 2019 07 20;105(1):132-150. Epub 2019 Jun 20.

Department of Physiotherapy and Rehabilitation, Hasan Kalyoncu University, School of Health Sciences, Gaziantep 27000, Turkey.

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612529PMC
July 2019

Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease.

J Clin Endocrinol Metab 2019 08;104(8):3049-3067

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Context: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait.

Objective: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI.

Design, Setting, And Participants: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity.

Results: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds.

Conclusions: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.
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http://dx.doi.org/10.1210/jc.2019-00248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563799PMC
August 2019

PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans.

Eur J Endocrinol 2019 May;180(5):291-309

Department of Paediatric Endocrinology and Diabetes, Marmara University.

Context Most of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C gene. This gene encodes B″gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C gene is most abundantly expressed in testis in humans, while its function was hitherto unknown. Patients and methods Four girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics. Results We have identified three different homozygous PPP2R3C variants, c.308T>C (p.L103P), c.578T>C (p.L193S) and c.1049T>C (p.F350S), in four girls with 46, XY complete gonadal dysgenesis. Patients also manifested a unique syndrome of extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay. We have shown a decreased SOX9-Phospho protein expression in the dysgenetic gonads of the patients with homozygous PPP2R3C variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility. Conclusion Our findings suggest that PPP2R3C protein is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPPR3C provides insight into pathophysiology, as well as emerging as a potential therapeutic target for male infertility.
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http://dx.doi.org/10.1530/EJE-19-0067DOI Listing
May 2019
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