Person: YEŞİL, GÖZDE
10 results
Search Results
Now showing 1 - 10 of 10
Publication Open Access Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease(2019-08-01) Jolly, Angad; Bayram, Yavuz; Turan, Serap; Aycan, Zehra; Tos, Tulay; Abali, Zehra Yavas; Hacihamdioglu, Bulent; Akdemir, Zeynep Hande Coban; Hijazi, Hadia; Bas, Serpil; Atay, Zeynep; ABALI, Saygın; Guran, Tulay; Bas, Firdevs; Darendeliler, Feyza; Colombo, Roberto; Barakat, Tahsin Stefan; Rinne, Tuula; White, Janson J.; YEŞİL, GÖZDE; Gezdirici, Alper; Gulec, Elif Yilmaz; Karaca, Ender; Pehlivan, Davut; Jhangiani, Shalini N.; Muzny, Donna M.; Poyrazoglu, Sukran; Bereket, Abdullah; Gibbs, Richard A.; Posey, Jennifer E.; Lupski, James R.; YEŞİL, GÖZDEContext: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hyper-gonadotropic 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.Publication Open Access Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders(2017-01-01) Stray-Pedersen, Asbjorg; Sorte, Hanne Sormo; Samarakoon, Pubudu; Gambin, Tomasz; Chinn, Ivan K.; Akdemir, Zeynep H. Coban; Erichsen, Hans Christian; Forbes, Lisa R.; Gu, Shen; Yuan, Bo; Jhangiani, Shalini N.; Muzny, Donna M.; Rodningen, Olaug Kristin; Sheng, Ying; Nicholas, Sarah K.; Noroski, Lenora M.; Seeborg, Filiz O.; Davis, Carla M.; Canter, Debra L.; Mace, Emily M.; Vece, Timothy J.; Allen, Carl E.; Abhyankar, Harshal A.; Boone, Philip M.; Beck, Christine R.; Wiszniewski, Wojciech; Fevang, Borre; Aukrust, Pal; Tjonnfjord, Geir E.; Gedde-Dahl, Tobias; Hjorth-Hansen, Henrik; Dybedal, Ingunn; Nordoy, Ingvild; Jorgensen, Silje F.; Abrahamsen, Tore G.; Overland, Torstein; Bechensteen, Anne Grete; Skogen, Vegard; Osnes, Liv T. N.; Kulseth, Mari Ann; Prescott, Trine E.; Rustad, Cecilie F.; Heimdal, Ketil R.; Belmont, John W.; Rider, Nicholas L.; Chinen, Javier; Cao, Tram N.; Smith, Eric A.; Soledad Caldirola, Maria; Bezrodnik, Liliana; Lugo Reyes, Saul Oswaldo; Espinosa Rosales, Francisco J.; Guerrero-Cursaru, Nina Denisse; Pedroza, Luis Alberto; Poli, Cecilia M.; Franco, Jose L.; Trujillo Vargas, Claudia M.; Aldave Becerra, Juan Carlos; Wright, Nicola; Issekutz, Thomas B.; Issekutz, Andrew C.; Abbott, Jordan; Caldwell, Jason W.; Bayer, Diana K.; Chan, Alice Y.; Aiuti, Alessandro; Cancrini, Caterina; Holmberg, Eva; West, Christina; Burstedt, Magnus; Karaca, Ender; Yesil, GÖZDE; Artac, Hasibe; Bayram, Yavuz; Atik, Mehmed Musa; Eldomery, Mohammad K.; Ehlayel, Mohammad S.; Jolles, Stephen; Flato, Berit; Bertuch, Alison A.; Hanson, I. Celine; Zhang, Victor W.; Wong, Lee-Jun; Hu, Jianhong; Walkiewicz, Magdalena; Yang, Yaping; Eng, Christine M.; Boerwinkle, Eric; Gibbs, Richard A.; Shearer, William T.; Lyle, Robert; Orange, Jordan S.; Lupski, James R.; YEŞİL, GÖZDEBackground: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.Publication Open Access Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy(2016-03-03) Harel, Tamar; YEŞİL, GÖZDE; Bayram, Yavuz; Coban-Akdemir, Zeynep; Charng, Wu-Lin; Karaca, Ender; Al Asmari, Ali; Eldomery, Mohammad K.; Hunter, Jill V.; Jhangiani, Shalini N.; Rosenfeld, Jill A.; Pehlivan, Davut; El-Hattab, Ayman W.; Saleh, Mohammed A.; Leduc, Charles A.; Muzny, Donna; Boerwinkle, Eric; Gibbs, Richard A.; Chung, Wendy K.; Yang, Yaping; Belmont, John W.; Lupski, James R.; YEŞİL, GÖZDEThe paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.Publication Open Access Homozygous Loss-of-function Mutations in SOHLH1 in Patients With Nonsyndromic Hypergonadotropic Hypogonadism(2015-05-01) Bayram, Yavuz; Gulsuner, Suleyman; ABACI, Ayhan; Gulsuner, Hilal Unal; Atay, Zeynep; Pierce, Sarah B.; Gambin, Tomasz; Lee, Ming; Turan, Serap; Bober, Ece; Atik, Mehmed M.; Walsh, Tom; Karaca, Ender; Pehlivan, Davut; Jhangiani, Shalini N.; Muzny, Donna; Bereket, Abdullah; Buyukgebiz, Atilla; Boerwinkle, Eric; Gibbs, Richard A.; King, Mary-Claire; Lupski, James R.; YEŞİL, GÖZDEContext: Hypergonadotropic hypogonadism presents in females with delayed or arrested puberty, primary or secondary amenorrhea due to gonadal dysfunction, and is further characterized by elevated gonadotropins and low sex steroids. Chromosomal aberrations and various specific gene defects can lead to hypergonadotropic hypogonadism. Responsible genes include those with roles in gonadal development or maintenance, sex steroid synthesis, or end-organ resistance to gonadotropins. Identification of novel causative genes in this disorder will contribute to our understanding of the regulation of human reproductive function. Objectives: The aim of this study was to identify and report the gene responsible for autosomal-recessive hypergonadotropic hypogonadism in two unrelated families. Design and participants: Clinical evaluation and whole-exome sequencing were performed in two pairs of sisters with nonsyndromic hypergonadotropic hypogonadism from two unrelated families. Results: Exome sequencing analysis revealed two different truncating mutations in the same gene: SOHLH1 c.705delT (p.Pro235fs*4) and SOHLH1 c.27C>G (p.Tyr9stop). Both mutations were unique to the families and segregation was consistent with Mendelian expectations for an autosomal-recessive mode of inheritance. Conclusions: Sohlh1 was known from previous mouse studies to be a transcriptional regulator that functions in the maintenance and survival of primordial ovarian follicles, but loss-of-function mutations in human females have not been reported. Our results provide evidence that homozygous-truncating mutations in SOHLH1 cause female nonsyndromic hypergonadotropic hypogonadism.Publication Open Access Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities(2019-08-13) Karaca, Ender; Posey, Jennifer E.; Bostwick, Bret; Liu, Pengfei; Gezdirici, Alper; YEŞİL, GÖZDE; Akdemir, Zeynep Coban; Bayram, Yavuz; Harms, Frederike L.; Meinecke, Peter; Alawi, Malik; Bacino, Carlos A.; Sutton, V. Reid; Kortuem, Fanny; Lupski, James R.; YEŞİL, GÖZDECo-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 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.Publication Open Access The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance(2019-07-03) Pehlivan, Davut; Bayram, Yavuz; Gunes, Nilay; Akdemir, Zeynep Coban; Shukla, Anju; Bierhals, Tatjana; TABAKCI, BURCU; Sahin, Yavuz; Gezdirici, Alper; Fatih, Jawid M.; Gulec, Elif Yilmaz; YEŞİL, GÖZDE; Punetha, Jaya; Ocak, Zeynep; Grochowski, Christopher M.; Karaca, Ender; Albayrak, Hatice Mutlu; Radhakrishnan, Periyasamy; Erdem, Haktan Bagis; Sahin, Ibrahim; Yildirim, Timur; Bayhan, Ilhan A.; Bursali, Aysegul; Elmas, Muhsin; Yuksel, Zafer; Ozdemir, Ozturk; Silan, Fatma; Yildiz, Onur; Yesilbas, Osman; Isikay, Sedat; Balta, Burhan; Gu, Shen; Jhangiani, Shalini N.; Doddapaneni, Harsha; Hu, Jianhong; Muzny, Donna M.; Boerwinkle, Eric; Gibbs, Richard A.; Tsiakas, Konstantinos; Hempel, Maja; Girisha, Katta Mohan; Gul, Davut; Posey, Jennifer E.; Elcioglu, Nursel H.; Tuysuz, Beyhan; Lupski, James R.; YEŞİL, GÖZDEArthrogryposis 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.Publication Open Access Phenotypic expansion illuminates multilocus pathogenic variation(2018-12-01) Karaca, Ender; Posey, Jennifer E.; Akdemir, Zeynep Coban; Pehlivan, Davut; Harel, Tamar; Jhangiani, Shalini N.; Bayram, Yavuz; Song, Xiaofei; Bahrambeigi, Vahid; Yuregir, Ozge Ozalp; Bozdogan, Sevcan; YEŞİL, GÖZDE; Isikay, Sedat; Muzny, Donna; Gibbs, Richard A.; Lupski, James R.; YEŞİL, GÖZDEPurpose: Multilocus variation-pathogenic variants in two or more disease genes-can potentially explain the underlying genetic basis for apparent phenotypic expansion in cases for which the observed clinical features extend beyond those reported in association with a "known" disease gene. Methods: Analyses focused on 106 patients, 19 for whom apparent phenotypic expansion was previously attributed to variation at known disease genes. We performed a retrospective computational reanalysis of whole-exome sequencing data using stringent Variant Call File filtering criteria to determine whether molecular diagnoses involving additional disease loci might explain the observed expanded phenotypes. Results: Multilocus variation was identified in 31.6% (6/19) of families with phenotypic expansion and 2.3% (2/87) without phenotypic expansion. Intrafamilial clinical variability within two families was explained by multilocus variation identified in the more severely affected sibling. Conclusion: Our findings underscore the role of multiple rare variants at different loci in the etiology of genetically and clinically heterogeneous cohorts. Intrafamilial phenotypic and genotypic variability allowed a dissection of genotype-phenotype relationships in two families. Our data emphasize the critical role of the clinician in diagnostic genomic analyses and demonstrate that apparent phenotypic expansion may represent blended phenotypes resulting from pathogenic variation at more than one locus.Publication Open Access Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease(2015-11-04T00:00:00Z) Karaca, Ender; Harel, Tamar; Pehlivan, Davut; Jhangiani, Shalini N.; Gambin, Tomasz; Akdemir, Zeynep Coban; Gonzaga-Jauregui, Claudia; Erdin, Serkan; Bayram, Yavuz; Campbell, Ian M.; Hunter, Jill V.; Atik, Mehmed M.; Van Esch, Hilde; Yuan, Bo; Wiszniewski, Wojciech; Isikay, Sedat; Yesil, Gozde; Yuregir, Ozge O.; Bozdogan, Sevcan Tug; Aslan, Huseyin; Aydin, Hatip; Tos, Tulay; Aksoy, Ayse; De Vivo, Darryl C.; Jain, Preti; Geckinli, B. Bilge; Sezer, Ozlem; Gul, Davut; Durmaz, Burak; Cogulu, Ozgur; Ozkinay, Ferda; Topcu, Vehap; Candan, Sukru; Cebi, Alper Han; Ikbal, Mevlit; Gulec, Elif Yilmaz; Gezdirici, Alper; Koparir, Erkan; Ekici, Fatma; Coskun, Salih; Cicek, Salih; Karaer, Kadri; Koparir, Asuman; Duz, Mehmet Bugrahan; Kirat, Emre; Fenercioglu, Elif; Ulucan, Hakan; Seven, Mehmet; Guran, Tulay; Elcioglu, Nursel; Yildirim, Mahmut Selman; Aktas, Dilek; Alikasifoglu, Mehmet; Ture, Mehmet; Yakut, Tahsin; Overton, John D.; Yuksel, Adnan; Ozen, Mustafa; Muzny, Donna M.; Adams, David R.; Boerwinkle, Eric; Chung, Wendy K.; Gibbs, Richard A.; Lupski, James R.; YEŞİL, GÖZDEDevelopment of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.Publication Open Access Human CLP1 Mutations Alter tRNA Biogenesis, Affecting Both Peripheral and Central Nervous System Function(2014-04-24) Karaca, Ender; Weitzer, Stefan; Pehlivan, Davut; Shiraishi, Hiroshi; Gogakos, Tasos; Hanada, Toshikatsu; Jhangiani, Shalini N.; Wiszniewski, Wojciech; Withers, Marjorie; Campbell, Ian M.; Erdin, Serkan; Isikay, Sedat; Franco, Luis M.; Gonzaga-Jauregui, Claudia; Gambin, Tomasz; Gelowani, Violet; Hunter, Jill V.; YEŞİL, GÖZDE; Koparir, Erkan; Yilmaz, Sarenur; Brown, Miguel; Briskin, Daniel; Hafner, Markus; Morozov, Pavel; Farazi, Thalia A.; Bernreuther, Christian; Glatzel, Markus; Trattnig, Siegfried; Friske, Joachim; Kronnerwetter, Claudia; Bainbridge, Matthew N.; Gezdirici, Alper; Seven, Mehmet; Muzny, Donna M.; Boerwinkle, Eric; Ozen, Mustafa; Clausen, Tim; Tuschl, Thomas; Yuksel, Adnan; Hess, Andreas; Gibbs, Richard A.; Martinez, Javier; Penninger, Josef M.; Lupski, James R.; YEŞİL, GÖZDECLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a novel neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis.Publication Metadata only Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes(2015-02-01T00:00:00Z) Yuan, Bo; Pehlivan, Davut; Karaca, Ender; Patel, Nisha; Charng, Wu-Lin; Gambin, Tomasz; Gonzaga-Jauregui, Claudia; Sutton, V. Reid; Yesil, Gozde; Bozdogan, Sevcan Tug; Tos, Tulay; Koparir, Asuman; Koparir, Erkan; Beck, Christine R.; Gu, Shen; Aslan, Huseyin; Yuregir, Ozge Ozalp; Al Rubeaan, Ha Lid; Alnaqeb, Dhekra; Alshammari, Muneera J.; Bayram, Yavuz; Atik, Mehmed M.; Aydin, Hatip; Geckinli, B. Bilge; Seven, Mehmet; Ulucan, Hakan; Fenercioglu, Elif; Ozen, Mustafa; Jhangiani, Shalini; Muzny, Donna M.; Boerwinkle, Eric; Tuysuz, Beyhan; Alkuraya, Fowzan S.; Gibbs, Richard A.; Lupski, James R.; YEŞİL, GÖZDECornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de nova heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be -transcriptomopathies- rather than cohesinopathies.