Mariya S Balashova1, Inna G Tuluzanovskaya2, Oleg S Glotov3, Andrey S Glotov3, Yury A Barbitoff4, Mikhail A Fedyakov5, Diana A Alaverdian6, Tatiana E Ivashchenko7, Olga V Romanova8, Andrey M Sarana5, Sergey G Scherbak5, Vladislav S Baranov9, Marat I Filimonov2, Anatoly V Skalny10, Natalya A Zhuchenko2, Tatiana M Ignatova11, Aliy Y Asanov2. 1. Sechenov First Moscow State Medical University, Moscow, Russia; Center of Genetics and Reproductive Medicine «Genetico», Moscow, Russia. Electronic address: skalny3@microelements.ru. 2. Sechenov First Moscow State Medical University, Moscow, Russia. 3. D.O.Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russia; St.Petersburg State Health Care Establishment the City Hospital №40, St. Petersburg, Russia; Saint Petersburg State University, St. Petersburg, Russia. 4. Saint Petersburg State University, St. Petersburg, Russia; Bioinformatics Institute, St. Petersburg, Russia. 5. St.Petersburg State Health Care Establishment the City Hospital №40, St. Petersburg, Russia; Saint Petersburg State University, St. Petersburg, Russia. 6. St.Petersburg State Health Care Establishment the City Hospital №40, St. Petersburg, Russia. 7. D.O.Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russia. 8. D.O.Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russia; St.Petersburg State Health Care Establishment the City Hospital №40, St. Petersburg, Russia. 9. D.O.Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russia; Saint Petersburg State University, St. Petersburg, Russia. 10. Sechenov First Moscow State Medical University, Moscow, Russia; Taipei Medical University, Taipei, Taiwan. 11. Center of Endosurgery and Lithotripsy (CELT), Moscow, Russia; Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow, Russia.
Abstract
BACKGROUND: Wilson's disease (WD) is a rare inherited disorder caused by mutations in the ATP7B gene resulting in copper accumulation in different organs. However, data on ATP7B mutation spectrum in Russia and worldwide are insufficient and contradictory. The objective of the present study was estimation of the frequency of ATP7B gene mutations in the Russian population of WD patients. MATERIALS AND METHODS: 75 WDpatients were examined by next-generation sequencing (NGS). A targeted panel NimbleGen SeqCap EZ Choice: 151012_HG38_CysFib_EZ_HX3 (ROCHE)was designed for analysis of ATP7B gene and possible modifier genes. Retrospective assessment of a diagnostic WD score (Leipzig, 2001) was also performed. RESULTS: 31 mutations in ATP7B gene were detected. Two most frequent mutations were c.3207C > A (51,85% of alleles) and c.3190 G > A (8,64% of alleles). Single rare mutations were detected in 29% of cases. In 96% cases mutations of both copies of the ATP7B were revealed. We also observed 3 novel potentially pathogenic variants which were not previously described (c.1870-8A > G, c.3655A > T (p.Ile1219Phe), c.3036dupC (p.Lys1013fs). For 25% of patients at the time of the manifestation the diagnosis WD could not be established using the earlier proposed diagnostic score. There was a remarkable delay in diagnosis for the majority of patients. Only 33% of patients WD was diagnosed in three months after the first symptoms, 29%patients - in 3-12 months, 30% - in 1-10 years, in 8% - more than 10 years. Generally, clinical appearance of WD may be rather variable at manifestation and genetic profiling at this step is the only way to confirm the presence of WD.
BACKGROUND:Wilson's disease (WD) is a rare inherited disorder caused by mutations in the ATP7B gene resulting in copper accumulation in different organs. However, data on ATP7B mutation spectrum in Russia and worldwide are insufficient and contradictory. The objective of the present study was estimation of the frequency of ATP7B gene mutations in the Russian population of WDpatients. MATERIALS AND METHODS: 75 WDpatients were examined by next-generation sequencing (NGS). A targeted panel NimbleGen SeqCap EZ Choice: 151012_HG38_CysFib_EZ_HX3 (ROCHE)was designed for analysis of ATP7B gene and possible modifier genes. Retrospective assessment of a diagnostic WD score (Leipzig, 2001) was also performed. RESULTS: 31 mutations in ATP7B gene were detected. Two most frequent mutations were c.3207C > A (51,85% of alleles) and c.3190 G > A (8,64% of alleles). Single rare mutations were detected in 29% of cases. In 96% cases mutations of both copies of the ATP7B were revealed. We also observed 3 novel potentially pathogenic variants which were not previously described (c.1870-8A > G, c.3655A > T (p.Ile1219Phe), c.3036dupC (p.Lys1013fs). For 25% of patients at the time of the manifestation the diagnosis WD could not be established using the earlier proposed diagnostic score. There was a remarkable delay in diagnosis for the majority of patients. Only 33% of patientsWD was diagnosed in three months after the first symptoms, 29%patients - in 3-12 months, 30% - in 1-10 years, in 8% - more than 10 years. Generally, clinical appearance of WD may be rather variable at manifestation and genetic profiling at this step is the only way to confirm the presence of WD.
Authors: Juan Benito-Lozano; Greta Arias-Merino; Mario Gómez-Martínez; Alba Ancochea-Díaz; Aitor Aparicio-García; Manuel Posada de la Paz; Verónica Alonso-Ferreira Journal: Int J Environ Res Public Health Date: 2022-05-26 Impact factor: 4.614