86 results on '"Yesil, Gozde"'
Search Results
52. The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance
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Pehlivan, Davut, primary, Bayram, Yavuz, additional, Gunes, Nilay, additional, Coban Akdemir, Zeynep, additional, Shukla, Anju, additional, Bierhals, Tatjana, additional, Tabakci, Burcu, additional, Sahin, Yavuz, additional, Gezdirici, Alper, additional, Fatih, Jawid M., additional, Gulec, Elif Yilmaz, additional, Yesil, Gozde, additional, Punetha, Jaya, additional, Ocak, Zeynep, additional, Grochowski, Christopher M., additional, Karaca, Ender, additional, Albayrak, Hatice Mutlu, additional, Radhakrishnan, Periyasamy, additional, Erdem, Haktan Bagis, additional, Sahin, Ibrahim, additional, Yildirim, Timur, additional, Bayhan, Ilhan A., additional, Bursali, Aysegul, additional, Elmas, Muhsin, additional, Yuksel, Zafer, additional, Ozdemir, Ozturk, additional, Silan, Fatma, additional, Yildiz, Onur, additional, Yesilbas, Osman, additional, Isikay, Sedat, additional, Balta, Burhan, additional, Gu, Shen, additional, Jhangiani, Shalini N., additional, Doddapaneni, Harsha, additional, Hu, Jianhong, additional, Muzny, Donna M., additional, Boerwinkle, Eric, additional, Gibbs, Richard A., additional, Tsiakas, Konstantinos, additional, Hempel, Maja, additional, Girisha, Katta Mohan, additional, Gul, Davut, additional, Posey, Jennifer E., additional, Elcioglu, Nursel H., additional, Tuysuz, Beyhan, additional, and Lupski, James R., additional
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- 2019
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53. PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans
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Guran, Tulay, primary, Yesil, Gozde, additional, Turan, Serap, additional, Atay, Zeynep, additional, Bozkurtlar, Emine, additional, Aghayev, AghaRza, additional, Gul, Sinem, additional, Tinay, Ilker, additional, Aru, Basak, additional, Arslan, Sema, additional, Koroglu, M Kutay, additional, Ercan, Feriha, additional, Demirel, Gulderen Y, additional, Eren, Funda S, additional, Karademir, Betul, additional, and Bereket, Abdullah, additional
- Published
- 2019
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54. Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease
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Jolly, Angad, primary, Bayram, Yavuz, additional, Turan, Serap, additional, Aycan, Zehra, additional, Tos, Tulay, additional, Abali, Zehra Yavas, additional, Hacihamdioglu, Bulent, additional, Coban Akdemir, Zeynep Hande, additional, Hijazi, Hadia, additional, Bas, Serpil, additional, Atay, Zeynep, additional, Guran, Tulay, additional, Abali, Saygin, additional, Bas, Firdevs, additional, Darendeliler, Feyza, additional, Colombo, Roberto, additional, Barakat, Tahsin Stefan, additional, Rinne, Tuula, additional, White, Janson J, additional, Yesil, Gozde, additional, Gezdirici, Alper, additional, Gulec, Elif Yilmaz, additional, Karaca, Ender, additional, Pehlivan, Davut, additional, Jhangiani, Shalini N, additional, Muzny, Donna M, additional, Poyrazoglu, Sukran, additional, Bereket, Abdullah, additional, Gibbs, Richard A, additional, Posey, Jennifer E, additional, and Lupski, James R, additional
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- 2019
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55. Novel PTCH1 Gene Mutation in a Patient with Gorlin–Goltz Syndrome
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Ozlu, Emin, primary, Karadag, Ayse Serap, additional, Akalın, Ibrahim, additional, Yesil, Gozde, additional, Yılmaz, Sarenur, additional, Zindancı, Ilkin, additional, Uzuncakmak, Tugba Kevser, additional, Ozkanlı, Seyma, additional, and Akdeniz, Necmettin, additional
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- 2019
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56. Phenotypic expansion illuminates multilocus pathogenic variation
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Karaca, Ender, primary, Posey, Jennifer E., additional, Coban Akdemir, Zeynep, additional, Pehlivan, Davut, additional, Harel, Tamar, additional, Jhangiani, Shalini N., additional, Bayram, Yavuz, additional, Song, Xiaofei, additional, Bahrambeigi, Vahid, additional, Yuregir, Ozge Ozalp, additional, Bozdogan, Sevcan, additional, Yesil, Gozde, additional, Isikay, Sedat, additional, Muzny, Donna, additional, Gibbs, Richard A., additional, and Lupski, James R., additional
- Published
- 2018
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57. Parents of ataxia‐telangiectasia patients display a distinct cellular immune phenotype mimicking ATM‐mutated patients.
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Ogulur, Ismail, Ertuzun, Tugce, Kocamis, Burcu, Kendir Demirkol, Yasemin, Uyar, Emel, Kiykim, Ayca, Baser, Dilek, Yesil, Gozde, Akturk, Hacer, Somer, Ayper, Ozen, Ahmet, Karakoc‐Aydiner, Elif, Muftuoglu, Meltem, Baris, Safa, and Atanaskovic‐Markovic, Marina
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DOUBLE-strand DNA breaks ,PHENOTYPES ,PARENTS ,DISEASE relapse ,T cells - Abstract
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 H2O2‐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. [ABSTRACT FROM AUTHOR]
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- 2021
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58. Novel CLPB mutation in a patient with 3-methylglutaconic aciduria causing severe neurological involvement and congenital neutropenia
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Kiykim, Ayca, Garncarz, Wojciech, Karakoc-Aydiner, Elif, Ozen, Ahmet, Kiykim, Ertugrul, Yesil, Gozde, Boztug, Kaan, and Baris, Safa
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- 2016
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59. The Contribution of DTI in Determining the Relationship of Epilepsy and Brain Lesions in Children with Tuberous Sclerosis
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Kurtcan, Serpil, primary, Alkan, Alpay, additional, Guler, Serhat, additional, Yesil, Gozde, additional, Toprak, Huseyin, additional, Tuzun, Umit, additional, Yetis, Huseyin, additional, Aralasmak, Ayse, additional, Ozdemir, Huseyin, additional, and Iscan, Akin, additional
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- 2018
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60. Early diagnosed cerebrotendinous xanthomatosis patients: clinical, neuroradiological characteristics and therapy results of a single center from Turkey
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Zubarioglu, Tanyel, primary, Kiykim, Ertugrul, additional, Yesil, Gozde, additional, Demircioglu, Duhan, additional, Cansever, Mehmet Serif, additional, Yalcinkaya, Cengiz, additional, and Aktuglu-Zeybek, Cigdem, additional
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- 2017
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61. Evaluation of mental retardation - Part 2: The factors that elucidate the etiologic diagnosis of the patients with mental retardation or multiple congenital abnormality and mental retardation
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Yuksel, Adnan, Kayserili, Hulya, Yesil, Gozde, and Apak, Memnune
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Mental retardation -- Diagnosis -- Risk factors -- Research ,Pediatric neurology -- Research ,Diseases -- Causes and theories of causation ,Health - Abstract
Byline: Adnan. Yuksel, Hulya. Kayserili, Gozde. Yesil, Memnune. Apak Two thousand nine hundred and seventy-five patients with mental retardation or multiple congenital anomaly and mental retardation (MR or MCA/MR), who [...]
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- 2007
62. Evaluation of mental retardation - Part 1: Etiologic classification of 4659 patients with mental retardation or multiple congenital abnormality and mental retardation
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Yuksel, Adnan, Kayserili, Hulya, Yesil, Gozde, and Apak, Memnune
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Genetic disorders -- Diagnosis -- Identification and classification -- Research -- Development and progression -- Risk factors ,Mental retardation -- Diagnosis -- Risk factors -- Development and progression -- Identification and classification -- Research ,Pediatric neurology -- Research ,Diseases -- Causes and theories of causation ,Health - Abstract
Byline: Adnan. Yuksel, Hulya. Kayserili, Gozde. Yesil, Memnune. Apak Patients with multiple congenital abnormalities and mental retardation are the most frequent patient group who are referred to a genetic clinic. [...]
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- 2007
63. Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1pathogenic alleles worldwide
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Gonzaga-Jauregui, Claudia, Yesil, Gozde, Nistala, Harikiran, Gezdirici, Alper, Bayram, Yavuz, Nannuru, Kalyan C., Pehlivan, Davut, Yuan, Bo, Jimenez, Johanna, Sahin, Yavuz, Paine, Ingrid S., Akdemir, Zeynep Coban, Rajamani, Saathyaki, Staples, Jeffrey, Dronzek, John, Howell, Kristen, Fatih, Jawid M., Smaldone, Silvia, Schlesinger, Alan E., Ramírez, Norman, Cornier, Alberto S., Kelly, Melissa A., Haber, Robert, Chim, Shek Man, Nieman, Kristy, Wu, Nan, Walls, Johnathon, Poueymirou, William, Siao, Chia-Jen, Sutton, V. Reid, Williams, Marc S., Posey, Jennifer E., Gibbs, Richard A., Carlo, Simon, Tegay, David H., Economides, Aris N., and Lupski, James R.
- Abstract
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 Col27a1and 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 COL27A1pathogenic 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 COL27A1biology 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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- 2020
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64. Congenital Agenesis of Scrotum and Labia Majora in Siblings
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Silay, Mesrur Selcuk, Yesil, Gozde, Yildiz, Kemalettin, Kilincaslan, Huseyin, Ozgen, Ilker Tolga, and Armagan, Abdullah
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- 2013
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65. MRI and MRS findings in fucosidosis; a rare lysosomal storage disease
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Ediz, Suna Sahin, primary, Aralasmak, Ayse, additional, Yilmaz, Temel Fatih, additional, Toprak, Huseyin, additional, Yesil, Gozde, additional, and Alkan, Alpay, additional
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- 2016
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66. Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy
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Harel, Tamar, primary, Yesil, Gozde, additional, Bayram, Yavuz, additional, Coban-Akdemir, Zeynep, additional, Charng, Wu-Lin, additional, Karaca, Ender, additional, Al Asmari, Ali, additional, Eldomery, Mohammad K., additional, Hunter, Jill V., additional, Jhangiani, Shalini N., additional, Rosenfeld, Jill A., additional, Pehlivan, Davut, additional, El-Hattab, Ayman W., additional, Saleh, Mohammed A., additional, LeDuc, Charles A., additional, Muzny, Donna, additional, Boerwinkle, Eric, additional, Gibbs, Richard A., additional, Chung, Wendy K., additional, Yang, Yaping, additional, Belmont, John W., additional, and Lupski, James R., additional
- Published
- 2016
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67. Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease
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Karaca, Ender, primary, Harel, Tamar, additional, Pehlivan, Davut, additional, Jhangiani, Shalini N., additional, Gambin, Tomasz, additional, Coban Akdemir, Zeynep, additional, Gonzaga-Jauregui, Claudia, additional, Erdin, Serkan, additional, Bayram, Yavuz, additional, Campbell, Ian M., additional, Hunter, Jill V., additional, Atik, Mehmed M., additional, Van Esch, Hilde, additional, Yuan, Bo, additional, Wiszniewski, Wojciech, additional, Isikay, Sedat, additional, Yesil, Gozde, additional, Yuregir, Ozge O., additional, Tug Bozdogan, Sevcan, additional, Aslan, Huseyin, additional, Aydin, Hatip, additional, Tos, Tulay, additional, Aksoy, Ayse, additional, De Vivo, Darryl C., additional, Jain, Preti, additional, Geckinli, B. Bilge, additional, Sezer, Ozlem, additional, Gul, Davut, additional, Durmaz, Burak, additional, Cogulu, Ozgur, additional, Ozkinay, Ferda, additional, Topcu, Vehap, additional, Candan, Sukru, additional, Cebi, Alper Han, additional, Ikbal, Mevlit, additional, Yilmaz Gulec, Elif, additional, Gezdirici, Alper, additional, Koparir, Erkan, additional, Ekici, Fatma, additional, Coskun, Salih, additional, Cicek, Salih, additional, Karaer, Kadri, additional, Koparir, Asuman, additional, Duz, Mehmet Bugrahan, additional, Kirat, Emre, additional, Fenercioglu, Elif, additional, Ulucan, Hakan, additional, Seven, Mehmet, additional, Guran, Tulay, additional, Elcioglu, Nursel, additional, Yildirim, Mahmut Selman, additional, Aktas, Dilek, additional, Alikaşifoğlu, Mehmet, additional, Ture, Mehmet, additional, Yakut, Tahsin, additional, Overton, John D., additional, Yuksel, Adnan, additional, Ozen, Mustafa, additional, Muzny, Donna M., additional, Adams, David R., additional, Boerwinkle, Eric, additional, Chung, Wendy K., additional, Gibbs, Richard A., additional, and Lupski, James R., additional
- Published
- 2015
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68. Evaluation of growth and puberty in a child with a novel TBX19gene mutation and review of the literature
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Abali, Zehra, Yesil, Gozde, Kirkgoz, Tarik, Kaygusuz, Sare, Eltan, Mehmet, Turan, Serap, Bereket, Abdullah, and Guran, Tulay
- Abstract
Biallelic mutations in the TBX19gene cause severe early-onset adrenal failure due to isolated ACTH deficiency (IAD). This rare disease is characterized by low plasma ACTH and cortisol levels, with normal secretion of other pituitary hormones. Herein, we report a patient with IAD due to a novel TBX19gene mutation, who is also of tall stature. A 48/12-year-old girl was presented with loss of consciousness due to hypoglycemia. The patient was born at term with a birth weight of 3800 g. Her parents were first-degree cousins. She had a history of several hospitalizations for recurrent seizures, abdominal pain, and vomiting. At presentation, her weight and height were + 1.8 and + 2.2 SDS, respectively. Serum glucose was 25 mg/dl (1.4 mmol/L), with normal sodium, potassium, and insulin concentrations. The child was hypocortisolemic (0.1 μg/dl), and ACTH levels were extremely low (< 5.0 pg/ml). A diagnosis of IAD was made and hydrocortisone treatment was started. Hypoglycemic episodes, seizures, and recurrent gastrointestinal complaints disappeared after hydrocortisone replacement. Magnetic resonance imaging of the pituitary was normal. Whole exome sequencing revealed a novel homozygous c.302G > A (W101*) mutation in the TBX19gene. We report a new mutation in the TBX19gene in a patient with isolated ACTH deficiency. While overgrowth is a known feature of some types of adrenal insufficiencies, including MC2Rgene defects and POMC deficiency, it may be a novel feature for TPIT deficiency, as in our patient.
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- 2019
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69. Homozygous Loss-of-function Mutations inSOHLH1in Patients With Nonsyndromic Hypergonadotropic Hypogonadism
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Bayram, Yavuz, primary, Gulsuner, Suleyman, additional, Guran, Tulay, additional, Abaci, Ayhan, additional, Yesil, Gozde, additional, Gulsuner, Hilal Unal, additional, Atay, Zeynep, additional, Pierce, Sarah B., additional, Gambin, Tomasz, additional, Lee, Ming, additional, Turan, Serap, additional, Bober, Ece, additional, Atik, Mehmed M., additional, Walsh, Tom, additional, Karaca, Ender, additional, Pehlivan, Davut, additional, Jhangiani, Shalini N., additional, Muzny, Donna, additional, Bereket, Abdullah, additional, Buyukgebiz, Atilla, additional, Boerwinkle, Eric, additional, Gibbs, Richard A., additional, King, Mary-Claire, additional, and Lupski, James R., additional
- Published
- 2015
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70. Comparison of metabolic profile and abdominal fat distribution between karyotypically normal women with premature ovarian insufficiency and age matched controls
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Ates, Seda, primary, Yesil, Gozde, additional, Sevket, Osman, additional, Molla, Taner, additional, and Yildiz, Seyma, additional
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- 2014
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71. Human CLP1 Mutations Alter tRNA Biogenesis, Affecting Both Peripheral and Central Nervous System Function
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Karaca, Ender, primary, Weitzer, Stefan, additional, Pehlivan, Davut, additional, Shiraishi, Hiroshi, additional, Gogakos, Tasos, additional, Hanada, Toshikatsu, additional, Jhangiani, Shalini N., additional, Wiszniewski, Wojciech, additional, Withers, Marjorie, additional, Campbell, Ian M., additional, Erdin, Serkan, additional, Isikay, Sedat, additional, Franco, Luis M., additional, Gonzaga-Jauregui, Claudia, additional, Gambin, Tomasz, additional, Gelowani, Violet, additional, Hunter, Jill V., additional, Yesil, Gozde, additional, Koparir, Erkan, additional, Yilmaz, Sarenur, additional, Brown, Miguel, additional, Briskin, Daniel, additional, Hafner, Markus, additional, Morozov, Pavel, additional, Farazi, Thalia A., additional, Bernreuther, Christian, additional, Glatzel, Markus, additional, Trattnig, Siegfried, additional, Friske, Joachim, additional, Kronnerwetter, Claudia, additional, Bainbridge, Matthew N., additional, Gezdirici, Alper, additional, Seven, Mehmet, additional, Muzny, Donna M., additional, Boerwinkle, Eric, additional, Ozen, Mustafa, additional, Clausen, Tim, additional, Tuschl, Thomas, additional, Yuksel, Adnan, additional, Hess, Andreas, additional, Gibbs, Richard A., additional, Martinez, Javier, additional, Penninger, Josef M., additional, and Lupski, James R., additional
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- 2014
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72. Report of a patient with Temple–Baraitser syndrome
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Yesil, Gozde, primary, Guler, Serhat, additional, Yuksel, Adnan, additional, and Alanay, Yasemin, additional
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- 2013
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73. The Effect of Genetic Polymorphisms of Cytochrome P450 CYP2C9, CYP2C19, and CYP2D6 on Drug-Resistant Epilepsy in Turkish Children
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Seven, Mehmet, primary, Batar, Bahadir, additional, Unal, Selin, additional, Yesil, Gozde, additional, Yuksel, Adnan, additional, and Guven, Mehmet, additional
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- 2013
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74. The drug-transporter gene MDR1 C3435T and G2677T/A polymorphisms and the risk of multidrug-resistant epilepsy in Turkish children
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Seven, Mehmet, primary, Batar, Bahadir, additional, Unal, Selin, additional, Yesil, Gozde, additional, Yuksel, Adnan, additional, and Guven, Mehmet, additional
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- 2013
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75. A Novel GJC2 Mutation Associated with Hypomyelination and Müllerian Agenesis Syndrome: Coincidence or a New Entity?
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Yalcinkaya, Cengiz, additional, Erturk, Ozdem, additional, Tuysuz, Beyhan, additional, Yesil, Gozde, additional, Verbeke, Jonathan, additional, Keyser, Britta, additional, Stuhrmann, Manfred, additional, Steinemann, Doris, additional, Sistermans, Erik, additional, and van der Knaap, Marjo, additional
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- 2012
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76. Homozygous Loss-of-function Mutations in SOHLH1in Patients With Nonsyndromic Hypergonadotropic Hypogonadism
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Bayram, Yavuz, Gulsuner, Suleyman, Guran, Tulay, Abaci, Ayhan, Yesil, Gozde, 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, and Lupski, James R.
- Abstract
Context: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: SOHLH1c.705delT (p.Pro235fs*4) and SOHLH1c.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:Sohlh1was 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 SOHLH1cause female nonsyndromic hypergonadotropic hypogonadism.
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- 2015
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77. Functional characterization of <italic>KCNMA1</italic> mutation associated with dyskinesia, seizure, developmental delay, and cerebellar atrophy.
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Yucesan, Emrah, Goncu, Beyza, Ozgul, Cemil, Kebapci, Arda, Aslanger, Ayca Dilruba, Akyuz, Enes, and Yesil, Gozde
- Abstract
Abstract
KCNMA1 located on chromosome 10q22.3, encodes the pore-forming α subunit of the ‘Big K+’ (BK) large conductance calcium and voltage-activated K + channel. Numerous evidence suggests the functional BK channel alterations produced by differentKCNMA1 alleles may associate with different symptoms, such as paroxysmal non kinesigenic dyskinesia with gain of function and ataxia with loss of function. Functional classifications revealed two major patterns, gain of function and loss of function effects on channel properties in different cell lines. In the literature, two mutations have been shown to confer gain of function properties to BK channels: D434G and N995S. In this study, we report the functional characterization of a variant which was previously reported the whole exome sequencing revealed bi-allelic nonsense variation of the cytoplasmic domain of calcium-activated potassium channel subunit alpha-1 protein. To detect functional consequences of the variation, we parallely conducted two independent approaches. One is immunostaining using and the other one is electrophysiological recording using patch-clamp on wild-type and R458X mutant cells to detect the differences between wild-type and the mutant cells. We detected the gain of function effect for the mutation (NM_001161352.1 (ENST00000286628.8):c.1372C > T;Arg458*) using two parallel approaches. According to the result we found, the reported mutation causes the loss of function in the cell. It should be noted that in future studies, it can be thought that the functions of genes associated with channelopathies may have a dual effect such as loss and gain. [ABSTRACT FROM AUTHOR]- Published
- 2023
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78. Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease
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Serap Turan, Zeynep Coban Akdemir, Angad Jolly, Firdevs Bas, Davut Pehlivan, Hadia Hijazi, Zehra Yavas Abali, Tuula Rinne, Jennifer E. Posey, Yavuz Bayram, Tahsin Stefan Barakat, Tulay Tos, Roberto Colombo, Shalini N. Jhangiani, Gozde Yesil, Sukran Poyrazoglu, Zeynep Atay, Alper Gezdirici, James R. Lupski, Donna M. Muzny, Tulay Guran, Zehra Aycan, Richard A. Gibbs, Elif Yilmaz Gulec, Janson White, Serpil Bas, Ender Karaca, Feyza Darendeliler, Abdullah Bereket, Bülent Hacıhamdioğlu, Saygin Abali, İstinye Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Bülent Hacıhamdioğlu / 0000-0001-7070-6429, Hacihamdioglu, Bulent, Bülent Hacıhamdioğlu / GBK-6773-2022, Bülent Hacıhamdioğlu / 22134579900, Clinical Genetics, YEŞİL, Gözde, Jolly, Angad, Bayram, Yavuz, Turan, Serap, Aycan, Zehra, Tos, Tulay, Abali, Zehra Yavas, Akdemir, Zeynep Hande Coban, Hijazi, Hadia, Bas, Serpil, Atay, Zeynep, Guran, Tulay, Abali, Saygin, Bas, Firdevs, Darendeliler, Feyza, Colombo, Roberto, Barakat, Tahsin Stefan, Rinne, Tuula, White, Janson J., Yesil, Gozde, 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., and Lupski, James R.
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MECHANISM ,0301 basic medicine ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,PROTEIN ,Cell Cycle Proteins ,Disease ,Primary Ovarian Insufficiency ,VARIANTS ,Biochemistry ,Cohort Studies ,0302 clinical medicine ,Endocrinology ,Gene Frequency ,Locus heterogeneity ,FAILURE ,Exome sequencing ,Jolly A., Bayram Y., Turan S., Aycan Z., Tos T., Abali Z. Y. , Hacihamdioglu B., Akdemir Z. H. C. , Hijazi H., Bas S., et al., -Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease-, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, cilt.104, ss.3049-3067, 2019 ,Genetics ,030219 obstetrics & reproductive medicine ,Minichromosome Maintenance Proteins ,REARRANGEMENTS ,Oligogenic Inheritance ,DNA-Binding Proteins ,INSIGHTS ,Female ,medicine.medical_specialty ,Immunoglobulins ,Locus (genetics) ,Genomics ,Biology ,03 medical and health sciences ,Hypergonadotropic hypogonadism ,All institutes and research themes of the Radboud University Medical Center ,Internal medicine ,Exome Sequencing ,medicine ,Humans ,HOP2-MND1 ,Settore BIO/10 - BIOCHIMICA ,Allele frequency ,Clinical Research Articles ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,IDENTIFICATION ,MUTATIONS ,Hypogonadism ,Biochemistry (medical) ,DNA Helicases ,medicine.disease ,GENE ,030104 developmental biology ,exome - Abstract
Context: 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. 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. National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); National Heart Lung and Blood Institute (NHBLI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [UM1 HG006542]; National Institute of Neurologic Disorders and Stroke (NINDS)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R35NS105078]; NHGRIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08 HG008986, U54HG003273]; Howard Hughes Medical Research Fellows Program; Baylor College of Medicine Medical Scientist Training Program; Clinical Research Training Scholarship in Neuromuscular Disease; American Academy of Neurology (AAN); American Brain Foundation (ABF); Netherlands Organization for Scientific Research (ZonMW Veni)Netherlands Organization for Scientific Research (NWO) [91617021]; NARSAD Young Investigator Grant from the Brain & Behavior Research FoundationNARSAD; Muscle Study Group (MSG) This study was supported in part by the National Human Genome Research Institute (NHGRI) and National Heart Lung and Blood Institute (NHBLI) to the Baylor-Hopkins Center for Mendelian Genomics (BHCMG; UM1 HG006542 to J.R.L.); NHGRI grant to Baylor College of Medicine Human Genome Sequencing Center (U54HG003273 to R.A.G.), and National Institute of Neurologic Disorders and Stroke (NINDS; R35NS105078 to J.R.L.). J.E.P. was supported by NHGRI K08 HG008986. A.J. was supported in part by the Howard Hughes Medical Research Fellows Program and the Baylor College of Medicine Medical Scientist Training Program. D. P. is supported by Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Academy of Neurology (AAN), American Brain Foundation (ABF), and Muscle Study Group (MSG). T.S.B. was supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021) and by an NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. WOS:000482558500001 31042289 Q1
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- 2019
79. Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.
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Bo Yuan, Pehlivan, Davut, Karaca, Ender, Patel, Nisha, Wu-Lin Charng, Gambin, Tomasz, Gonzaga-Jauregui, Claudia, Sutton, V. Reid, Yesil, Gozde, Bozdogan, Sevcan Tug, Tos, Tulay, Koparir, Asuman, Koparir, Erkan, Beck, Christine R., Shen Gu, Aslan, Huseyin, Yuregir, Ozge Ozalp, Al Rubeaan, Khalid, Alnaqeb, Dhekra, and Alshammari, Muneera J.
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DE Lange's syndrome , *PHENOTYPES , *GENE regulatory networks , *GENETIC disorders , *DEVELOPMENTAL delay - Abstract
Cornelia 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 thecohesin complex, including NIPBL, SMCIA, SMC3, RAD21, and HD ACS. 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 novo 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" ratherthan cohesinopathies. [ABSTRACT FROM AUTHOR]
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- 2015
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80. The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance
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Maja Hempel, Jennifer E. Posey, Yavuz Bayram, Eric Boerwinkle, Katta M. Girisha, Ender Karaca, Timur Yildirim, Anju Shukla, Jaya Punetha, Ilhan A. Bayhan, Harsha Doddapaneni, Christopher M. Grochowski, Davut Gul, Aysegul Bursali, Davut Pehlivan, Elif Yilmaz Gulec, Richard A. Gibbs, Zeynep Ocak, Jawid M Fatih, Ibrahim Sahin, Gozde Yesil, Burhan Balta, Onur Yildiz, Alper Gezdirici, Tatjana Bierhals, James R. Lupski, Zafer Yüksel, Hatice Mutlu Albayrak, Donna M. Muzny, Jianhong Hu, Fatma Silan, Zeynep Coban Akdemir, Shen Gu, Öztürk Özdemir, Haktan Bağış Erdem, Periyasamy Radhakrishnan, Burcu Tabakci, Beyhan Tüysüz, Nilay Güneş, Shalini N. Jhangiani, Osman Yeşilbaş, Yavuz Sahin, Nursel Elcioglu, Muhsin Elmas, Konstantinos Tsiakas, Sedat Isikay, 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, Yesil, Gozde, 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., HKÜ, Sağlık Bilimleri Fakültesi, Fizyoterapi ve Rehabilitasyon Bölümü, YEŞİL, Gözde, İÜC, Cerrahpaşa Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, and OMÜ
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Male ,0301 basic medicine ,Multifactorial Inheritance ,Candidate gene ,Vesicular Transport Proteins ,DE-NOVO ,DISEASE ,Cohort Studies ,MYOPATHY ,MULTIPLEX CONGENITA ,SKELETAL-MUSCLE ,MUTATIONS ,PATIENT ,FAT1 ,MECHANISMS ,DELETION ,0302 clinical medicine ,Candidate Genes and Further Evidence for Oligogenic Inheritance-, AMERICAN JOURNAL OF HUMAN GENETICS, cilt.105, ss.132-150, 2019 [Pehlivan D., Bayram Y., Gunes N., Akdemir Z. C. , Shukla A., Bierhals T., TABAKCI B., Sahin Y., Gezdirici A., Fatih J. M. , et al., -The Genomics of Arthrogryposis, a Complex Trait] ,Connectin ,Copy-number variation ,Child ,Genetics (clinical) ,Exome sequencing ,Arthrogryposis ,Genetics ,Mosaicism ,Oligogenic Inheritance ,Genomics ,Pedigree ,3. Good health ,Child, Preschool ,Female ,medicine.symptom ,Adult ,Genetic Markers ,Adolescent ,DNA Copy Number Variations ,Gestational Age ,Locus (genetics) ,Biology ,Article ,Young Adult ,03 medical and health sciences ,Exome Sequencing ,medicine ,Humans ,Genetic heterogeneity ,Infant, Newborn ,Infant ,Ryanodine Receptor Calcium Release Channel ,030104 developmental biology ,Mutation ,030217 neurology & neurosurgery ,Comparative genomic hybridization - Abstract
Erdem, Haktan Bagis/0000-0002-4391-1387; Albayrak, Hatice Mutlu/0000-0001-5624-3878; isikay, sedat/0000-0003-0103-9612; Grochowski, Christopher/0000-0002-3884-7720; Gezdirici, Alper/0000-0002-2432-9279; KM, Girisha/0000-0002-0139-8239; Gu, Shen/0000-0003-3107-1218; YESIL, GOZDE/0000-0003-1964-6306; Gezdirici, Alper/0000-0002-2432-9279; Tuysuz, Beyhan/0000-0002-9620-5021; Fatih, Jawid/0000-0002-3927-2711; YUKSEL, Zafer/0000-0002-2085-5773; Balta, Burhan/0000-0003-2672-2493; Posey, Jennifer/0000-0003-4814-6765; Bayhan, Ilhan/0000-0001-8308-1309; Punetha, Jaya/0000-0002-6774-4464; YILDIRIM, Timur/0000-0003-0291-7632 WOS:000473723000011 PubMed ID: 31230720 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. National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [UM1 HG006542]; National Heart, Lung, and Blood Institute (NHLBI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [UM1 HG006542]; NHGRIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08 HG008986]; National Institutes of Health - Brain Disorders and Development Training Grant [T32 NS043124-17]; Clinical Research Training Scholarship in Neuromuscular Disease; Tubitak project, TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [217S675]; Indian Council of Medical Research, New Delhi, IndiaIndian Council of Medical Research (ICMR) [5/13/58/2015/NCD-III]; [R35 NS105078]; [512848]; NATIONAL HUMAN GENOME RESEARCH INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08HG008986, UM1HG006542, K08HG008986, UM1HG006542, UM1HG006542, UM1HG006542, K08HG008986, UM1HG006542] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R35NS105078, T32NS043124, T32NS043124, T32NS043124, R35NS105078, T32NS043124, T32NS043124, R35NS105078, T32NS043124, T32NS043124, T32NS043124, R35NS105078] Funding Source: NIH RePORTER This work was supported in part by R35 NS105078 and MDA#512848 to J.R.L. and a jointly funded National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) grant to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542). J.E.P. is supported by NHGRI K08 HG008986. D.P. is supported by the National Institutes of Health - Brain Disorders and Development Training Grant (T32 NS043124-17) and a Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Brain Foundation (ABF) and Muscle Study Group (MSG). This study is partly funded by Tubitak project number 217S675, Turkey to N.E. and B.T.. This study is partly funded by Indian Council of Medical Research, New Delhi, India with File no.: No. 5/13/58/2015/NCD-III to A.S.
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- 2019
81. Homozygous Loss-of-function Mutations inSOHLH1in Patients With Nonsyndromic Hypergonadotropic Hypogonadism
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Ming Lee, Tom Walsh, Mehmed M. Atik, Yavuz Bayram, Serap Turan, Davut Pehlivan, Tulay Guran, Ece Böber, Mary Claire King, Richard A. Gibbs, Hilal Unal Gulsuner, James R. Lupski, Ayhan Abaci, Ender Karaca, Suleyman Gulsuner, Sarah B. Pierce, Gozde Yesil, Atilla Büyükgebiz, Shalini N. Jhangiani, Abdullah Bereket, Tomasz Gambin, Donna M. Muzny, Eric Boerwinkle, Zeynep Atay, Bayram, Yavuz, Gulsuner, Suleyman, Guran, Tulay, Abaci, Ayhan, Yesil, Gozde, 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., and YEŞİL, Gözde
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endocrine system ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,TRANSFER-RNA SYNTHETASE ,Context (language use) ,Biology ,Biochemistry ,PREMATURE OVARIAN FAILURE ,Endocrinology ,Hypergonadotropic hypogonadism ,Internal medicine ,Basic Helix-Loop-Helix Transcription Factors ,medicine ,Humans ,Exome ,TRANSCRIPTION FACTOR ,Child ,Loss function ,Exome sequencing ,GENE-EXPRESSION ,JCEM Online: Advances in Genetics ,HEARING-LOSS ,Hypogonadism ,SOHLH1 ,Homozygote ,Biochemistry (medical) ,PERRAULT SYNDROME ,OOGENESIS ,medicine.disease ,Sex steroid ,Mutation ,Chromosome abnormality ,FOLLICULOGENESIS ,Female ,Gonadotropin ,STEM-CELLS ,DYSGENESIS - Abstract
Copyright © 2015 by the Endocrine Society.Context: 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.
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- 2015
82. Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease
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Asuman Koparir, Ender Karaca, Tulay Guran, Nursel Elcioglu, Salih Coşkun, Özlem Sezer, Sevcan Tug Bozdogan, Alper Han Cebi, Jill V. Hunter, James R. Lupski, Shalini N. Jhangiani, Sedat Işıkay, Hatip Aydin, Erkan Koparir, Dilek Aktas, Adnan Yuksel, Davut Gul, Mehmed M. Atik, Burak Durmaz, Mehmet Ture, Ian M. Campbell, Wendy K. Chung, Tamar Harel, Emre Kirat, Mahmut Selman Yildirim, Ayse Aksoy, Mehmet Bugrahan Duz, John D. Overton, Tulay Tos, Claudia Gonzaga-Jauregui, Darryl C. De Vivo, Yavuz Bayram, Kadri Karaer, Gozde Yesil, Wojciech Wiszniewski, Davut Pehlivan, Eric Boerwinkle, Huseyin Aslan, Hakan Ulucan, Ozgur Cogulu, Fatma Ekici, Vehap Topcu, Elif Fenercioglu, Mehmet Seven, Alper Gezdirici, Salih Cicek, Tomasz Gambin, Tahsin Yakut, Mustafa Ozen, Mevlit Ikbal, Donna M. Muzny, Zeynep Coban Akdemir, Elif Yilmaz Gulec, Preti Jain, Bilge Geckinli, Sukru Candan, Richard A. Gibbs, Serkan Erdin, Mehmet Alikasifoglu, Ozge Ozalp Yuregir, Ferda Ozkinay, Hilde Van Esch, David R. Adams, Bo Yuan, YEŞİL, Gözde, Ege Üniversitesi, Biruni Üniversitesi, 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., and Lupski, James R.
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Male ,PONTOCEREBELLAR HYPOPLASIA ,Candidate gene ,Rna Helicases ,PROTEIN ,Cohort Studies ,0302 clinical medicine ,Snx14 Cause ,Databases, Genetic ,Gene Regulatory Networks ,Copy-number variation ,Pontocerebellar Hypoplasia ,Exome sequencing ,Alzheimers-Disease ,Genetics ,0303 health sciences ,H-Prune ,General Neuroscience ,Brain ,Mendelian Randomization Analysis ,Neurologic Disease ,Pedigree ,3. Good health ,ALZHEIMERS-DISEASE ,H-PRUNE ,symbols ,Female ,Mutations ,Neuroscience(all) ,SNX14 CAUSE ,Biology ,TRIPLE T COMPLEX ,Article ,03 medical and health sciences ,symbols.namesake ,Genetic variation ,CHROMATIN REMODELING COMPLEX ,Humans ,Allele ,Gene ,Genetic Association Studies ,030304 developmental biology ,RNA HELICASES ,MUTATIONS ,Protein ,Genetic Variation ,Triple T Complex ,INTELLECTUAL-DISABILITY SYNDROME ,Intellectual-Disability Syndrome ,Mendelian inheritance ,Chromatin Remodeling Complex ,Nervous System Diseases ,030217 neurology & neurosurgery - Abstract
WOS: 000365765400011, PubMed ID: 26539891, Development 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., U.S. National Human Genome Research Institute (NHGRI) NHLBI grant [U54HG006542]; NINDSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [RO1 NS058529, K23NS078056]; NHGRIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [5U54HG003273]; Medical Genetics Research Fellowship Program [T32 GM07526]; Regeneron, We thank all the family members and collaborators who participated in this study. This work was supported by U.S. National Human Genome Research Institute (NHGRI) NHLBI grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, NINDS grant RO1 NS058529 to J. R. L., and NHGRI 5U54HG003273 to R. A. G. T. H. is supported by the Medical Genetics Research Fellowship Program (T32 GM07526). W. W. is supported by Career Development Award K23NS078056 from NINDS. The authors would like to thank the ExAC and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. J.R.L. has stock ownership in 23andMe and Lasergen and is a paid consultant for Regeneron. J. R. L. is also a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Medical Genetics Laboratory (https://www.bcm.edu/geneticlabs/). W. K. C. is a paid consultant for Regeneron and BioReference Laboratories. C.G.-J. and J. D. O. are employees of the RGC.
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83. Clinical and Molecular Spectrum of Autosomal Recessive CA8-Related Cerebellar Ataxia.
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Kaiyrzhanov R, Ortigoza-Escobar JD, Stringer BW, Ganieva M, Gowda VK, Srinivasan VM, Macaya A, Laner A, Onbool E, Al-Shammari R, Al-Owain M, Deconinck N, Vilain C, Dontaine P, Self E, Akram R, Hussain G, Baig SM, Iqbal J, Salpietro V, Neshatdoust M, Kasiri M, Yesil G, Uygur T, Pysden K, Berry IR, Alves CA, Giacomotto J, Houlden H, and Maroofian R
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- Humans, Child, Adolescent, Male, Female, Child, Preschool, Animals, Adult, Young Adult, Anoctamins genetics, Intellectual Disability genetics, Phenotype, Neurodevelopmental Disorders genetics, Cerebellar Ataxia genetics, Zebrafish
- Abstract
Background: Based on a limited number of reported families, biallelic CA8 variants have currently been associated with a recessive neurological disorder named, cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CAMRQ-3)., Objectives: We aim to comprehensively investigate CA8-related disorders (CA8-RD) by reviewing existing literature and exploring neurological, neuroradiological, and molecular observations in a cohort of newly identified patients., Methods: We analyzed the phenotype of 27 affected individuals from 14 families with biallelic CA8 variants (including data from 15 newly identified patients from eight families), ages 4 to 35 years. Clinical, genetic, and radiological assessments were performed, and zebrafish models with ca8 knockout were used for functional analysis., Results: Patients exhibited varying degrees of neurodevelopmental disorders (NDD), along with predominantly progressive cerebellar ataxia and pyramidal signs and variable bradykinesia, dystonia, and sensory impairment. Quadrupedal gait was present in only 10 of 27 patients. Progressive selective cerebellar atrophy, predominantly affecting the superior vermis, was a key diagnostic finding in all patients. Seven novel homozygous CA8 variants were identified. Zebrafish models demonstrated impaired early neurodevelopment and motor behavior on ca8 knockout., Conclusion: Our comprehensive analysis of phenotypic features indicates that CA8-RD exhibits a wide range of clinical manifestations, setting it apart from other subtypes within the category of CAMRQ. CA8-RD is characterized by cerebellar atrophy and should be recognized as part of the autosomal-recessive cerebellar ataxias associated with NDD. Notably, the presence of progressive superior vermis atrophy serves as a valuable diagnostic indicator. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
- Published
- 2024
- Full Text
- View/download PDF
84. Autism Spectrum Disorder in Two Unrelated Patients with Homozygous Variants in Either ALG8 or ALG11.
- Author
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Uzunyayla-Inci G, Kiykim E, Zubarioglu T, Yesil G, and Aktuglu Zeybek C
- Abstract
Background: Autism spectrum disorder (ASD) is used to describe individuals with a specific combination of disorders in social communication and repetitive behaviors, highly restricted interests, and/or sensory behavior that begin early in life. The prevalence of ASD has been increasing rapidly in recent years. Pathophysiology of ASDs remains still unclear; however, genetic defects and multifactorial causes have been reported to play an important role in genetic disorders. The prevalence of inborn errors of metabolism (IEM) reported among patients with ASD is 2-5%. The clinical presentation of congenital disorders of glycosylation (CDG) may be in the form of psychiatric disorder only., Case Study: Case 1: a 5-year-old female patient was admitted for investigation of ASD. She had a dysmorphic facial appearance, inverted nipples, abnormal fat distribution, ataxic gait, and autistic features. Her transferrin isoelectric focusing test was compatible with a type 1 CDG pattern. A homozygous variant in ALG8 gene revealed the diagnosis of ALG8-CDG (CDG Type 1H). Case 2: a 2-year-old male patient was admitted with complaints of ASD for investigation of an underlying IEM due to speech delay. Physical examination revealed hypertelorism, small hands, and autistic behavior. Transferrin isoelectric focusing test was also found normal. As a result of the WES, a homozygous variant was detected in ALG11 confirming the diagnosis of CDG type 1p., Conclusion: CDG should also be considered in the differential diagnosis of autistic patients with dysmorphic findings. The aim of our study was to emphasize that autism should be listed among the neurological findings of CDG., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 S. Karger AG, Basel.)
- Published
- 2023
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85. Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.
- Author
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Gonzaga-Jauregui C, Yesil G, Nistala H, Gezdirici A, Bayram Y, Nannuru KC, Pehlivan D, Yuan B, Jimenez J, Sahin Y, Paine IS, Akdemir ZC, Rajamani S, Staples J, Dronzek J, Howell K, Fatih JM, Smaldone S, Schlesinger AE, Ramírez N, Cornier AS, Kelly MA, Haber R, Chim SM, Nieman K, Wu N, Walls J, Poueymirou W, Siao CJ, Sutton VR, Williams MS, Posey JE, Gibbs RA, Carlo S, Tegay DH, Economides AN, and Lupski JR
- Subjects
- Abnormalities, Multiple pathology, Adolescent, Animals, Bone Development, Child, Child, Preschool, Consanguinity, Extracellular Matrix metabolism, Extracellular Matrix pathology, Female, Fibrillar Collagens metabolism, Gene Frequency, Hip Dislocation pathology, Homozygote, Humans, Male, Mice, Mice, Inbred C57BL, Mutation, Pedigree, Scoliosis pathology, Syndrome, Abnormalities, Multiple genetics, Fibrillar Collagens genetics, Founder Effect, Hip Dislocation genetics, Scoliosis genetics
- Abstract
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.
- Published
- 2020
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86. Correlation Between DTI Findings and Volume of Corpus Callosum in Children with AUTISM.
- Author
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Temur HO, Yurtsever I, Yesil G, Sharifov R, Yilmaz FT, Dundar TT, and Alkan A
- Subjects
- Child, Child, Preschool, Correlation of Data, Female, Humans, Male, Organ Size, Autism Spectrum Disorder diagnostic imaging, Corpus Callosum anatomy & histology, Corpus Callosum diagnostic imaging, Diffusion Tensor Imaging
- Abstract
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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2019
- Full Text
- View/download PDF
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