Abstract: Multi-Gene Testing For Noonan Spectrum Disorders In A Prenatal Setting
Meeting: ISPD 2012; Miami, FL
Presenter(s): E. Kramer, B. Williams, D. Goldberg-Strassler, A. Frayna, S. Han, L. Vincent, I. Olivos-Glander, K. Hruska, S. Aradhya, J. Meck, G. Richard, E. Haverfield
Objective: To recognize the utility of multi-gene testing for prenatal diagnosis of autosomal dominant Noonan spectrum disorders and the importance of concurrent targeted parental testing.
Methods: 299 pregnancies with abnormal fetal sonogram findings were referred for prenatal diagnostic testing for Noonan syndrome. Testing was performed using a 9-gene panel, which includes the complete coding regions of PTPN11 and 7 other genes in the RAS/MAPK pathway and 1 common mutation in SHOC2. Parental samples were requested for targeted testing if a novel or unclassified variant was detected.
Results: A known pathogenic mutation was identified in 15/299 fetuses (5%). Mutations were detected in genes associated with Noonan syndrome (n=11), but also in those causing cardio-facio-cutaneous (CFC; n=3) and Costello syndromes (n=1). In 13/299 fetuses (4.3%), a variant of uncertain significance (VUS) was identified, which prompted parental testing. From these results, 9 VUS were reported as likely benign, due to the nature of the amino acid change and inheritance from an unaffected parent. Two VUS results were subsequently identified as apparently de novo changes, thus increasing the mutation rate to 5.7%. The clinical implications of two VUS remained unresolved despite positive parental testing results because it was unknown if the carrier parent had clinical features consistent with a Noonan spectrum disorder.
Conclusions: Mutations in PTPN11 have been described in fetuses with cystic hygroma, increased nuchal translucency and other ultrasound abnormalities, but data have been limited for mutations in other genes associated with Noonan spectrum disorders in the prenatal setting. Our results demonstrate that mutations in many genes of the RAS/MAPK pathway may manifest prenatally with clinically indistinguishable findings. While prenatal multi-gene testing may increase the possibility of identifying novel or unclassified sequence variants, our experience shows that parental clinical evaluation and targeted testing can resolve the clinical significance of >80% of fetal VUS. Our results underscore the need for comprehensive pre-test genetic counseling as well as the importance of submitting parental samples and parental clinical information concurrently with a fetal sample.