Keren Rotshenker-Olshinka1,2,3, Naama Srebnik Moshe4,5, Omri Weiss5,6, Shira Shaviv5,7, Orit Freireich5,7, Reeval Segel5,7, Sharon Zeligson5,7, Talia Eldar-Geva4,5, Gheona Altarescu5,7. 1. Reproductive Endocrinology and Genetics Unit, IVF Unit, Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem, Israel. Kerenlogic@gmail.com. 2. Faculty of Medicine, Hebrew University, Jerusalem, Israel. Kerenlogic@gmail.com. 3. Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, McGill University, Montréal, Quebec, H3A 0G4, Canada. Kerenlogic@gmail.com. 4. Reproductive Endocrinology and Genetics Unit, IVF Unit, Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem, Israel. 5. Faculty of Medicine, Hebrew University, Jerusalem, Israel. 6. Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel. 7. ZOHAR PGD Unit, Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
Abstract
PURPOSE: To review cases of couples presented to our PGT-unit with copy number variants (CNVs) classified as variants of uncertain significance (VUS) in order to better understand their needs. METHODS: Retrospective cohort study conducted in a tertiary medical-center, 2014-2019. We reviewed files of all couples applying for genetic counseling with CNVs classified as VUS. The main outcomes measured: number of VUS findings and their description, PGT-M procedures planned and performed, IVF cycles, clinical pregnancy, and live birth rates (LBR). VUS were classified according to the American-College of Medical-Genetics and Genomics classification at time of first consultation, and updated-December 2018. RESULTS: Twenty-four couples presented with a total of 30 VUS. Twelve couples (50%) had isolated VUS and 12 (50%) had VUS diagnosed in addition to a pathogenic mutation. Initially, nine findings (30%) were defined as VUS; eight (27%) as likely benign (b-VUS); and 13 (43%) as likely pathogenic (p-VUS). PGT-M was recommended for 17/30 CNVs (56.6%), 12 (70%) of which, isolated VUS. No couple had other indications for IVF. To date, nine couples performed PGT-M for isolated VUS; LBR per-couple-55.5%. Five couples performed PGT-M for both pathogenic findings and VUS, LBR-80%. After reviewing VUS classifications, 30% remained unchanged, 20% were more severely defined, and 50% less severely defined. CONCLUSION: The genomic era enables detection of VUS whose definition is subject to change as additional information becomes available. The uncertainty of variants' clinical significance and changes in VUS definition over time complicates genetic counseling. Revised guidelines for VUS interpretation and reevaluation of patient counseling before each pregnancy must be practiced when counseling them regarding the justification of PGT-M for their diagnosed VUS.
PURPOSE: To review cases of couples presented to our PGT-unit with copy number variants (CNVs) classified as variants of uncertain significance (VUS) in order to better understand their needs. METHODS: Retrospective cohort study conducted in a tertiary medical-center, 2014-2019. We reviewed files of all couples applying for genetic counseling with CNVs classified as VUS. The main outcomes measured: number of VUS findings and their description, PGT-M procedures planned and performed, IVF cycles, clinical pregnancy, and live birth rates (LBR). VUS were classified according to the American-College of Medical-Genetics and Genomics classification at time of first consultation, and updated-December 2018. RESULTS: Twenty-four couples presented with a total of 30 VUS. Twelve couples (50%) had isolated VUS and 12 (50%) had VUS diagnosed in addition to a pathogenic mutation. Initially, nine findings (30%) were defined as VUS; eight (27%) as likely benign (b-VUS); and 13 (43%) as likely pathogenic (p-VUS). PGT-M was recommended for 17/30 CNVs (56.6%), 12 (70%) of which, isolated VUS. No couple had other indications for IVF. To date, nine couples performed PGT-M for isolated VUS; LBR per-couple-55.5%. Five couples performed PGT-M for both pathogenic findings and VUS, LBR-80%. After reviewing VUS classifications, 30% remained unchanged, 20% were more severely defined, and 50% less severely defined. CONCLUSION: The genomic era enables detection of VUS whose definition is subject to change as additional information becomes available. The uncertainty of variants' clinical significance and changes in VUS definition over time complicates genetic counseling. Revised guidelines for VUS interpretation and reevaluation of patient counseling before each pregnancy must be practiced when counseling them regarding the justification of PGT-M for their diagnosed VUS.
Entities:
Keywords:
Copy number variants (CNVs); In vitro fertilization (IVF); PGT for monogenic disorders (PGT-M); Preimplantation genetic testing (PGT); Variants of uncertain significance (VUS)