BACKGROUND AND PURPOSE:

• RASopathies are a group of relatively common genetic conditions
  • 1:1000 to 1:2500 live births
  • Likely more common in the prenatal period
  • Example of important rasopathy is Noonan syndrome which can appear prenatally with cystic hygroma or enlarged nuchal translucency (NT) but normal chromosomes
• Scott et al. (Genetics in Medicine, 2021) studied genotype–phenotype correlations to further understand the role of prenatal testing for these disorders

METHODS:

• Retrospective study | Systematic Review (2021 to 2019)
• Population
  • Fetuses referred for genetic testing because of findings suggestive of RASopathy
  • Chromosomal microarray–negative cases
• Study design
  • Most cases sent for testing examined 11 RASopathy genes
  • The authors used postnatal cohorts (25 patients with available prenatal information and 108 institutional database genotypes) and the NSeuroNet database

RESULTS:

• 352 chromosomal microarray–negative cases
• Prevalence of ultrasound findings
  • Increased nuchal translucency (NT): 74%
  • Cystic hygroma: 58%
• NT
  • Diagnostic yield greatest for NT >6mm (20%)
  • Yield very low for isolated NT <6mm (1%; 1/90)
• Nuchal fold
  • Diagnostic yield was 25% for increased nuchal fold
• Pathogenic variants identified
  • Overall: 14% (50 cases)
• The following ultrasound findings had diagnostic yields >20%
  • Effusions
  • Hydrops
  • Congenital heart disease
• Diagnostic yield was greater for the following
  • Hypertrophic cardiomyopathy
  • Persistent or associated cystic hygroma
  • Any suggestive finding plus renal anomaly or polyhydramnios
  • ≥2 ultrasound findings
• Largest prenatal contributors of pathogenic variants
  • PTPN11: 30%
  • RIT1: 16%
  • RAF1: 14%
  • HRAS: 12%
• HRAS, LZTR1, and RAF1 variants correlated with hydrops/effusions
  • RIT1 correlated with prenatal onset of hypertrophic cardiomyopathy

CONCLUSION:

• In the setting of prenatal evidence of lymphatic abnormality or congenital heart defects where the microarray result is normal, fetal genetic testing appears to be warranted for Noonan syndrome and other RASopathies
• They authors conclude

…after a normal CMA, RASopathy prenatal testing should be offered when any prenatal US finding suggestive of lymphatic dysplasia (CH, increased NT or NF, hydrops, effusions, other lymphatic anomalies) or suggestive CHD (like valvular dysplasia and/or HCM) is found alone or in association, except for isolated increased NT below 6 mm or isolated increased NF

Learn More – Primary Sources:

When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort

Related ObG Topics:

Large NT but Normal Karyotype? Noonan Syndrome Basics

Cystic Hygroma: Definition, Genetics and Prognosis

How Common is Noonan Syndrome When the NT is Large but Chromosomes Appear Normal?

Is There Value to an Early Anatomy Scan with an Enlarged NT?