Svetlana A Yatsenko1,2,3, Fatih Gurbuz4, Ali Kemal Topaloglu4,5, Andrea J Berman6, Pierre-Marie Martin7, Marta Rodrigue-Escribà8, Yingying Qin9, Aleksandar Rajkovic7,8,10. 1. Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213,USA. 2. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15213,USA. 3. Magee-Womens Research Institute, Pittsburgh, PA 15213,USA. 4. Division of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, Adana 1380,Turkey. 5. Division of Pediatric Endocrinology, University of Mississippi Medical Center, Jackson, MS 39216,USA. 6. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15213,USA. 7. Institute of Human Genetics, University of California San Francisco, San Francisco, CA 94143,USA. 8. Department of Pathology, University of California San Francisco, San Francisco, CA 94143,USA. 9. Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan Shandong 250100, China. 10. Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143,USA.
Abstract
CONTEXT: Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers. OBJECTIVE: We sought to identify and characterize patients affected by POI caused by pathogenic variants in genes involved in DNA damage response during meiosis. SETTING: Study subjects were recruited at academic centers. PATIENTS OR OTHER PARTICIPANTS: Individuals with a diagnosis of POI and their family members were enrolled for genetic analysis. Clinical findings, family history, and peripheral blood samples were collected. RESEARCH DESIGN: Exome sequencing was performed on the study participants and their family members (when available). Protein conservation analysis and in silico modeling were used to obtain the structural model of the detected variants in the ZSWIM7 gene. MAIN OUTCOME MEASURE(S): Rare deleterious variants in known and candidate genes associated with POI. RESULTS: Homozygous deleterious variants in the ZSWIM7 gene were identified in 2 unrelated patients with amenorrhea, an absence of puberty, and prepubertal ovaries and uterus. Observed variants were shown to alter the ZSWIM7 DNA-binding region, possibly affecting its function. CONCLUSIONS: Our study highlights the pivotal role of the ZSWIM7 gene involved in DNA damage response during meiosis on ovarian development and function. Characterization of patients with defects in DNA repair genes has important diagnostic and prognostic consequences for clinical management and reproductive decisions.
CONTEXT: Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers. OBJECTIVE: We sought to identify and characterize patients affected by POI caused by pathogenic variants in genes involved in DNA damage response during meiosis. SETTING: Study subjects were recruited at academic centers. PATIENTS OR OTHER PARTICIPANTS: Individuals with a diagnosis of POI and their family members were enrolled for genetic analysis. Clinical findings, family history, and peripheral blood samples were collected. RESEARCH DESIGN: Exome sequencing was performed on the study participants and their family members (when available). Protein conservation analysis and in silico modeling were used to obtain the structural model of the detected variants in the ZSWIM7 gene. MAIN OUTCOME MEASURE(S): Rare deleterious variants in known and candidate genes associated with POI. RESULTS: Homozygous deleterious variants in the ZSWIM7 gene were identified in 2 unrelated patients with amenorrhea, an absence of puberty, and prepubertal ovaries and uterus. Observed variants were shown to alter the ZSWIM7 DNA-binding region, possibly affecting its function. CONCLUSIONS: Our study highlights the pivotal role of the ZSWIM7 gene involved in DNA damage response during meiosis on ovarian development and function. Characterization of patients with defects in DNA repair genes has important diagnostic and prognostic consequences for clinical management and reproductive decisions.
Authors: Aaron McKenna; Matthew Hanna; Eric Banks; Andrey Sivachenko; Kristian Cibulskis; Andrew Kernytsky; Kiran Garimella; David Altshuler; Stacey Gabriel; Mark Daly; Mark A DePristo Journal: Genome Res Date: 2010-07-19 Impact factor: 9.043
Authors: Michelle A Wood-Trageser; Fatih Gurbuz; Svetlana A Yatsenko; Elizabeth P Jeffries; L Damla Kotan; Urvashi Surti; Deborah M Ketterer; Jelena Matic; Jacqueline Chipkin; Huaiyang Jiang; Michael A Trakselis; A Kemal Topaloglu; Aleksandar Rajkovic Journal: Am J Hum Genet Date: 2014-12-04 Impact factor: 11.025
Authors: Saleh AlAsiri; Sulman Basit; Michelle A Wood-Trageser; Svetlana A Yatsenko; Elizabeth P Jeffries; Urvashi Surti; Deborah M Ketterer; Sibtain Afzal; Khushnooda Ramzan; Muhammad Faiyaz-Ul Haque; Huaiyang Jiang; Michael A Trakselis; Aleksandar Rajkovic Journal: J Clin Invest Date: 2014-12-01 Impact factor: 14.808
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