Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions

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)...

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Veröffentlicht in:Genetics in medicine 2019-02, Vol.21 (2), p.417-425
Hauptverfasser: Leach, N. T., Wilson Mathews, D. R., Rosenblum, L. S., Zhou, Z., Zhu, H., Heim, R. A.
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Sprache:eng
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Zusammenfassung: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.
ISSN:1098-3600
1530-0366
DOI:10.1038/s41436-018-0062-0