Fahad Hakami1,2,3, Mitchell W Dillon2, Matthew Lebo1,2, Heather Mason-Suares1,2. 1. Departments of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. 2. Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, USA. 3. Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City-WR, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Kingdom of Saudi Arabia.
Abstract
OBJECTIVES: Noonan spectrum disorders (NSDs) occur in 1:1000-2500 live births. Currently, there are no guidelines for prenatal molecular genetic testing for NSDs. Recent studies recommend prenatal testing for NSDs when ultrasonography detects two or more associated abnormalities. A stronger association between ultrasound findings and NSDs would enable more informed prenatal genetic testing. METHODS: A total of 212 newborns (0-12 weeks) with prenatal ultrasound findings and a clinical suspicion of a NSD were referred for molecular genetic testing. Of these, 159/212 newborns tested had a single ultrasound abnormality and 53/212 newborns had two or more. Testing was performed by either a microarray-based resequencing assay or next generation sequencing of RAS/MAPK pathway genes associated with NSDs. Prenatal ultrasound findings in positive and negative cases were compared. RESULTS: A disease-causing variant was identified in 21.7% (46/212) of newborns tested. Of these positive cases, 67.4% (31/46) had only one ultrasound abnormality reported. The rate of detecting a disease-causing variant in cases with one ultrasound finding was 19.5% (31/159), which was not significantly different (p-value = 0.36) than that in cases with two or more ultrasound findings (28.3%; 15/53). CONCLUSIONS: Prenatal molecular testing for NSDs should be considered even in the presence of a single associated abnormal ultrasound finding.
OBJECTIVES:Noonan spectrum disorders (NSDs) occur in 1:1000-2500 live births. Currently, there are no guidelines for prenatal molecular genetic testing for NSDs. Recent studies recommend prenatal testing for NSDs when ultrasonography detects two or more associated abnormalities. A stronger association between ultrasound findings and NSDs would enable more informed prenatal genetic testing. METHODS: A total of 212 newborns (0-12 weeks) with prenatal ultrasound findings and a clinical suspicion of a NSD were referred for molecular genetic testing. Of these, 159/212 newborns tested had a single ultrasound abnormality and 53/212 newborns had two or more. Testing was performed by either a microarray-based resequencing assay or next generation sequencing of RAS/MAPK pathway genes associated with NSDs. Prenatal ultrasound findings in positive and negative cases were compared. RESULTS: A disease-causing variant was identified in 21.7% (46/212) of newborns tested. Of these positive cases, 67.4% (31/46) had only one ultrasound abnormality reported. The rate of detecting a disease-causing variant in cases with one ultrasound finding was 19.5% (31/159), which was not significantly different (p-value = 0.36) than that in cases with two or more ultrasound findings (28.3%; 15/53). CONCLUSIONS: Prenatal molecular testing for NSDs should be considered even in the presence of a single associated abnormal ultrasound finding.