Elif Yilmaz Gulec - Academia.edu (original) (raw)

Papers by Elif Yilmaz Gulec

Research paper thumbnail of Phenotypic and mutational spectrum of ROR2-related Robinow syndrome

Human Mutation, Mar 28, 2022

Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb ... more Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the non-canonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable AR trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Common Polymorphisms of Growth Hormone: Growth Hormone Receptor Axis in Turkish Children with Short Stature

Turkish Archives of Pediatrics, 2022

Research paper thumbnail of Case Report Cernunnos/XLF Deficiency: A Syndromic Primary Immunodeficiency

Artemis, DNA ligase IV, DNA protein kinase catalytic subunit, and Cernunnos/XLF genes in nonhomol... more Artemis, DNA ligase IV, DNA protein kinase catalytic subunit, and Cernunnos/XLF genes in nonhomologous end joining pathways of DNA repair mechanisms have been identified as responsible for radiosensitive SCID. Here, we present a 3-year-old girl patient with severe growth retardation, bird-like face, recurrent perianal abscess, pancytopenia, and polydactyly. Firstly, she was thought as Fanconi anemia and spontaneous DNA breaks were seen on chromosomal analysis. After that DEB test was found to be normal and Fanconi anemia was excluded. Because of that she had low IgG and IgA levels, normal IgM level, and absence of B cells in peripheral blood; she was considered as primary immunodeficiency, Nijmegen breakage syndrome. A mutation in NBS1 gene was not found; then Cernunnos/XLF deficiency was investigated due to clinical similarities with previously reported cases. Homozygous mutation in Cernunnos/XLF gene (NHEJ1) was identified. She is now on regular IVIG prophylaxis and has no new inf...

Research paper thumbnail of Loss-of-Function Variants in EFEMP1 Cause a Recognizable Connective Tissue Disorder Characterized by Cutis Laxa and Multiple Herniations

Genes, 2021

Hereditary disorders of connective tissue (HDCT) compromise a heterogeneous group of diseases cau... more Hereditary disorders of connective tissue (HDCT) compromise a heterogeneous group of diseases caused by pathogenic variants in genes encoding different components of the extracellular matrix and characterized by pleiotropic manifestations, mainly affecting the cutaneous, cardiovascular, and musculoskeletal systems. We report the case of a 9-year-old boy with a discernible connective tissue disorder characterized by cutis laxa (CL) and multiple herniations and caused by biallelic loss-of-function variants in EFEMP1. Hence, we identified EFEMP1 as a novel disease-causing gene in the CL spectrum, differentiating it from other HDCT.

Research paper thumbnail of İkinci Trimester Sonografik Taramasında Multipl Yapısal Anomaliler Gösteren Trizomi 22 Olgusu ve Literatür Derlemesi

Mozaik olmayan trizomi 22, ilk trimester abortuslarinin yaygin nedenlerinden biridir. Canli dogum... more Mozaik olmayan trizomi 22, ilk trimester abortuslarinin yaygin nedenlerinden biridir. Canli dogumda gorulme orani oldukca dusuktur ve yaklasik 1/30000-50000’dir. Ikinci ve ucuncu trimesterde saptanma orani da oldukca dusuktur ve fetal ultrasonografide (USG) ciddi buyume geriligi ve multipl yapisal anomaliler ile kendini gosterir. Bu makalede, ikinci trimesterde fetal ultrasonda multipl anomali nedeni ile Tibbi Genetik Poliklinigi’ne yonlendirilen ve kordosentez ile yapilan fetal karyotip analizi sonucu trizomi 22 bulunan bir fetus sunulmus ve literaturdeki trizomi 22 olgularinin prenatal sonografik ozellikleri tartisilmistir. Genellikle ilk trimester abortusu ile sonuclanan anoploidilerin, nadir de olsa ikinci trimesterde karsimiza anormal USG bulgulari ile cikabilecegi, anormal USG bulgularinda prenatal karyotip analizinin onemi ve anoploidilerin sonraki gebeliklerde tekrarlama riski nedeniyle ayrinti bir genetik danisma verilmesinin onemi vurgulanmak istenmistir.

Research paper thumbnail of Late termination of pregnancy due to fetal abnormalities: An analysis of 229 cases

İstanbul Kanuni Sultan Süleyman Tıp Dergisi, 2017

Research paper thumbnail of The Evaluation Potential Global Impact of the N501Y Mutation in SARS‐COV‐2 Positive Patients

Journal of Medical Virology, 2021

Rapid and reliable detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) muta... more Rapid and reliable detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations are significant to control the contagion and spread rate of the virus. We aimed to evaluate the N501Y mutation rate in randomly chosen positive patients with polymerase chain reaction (PCR). The evaluation and analysis of the data in terms of public health will contribute to the literature on the global pandemic that affects our society with a retrospective approach in cases with mutations. Public health will take the necessary precautions and evaluate the current situation. The N501Y mutation detected in patients with positive Covid-19 PCR test results. The positive samples were examined based on the 6-carboxy-fluorescein (FAM) channel in reverse transcription PCR (RT-PCR) quantitation cycle (Cq) values as low Cq (<25), medium Cq (25-32), and high Cq (32-38) groups. In the study, 2757 (19.7%) of 13,972 cases were detected as mutation suspects and 159 (5.8%) of them were found to have mutations. The ages of the cases with mutations ranged from 1 to 88 years (mean age of 40.99±17.55). The 49.7% (n=79) of the cases with mutations were male, and 50.3% (n=80) were female. When the RT-PCR-Cq results were examined, it was seen that it varied between 11.3 and 35.03 with an average 20.75±3.32. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Two novel bi‐allelic KDELR2 missense variants cause osteogenesis imperfecta with neurodevelopmental features

American Journal of Medical Genetics Part A, 2021

Research paper thumbnail of Effect of different storage conditions on COVID‐19 RT‐PCR results

Journal of Medical Virology, 2021

Research paper thumbnail of SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype

The American Journal of Human Genetics, 2021

Upregulated signal flow through RAS and the mitogen-associated protein kinase (MAPK) cascade is t... more Upregulated signal flow through RAS and the mitogen-associated protein kinase (MAPK) cascade is the unifying mechanistic theme of the RASopathies, a family of disorders affecting development and growth. Pathogenic variants in more than 20 genes have been causally linked to RASopathies, the majority having a dominant role in promoting enhanced signaling. Here, we report that SPRED2 loss of function is causally linked to a recessive phenotype evocative of Noonan syndrome. Homozygosity for three different variants-c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95)-were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behavior. When overexpressed in cells, all variants were unable to negatively modulate EGF-promoted RAF1, MEK, and ERK phosphorylation, and time-course experiments in primary fibroblasts (p.Leu100Pro and p.Leu381Hisfs∗95) documented an increased and prolonged activation of the MAPK cascade in response to EGF stimulation. Morpholino-mediated knockdown of spred2a and spred2b in zebrafish induced defects in convergence and extension cell movements indicating upregulated RAS-MAPK signaling, which were rescued by expressing wild-type SPRED2 but not the SPRED2Leu381Hisfs∗95 protein. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome. These features, in part, characterize the phenotype of Spred2-/- mice. Our findings identify the second recessive form of Noonan syndrome and document pleiotropic consequences of SPRED2 loss of function in development.

Research paper thumbnail of Spondylometaepiphyseal Dysplasia Short Limb-Abnormal Calcification Type in Turkish Patients Reveals a Novel Mutation and New Features

Molecular Syndromology, 2021

Spondylometaepiphyseal dysplasia short limb-abnormal calcification type (SMED-SL/AC) is a rare au... more Spondylometaepiphyseal dysplasia short limb-abnormal calcification type (SMED-SL/AC) is a rare autosomal recessive disorder. It is a severe dwarfism syndrome with a characteristic feature of progressive calcification of epiphyseal and other cartilaginous tissues. It is caused by pathogenic variants in the DDR2 gene encoding the discoidin domain receptor tyrosine kinase 2. Thus far, 37 cases and 8 pathogenic variants have been reported. Most of the reported cases are of Middle Eastern and Puerto Rican origins. Only one Turkish case has been reported previously with a novel truncating variant p.(R489*). Here, we report 2 new cases, 1 with a novel variant p.(S311G) and 1 with a splice site variant c.2283+1G>A. In addition, we reviewed a previously reported case, and sequencing of stored DNA revealed the recently reported nonsense variant p.(R489*) as the underlying cause. Therefore, our data increase the number of SMED-SL/AC Turkish patients with molecular results to 4. Furthermore,...

Research paper thumbnail of High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population

The American Journal of Human Genetics, 2021

Research paper thumbnail of Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome

The American Journal of Human Genetics, 2021

Latent transforming growth factor β (TGFβ)-binding proteins (LTBPs) are microfibril-associated pr... more Latent transforming growth factor β (TGFβ)-binding proteins (LTBPs) are microfibril-associated proteins essential for anchoring TGFβ in the extracellular matrix (ECM) as well as for correct assembly of ECM components. Variants in LTBP2, LTBP3, and LTBP4 have been identified in several autosomal recessive Mendelian disorders with skeletal abnormalities with or without impaired development of elastin-rich tissues. Thus far, the human phenotype associated with LTBP1 deficiency has remained enigmatic. In this study, we report homozygous premature truncating LTBP1 variants in eight affected individuals from four unrelated consanguineous families. Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly). In vitro studies on proband-derived dermal fibroblasts indicate distinct molecular mechanisms depending on the position of the variant in LTBP1. C-terminal variants lead to an altered LTBP1 loosely anchored in the microfibrillar network and cause increased ECM deposition in cultured fibroblasts associated with excessive TGFβ growth factor activation and signaling. In contrast, N-terminal truncation results in a loss of LTBP1 that does not alter TGFβ levels or ECM assembly. In vivo validation with two independent zebrafish lines carrying mutations in ltbp1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae. In addition, one of the mutant zebrafish lines shows voluminous and hypo-mineralized vertebrae. Overall, our findings in humans and zebrafish show that LTBP1 function is crucial for skin and bone ECM assembly and homeostasis.

Research paper thumbnail of Left subclavian artery originating from left pulmonary artery in DiGeorge syndrome

The Turkish Journal of Thoracic and Cardiovascular Surgery, 2020

Left subclavian artery originating from the left pulmonary artery is a rare aortic arch anomaly. ... more Left subclavian artery originating from the left pulmonary artery is a rare aortic arch anomaly. Herein, we, for the first time in Turkey, present a case of left subclavian artery originating from the left pulmonary artery via ductus arteriosus in DiGeorge syndrome and causing subclavian steal syndrome.

Research paper thumbnail of The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered

European Journal of Human Genetics, 2020

The RASopathies are a group of clinically and genetically heterogeneous developmental disorders c... more The RASopathies are a group of clinically and genetically heterogeneous developmental disorders caused by dysregulation of the RAS/MAPK signalling pathway. Variants in several components and regulators of this pathway have been identified as the pathogenetic cause. In 2015, missense variants in A2ML1 were reported in three unrelated families with clinical diagnosis of Noonan syndrome (NS) and a zebrafish model was presented showing heart and craniofacial defects similar to those caused by a NS-associated Shp2 variant. However, a causal role of A2ML1 variants in NS has not been confirmed since. Herein, we report on 15 individuals who underwent screening of RASopathy-associated genes and were found to carry rare variants in A2ML1 , including variants previously proposed to be causative for NS. In cases where parental DNA was available, the respective A2ML1 variant was found to be inherited from an unaffected parent. Seven index patients carrying an A2ML1 variant presented with an alternate disease-causing genetic aberration. These findings underscore that current evidence is insufficient to support a causal relation between variants in A2ML1 and NS, questioning the inclusion of A2ML1 screening in diagnostic RASopathy testing.

Research paper thumbnail of Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility

PLOS Genetics, 2018

The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance... more The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality

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

The American Journal of Human Genetics, 2019

Research paper thumbnail of Exome sequencing of a primary ovarian insufficiency cohort reveals common molecular etiologies for a spectrum of disease

The Journal of Clinical Endocrinology & Metabolism, 2019

Context: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, inclu... more 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.

Research paper thumbnail of {"__content__"=>"Phenotypic expansion in - a common cause of intellectual disability in females.", "i"=>{"__content__"=>"DDX3X"}}

Annals of clinical and translational neurology, 2018

De variants in account for 1-3% of unexplained intellectual disability (ID) cases and are amongst... more De variants in account for 1-3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with disorders.

Research paper thumbnail of ATP6V0A2-related cutis laxa in ten novel patients: focus on clinical variability and expansion of the phenotype

Experimental dermatology, Jan 28, 2018

In ATP6V0A2-related cutis laxa, the skin phenotype varies from a wrinkly skin to prominent cutis ... more In ATP6V0A2-related cutis laxa, the skin phenotype varies from a wrinkly skin to prominent cutis laxa, and typically associates with skeletal and neurological manifestations. The phenotype remains incompletely characterized, especially in adult patients. Glycosylation defects and reduced acidification of secretory vesicles contribute to the pathogenesis, but the consequences at the clinical level remain to be determined. Moreover, the morphology of the elastic fibers has not been studied in ATP6V0A2-related cutis laxa, nor its relation with potential clinical risks. We report on the extreme variability in ATP6V0A2-related cutis laxa in 10 novel patients, expand the phenotype with emphysema and von Willebrand disease and hypothesize on the pathogenesis that might link both with deficiency of glycosylation and elastic fiber anomalies. Our data will affect clinical management of patients with ATP6V0A2-related cutis laxa. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Phenotypic and mutational spectrum of ROR2-related Robinow syndrome

Human Mutation, Mar 28, 2022

Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb ... more Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the non-canonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable AR trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Common Polymorphisms of Growth Hormone: Growth Hormone Receptor Axis in Turkish Children with Short Stature

Turkish Archives of Pediatrics, 2022

Research paper thumbnail of Case Report Cernunnos/XLF Deficiency: A Syndromic Primary Immunodeficiency

Artemis, DNA ligase IV, DNA protein kinase catalytic subunit, and Cernunnos/XLF genes in nonhomol... more Artemis, DNA ligase IV, DNA protein kinase catalytic subunit, and Cernunnos/XLF genes in nonhomologous end joining pathways of DNA repair mechanisms have been identified as responsible for radiosensitive SCID. Here, we present a 3-year-old girl patient with severe growth retardation, bird-like face, recurrent perianal abscess, pancytopenia, and polydactyly. Firstly, she was thought as Fanconi anemia and spontaneous DNA breaks were seen on chromosomal analysis. After that DEB test was found to be normal and Fanconi anemia was excluded. Because of that she had low IgG and IgA levels, normal IgM level, and absence of B cells in peripheral blood; she was considered as primary immunodeficiency, Nijmegen breakage syndrome. A mutation in NBS1 gene was not found; then Cernunnos/XLF deficiency was investigated due to clinical similarities with previously reported cases. Homozygous mutation in Cernunnos/XLF gene (NHEJ1) was identified. She is now on regular IVIG prophylaxis and has no new inf...

Research paper thumbnail of Loss-of-Function Variants in EFEMP1 Cause a Recognizable Connective Tissue Disorder Characterized by Cutis Laxa and Multiple Herniations

Genes, 2021

Hereditary disorders of connective tissue (HDCT) compromise a heterogeneous group of diseases cau... more Hereditary disorders of connective tissue (HDCT) compromise a heterogeneous group of diseases caused by pathogenic variants in genes encoding different components of the extracellular matrix and characterized by pleiotropic manifestations, mainly affecting the cutaneous, cardiovascular, and musculoskeletal systems. We report the case of a 9-year-old boy with a discernible connective tissue disorder characterized by cutis laxa (CL) and multiple herniations and caused by biallelic loss-of-function variants in EFEMP1. Hence, we identified EFEMP1 as a novel disease-causing gene in the CL spectrum, differentiating it from other HDCT.

Research paper thumbnail of İkinci Trimester Sonografik Taramasında Multipl Yapısal Anomaliler Gösteren Trizomi 22 Olgusu ve Literatür Derlemesi

Mozaik olmayan trizomi 22, ilk trimester abortuslarinin yaygin nedenlerinden biridir. Canli dogum... more Mozaik olmayan trizomi 22, ilk trimester abortuslarinin yaygin nedenlerinden biridir. Canli dogumda gorulme orani oldukca dusuktur ve yaklasik 1/30000-50000’dir. Ikinci ve ucuncu trimesterde saptanma orani da oldukca dusuktur ve fetal ultrasonografide (USG) ciddi buyume geriligi ve multipl yapisal anomaliler ile kendini gosterir. Bu makalede, ikinci trimesterde fetal ultrasonda multipl anomali nedeni ile Tibbi Genetik Poliklinigi’ne yonlendirilen ve kordosentez ile yapilan fetal karyotip analizi sonucu trizomi 22 bulunan bir fetus sunulmus ve literaturdeki trizomi 22 olgularinin prenatal sonografik ozellikleri tartisilmistir. Genellikle ilk trimester abortusu ile sonuclanan anoploidilerin, nadir de olsa ikinci trimesterde karsimiza anormal USG bulgulari ile cikabilecegi, anormal USG bulgularinda prenatal karyotip analizinin onemi ve anoploidilerin sonraki gebeliklerde tekrarlama riski nedeniyle ayrinti bir genetik danisma verilmesinin onemi vurgulanmak istenmistir.

Research paper thumbnail of Late termination of pregnancy due to fetal abnormalities: An analysis of 229 cases

İstanbul Kanuni Sultan Süleyman Tıp Dergisi, 2017

Research paper thumbnail of The Evaluation Potential Global Impact of the N501Y Mutation in SARS‐COV‐2 Positive Patients

Journal of Medical Virology, 2021

Rapid and reliable detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) muta... more Rapid and reliable detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations are significant to control the contagion and spread rate of the virus. We aimed to evaluate the N501Y mutation rate in randomly chosen positive patients with polymerase chain reaction (PCR). The evaluation and analysis of the data in terms of public health will contribute to the literature on the global pandemic that affects our society with a retrospective approach in cases with mutations. Public health will take the necessary precautions and evaluate the current situation. The N501Y mutation detected in patients with positive Covid-19 PCR test results. The positive samples were examined based on the 6-carboxy-fluorescein (FAM) channel in reverse transcription PCR (RT-PCR) quantitation cycle (Cq) values as low Cq (<25), medium Cq (25-32), and high Cq (32-38) groups. In the study, 2757 (19.7%) of 13,972 cases were detected as mutation suspects and 159 (5.8%) of them were found to have mutations. The ages of the cases with mutations ranged from 1 to 88 years (mean age of 40.99±17.55). The 49.7% (n=79) of the cases with mutations were male, and 50.3% (n=80) were female. When the RT-PCR-Cq results were examined, it was seen that it varied between 11.3 and 35.03 with an average 20.75±3.32. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Two novel bi‐allelic KDELR2 missense variants cause osteogenesis imperfecta with neurodevelopmental features

American Journal of Medical Genetics Part A, 2021

Research paper thumbnail of Effect of different storage conditions on COVID‐19 RT‐PCR results

Journal of Medical Virology, 2021

Research paper thumbnail of SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype

The American Journal of Human Genetics, 2021

Upregulated signal flow through RAS and the mitogen-associated protein kinase (MAPK) cascade is t... more Upregulated signal flow through RAS and the mitogen-associated protein kinase (MAPK) cascade is the unifying mechanistic theme of the RASopathies, a family of disorders affecting development and growth. Pathogenic variants in more than 20 genes have been causally linked to RASopathies, the majority having a dominant role in promoting enhanced signaling. Here, we report that SPRED2 loss of function is causally linked to a recessive phenotype evocative of Noonan syndrome. Homozygosity for three different variants-c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95)-were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behavior. When overexpressed in cells, all variants were unable to negatively modulate EGF-promoted RAF1, MEK, and ERK phosphorylation, and time-course experiments in primary fibroblasts (p.Leu100Pro and p.Leu381Hisfs∗95) documented an increased and prolonged activation of the MAPK cascade in response to EGF stimulation. Morpholino-mediated knockdown of spred2a and spred2b in zebrafish induced defects in convergence and extension cell movements indicating upregulated RAS-MAPK signaling, which were rescued by expressing wild-type SPRED2 but not the SPRED2Leu381Hisfs∗95 protein. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome. These features, in part, characterize the phenotype of Spred2-/- mice. Our findings identify the second recessive form of Noonan syndrome and document pleiotropic consequences of SPRED2 loss of function in development.

Research paper thumbnail of Spondylometaepiphyseal Dysplasia Short Limb-Abnormal Calcification Type in Turkish Patients Reveals a Novel Mutation and New Features

Molecular Syndromology, 2021

Spondylometaepiphyseal dysplasia short limb-abnormal calcification type (SMED-SL/AC) is a rare au... more Spondylometaepiphyseal dysplasia short limb-abnormal calcification type (SMED-SL/AC) is a rare autosomal recessive disorder. It is a severe dwarfism syndrome with a characteristic feature of progressive calcification of epiphyseal and other cartilaginous tissues. It is caused by pathogenic variants in the DDR2 gene encoding the discoidin domain receptor tyrosine kinase 2. Thus far, 37 cases and 8 pathogenic variants have been reported. Most of the reported cases are of Middle Eastern and Puerto Rican origins. Only one Turkish case has been reported previously with a novel truncating variant p.(R489*). Here, we report 2 new cases, 1 with a novel variant p.(S311G) and 1 with a splice site variant c.2283+1G>A. In addition, we reviewed a previously reported case, and sequencing of stored DNA revealed the recently reported nonsense variant p.(R489*) as the underlying cause. Therefore, our data increase the number of SMED-SL/AC Turkish patients with molecular results to 4. Furthermore,...

Research paper thumbnail of High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population

The American Journal of Human Genetics, 2021

Research paper thumbnail of Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome

The American Journal of Human Genetics, 2021

Latent transforming growth factor β (TGFβ)-binding proteins (LTBPs) are microfibril-associated pr... more Latent transforming growth factor β (TGFβ)-binding proteins (LTBPs) are microfibril-associated proteins essential for anchoring TGFβ in the extracellular matrix (ECM) as well as for correct assembly of ECM components. Variants in LTBP2, LTBP3, and LTBP4 have been identified in several autosomal recessive Mendelian disorders with skeletal abnormalities with or without impaired development of elastin-rich tissues. Thus far, the human phenotype associated with LTBP1 deficiency has remained enigmatic. In this study, we report homozygous premature truncating LTBP1 variants in eight affected individuals from four unrelated consanguineous families. Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly). In vitro studies on proband-derived dermal fibroblasts indicate distinct molecular mechanisms depending on the position of the variant in LTBP1. C-terminal variants lead to an altered LTBP1 loosely anchored in the microfibrillar network and cause increased ECM deposition in cultured fibroblasts associated with excessive TGFβ growth factor activation and signaling. In contrast, N-terminal truncation results in a loss of LTBP1 that does not alter TGFβ levels or ECM assembly. In vivo validation with two independent zebrafish lines carrying mutations in ltbp1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae. In addition, one of the mutant zebrafish lines shows voluminous and hypo-mineralized vertebrae. Overall, our findings in humans and zebrafish show that LTBP1 function is crucial for skin and bone ECM assembly and homeostasis.

Research paper thumbnail of Left subclavian artery originating from left pulmonary artery in DiGeorge syndrome

The Turkish Journal of Thoracic and Cardiovascular Surgery, 2020

Left subclavian artery originating from the left pulmonary artery is a rare aortic arch anomaly. ... more Left subclavian artery originating from the left pulmonary artery is a rare aortic arch anomaly. Herein, we, for the first time in Turkey, present a case of left subclavian artery originating from the left pulmonary artery via ductus arteriosus in DiGeorge syndrome and causing subclavian steal syndrome.

Research paper thumbnail of The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered

European Journal of Human Genetics, 2020

The RASopathies are a group of clinically and genetically heterogeneous developmental disorders c... more The RASopathies are a group of clinically and genetically heterogeneous developmental disorders caused by dysregulation of the RAS/MAPK signalling pathway. Variants in several components and regulators of this pathway have been identified as the pathogenetic cause. In 2015, missense variants in A2ML1 were reported in three unrelated families with clinical diagnosis of Noonan syndrome (NS) and a zebrafish model was presented showing heart and craniofacial defects similar to those caused by a NS-associated Shp2 variant. However, a causal role of A2ML1 variants in NS has not been confirmed since. Herein, we report on 15 individuals who underwent screening of RASopathy-associated genes and were found to carry rare variants in A2ML1 , including variants previously proposed to be causative for NS. In cases where parental DNA was available, the respective A2ML1 variant was found to be inherited from an unaffected parent. Seven index patients carrying an A2ML1 variant presented with an alternate disease-causing genetic aberration. These findings underscore that current evidence is insufficient to support a causal relation between variants in A2ML1 and NS, questioning the inclusion of A2ML1 screening in diagnostic RASopathy testing.

Research paper thumbnail of Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility

PLOS Genetics, 2018

The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance... more The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality

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

The American Journal of Human Genetics, 2019

Research paper thumbnail of Exome sequencing of a primary ovarian insufficiency cohort reveals common molecular etiologies for a spectrum of disease

The Journal of Clinical Endocrinology & Metabolism, 2019

Context: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, inclu... more 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.

Research paper thumbnail of {"__content__"=>"Phenotypic expansion in - a common cause of intellectual disability in females.", "i"=>{"__content__"=>"DDX3X"}}

Annals of clinical and translational neurology, 2018

De variants in account for 1-3% of unexplained intellectual disability (ID) cases and are amongst... more De variants in account for 1-3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with disorders.

Research paper thumbnail of ATP6V0A2-related cutis laxa in ten novel patients: focus on clinical variability and expansion of the phenotype

Experimental dermatology, Jan 28, 2018

In ATP6V0A2-related cutis laxa, the skin phenotype varies from a wrinkly skin to prominent cutis ... more In ATP6V0A2-related cutis laxa, the skin phenotype varies from a wrinkly skin to prominent cutis laxa, and typically associates with skeletal and neurological manifestations. The phenotype remains incompletely characterized, especially in adult patients. Glycosylation defects and reduced acidification of secretory vesicles contribute to the pathogenesis, but the consequences at the clinical level remain to be determined. Moreover, the morphology of the elastic fibers has not been studied in ATP6V0A2-related cutis laxa, nor its relation with potential clinical risks. We report on the extreme variability in ATP6V0A2-related cutis laxa in 10 novel patients, expand the phenotype with emphysema and von Willebrand disease and hypothesize on the pathogenesis that might link both with deficiency of glycosylation and elastic fiber anomalies. Our data will affect clinical management of patients with ATP6V0A2-related cutis laxa. This article is protected by copyright. All rights reserved.