N T Leach1, D R Wilson Mathews2, L S Rosenblum2, Z Zhou2, H Zhu2, R A Heim2. 1. Integrated Genetics, Laboratory Corporation of America Holdings, 3400 Computer Drive, Westborough, Massachusetts, USA. Natalia.Leach@integratedgenetics.com. 2. Integrated Genetics, Laboratory Corporation of America Holdings, 3400 Computer Drive, Westborough, Massachusetts, USA.
Abstract
PURPOSE: To compare the pattern of gene-specific involvement and the spectrum of variants observed in prenatal and postnatal (mean ± SD, 8.9 ± 9.4 years) cohorts tested for Noonan syndrome and related conditions. METHODS: Outcomes of sequencing panel testing were compared between prenatal (n = 845) and postnatal (n = 409) cohorts. RESULTS: PTPN11 and SOS1 harbored the majority of observed variants in both prenatal and postnatal cohorts, and BRAF, HRAS, KRAS, MAP2K1, MAP2K2, RAF1, and SHOC2 had similarities in their pattern of involvement in both cohorts. PTPN11 was the largest contributor of pathogenic variants and had the lowest frequency of variants of uncertain significance (VUS). SOS1 had the highest VUS frequency in both cohorts. The overall VUS frequency was twice as high in prenatal specimens (58.1 vs. 29.3%). PTPN11 and SOS1 had a 1.5-fold higher VUS frequency in the prenatal cohort (10.7 vs. 7.4% and 95 vs. 61.1%, respectively). The diagnostic yield was 3.7% for prenatal samples, with a higher yield of 12.3% in fetuses with cystic hygroma as a sole finding, and 21.3% for postnatal. CONCLUSION: Comparison of prenatal versus postnatal specimens demonstrates that the pattern of specific gene involvement is similar, whereas the classification spectrum of observed variants differs considerably.
PURPOSE: To compare the pattern of gene-specific involvement and the spectrum of variants observed in prenatal and postnatal (mean ± SD, 8.9 ± 9.4 years) cohorts tested for Noonan syndrome and related conditions. METHODS: Outcomes of sequencing panel testing were compared between prenatal (n = 845) and postnatal (n = 409) cohorts. RESULTS: PTPN11 and SOS1 harbored the majority of observed variants in both prenatal and postnatal cohorts, and BRAF, HRAS, KRAS, MAP2K1, MAP2K2, RAF1, and SHOC2 had similarities in their pattern of involvement in both cohorts. PTPN11 was the largest contributor of pathogenic variants and had the lowest frequency of variants of uncertain significance (VUS). SOS1 had the highest VUS frequency in both cohorts. The overall VUS frequency was twice as high in prenatal specimens (58.1 vs. 29.3%). PTPN11 and SOS1 had a 1.5-fold higher VUS frequency in the prenatal cohort (10.7 vs. 7.4% and 95 vs. 61.1%, respectively). The diagnostic yield was 3.7% for prenatal samples, with a higher yield of 12.3% in fetuses with cystic hygroma as a sole finding, and 21.3% for postnatal. CONCLUSION: Comparison of prenatal versus postnatal specimens demonstrates that the pattern of specific gene involvement is similar, whereas the classification spectrum of observed variants differs considerably.
Authors: Karen W Gripp; Lisa Schill; Lisa Schoyer; Beth Stronach; Anton M Bennett; Susan Blaser; Amanda Brown; Rebecca Burdine; Emma Burkitt-Wright; Pau Castel; Sandra Darilek; Alwyn Dias; Tuesdi Dyer; Michelle Ellis; Gregg Erickson; Bruce D Gelb; Tamar Green; Andrea Gross; Alan Ho; James Lloyd Holder; Shin-Ichi Inoue; Angie C Jelin; Annie Kennedy; Richard Klein; Maria I Kontaridis; Pilar Magoulas; Darryl B McConnell; Frank McCormick; Benjamin G Neel; Carlos E Prada; Katherine A Rauen; Amy Roberts; Pablo Rodriguez-Viciana; Neal Rosen; Gavin Rumbaugh; Anna Sablina; Maja Solman; Marco Tartaglia; Angelica Thomas; William C Timmer; Kartik Venkatachalam; Karin S Walsh; Pamela L Wolters; Jae-Sung Yi; Martin Zenker; Nancy Ratner Journal: Am J Med Genet A Date: 2019-12-11 Impact factor: 2.802
Authors: Mary E Norton; Jessica Van Ziffle; Billie R Lianoglou; Ugur Hodoglugil; W Patrick Devine; Teresa N Sparks Journal: Am J Obstet Gynecol Date: 2021-07-28 Impact factor: 8.661