Prenatal Ultrasound Phenotypes, Genetic Causes, and Inheritance Characteristics of Fetal Noonan Syndrome in Jiaxing

Background: Noonan syndrome (NS) is a rare autosomal dominant RASopathy characterized by high phenotypic and genetic heterogeneity. Prenatal diagnosis remains challenging due to nonspecific ultrasound (US) abnormalities and limited sensitivity of conventional genetic testing. Data on prenatal US phenotypes, genetic etiology, and inheritance characteristics of fetal NS in Jiaxing region are insufficient. This study aimed to explore the clinical value of whole exome sequencing (WES) in prenatal diagnosis of NS. Methods: A retrospective analysis was conducted on 5 cases of prenatally diagnosed NS at the Jiaxing Maternity and Children’s Health Care Hospital from January 2020 to January 2025. All fetuses underwent single nucleotide polymorphism (SNP)-array to exclude chromosomal abnormalities and copy number variations (CNVs). WES was performed on fetal amniotic fluid DNA and parental peripheral blood DNA, and candidate pathogenic variants were verified by Sanger sequencing. Variant pathogenicity was classified according to the 2015 American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) Standards and Guidelines combined with the Association for Clinical Genomic Science (ACGS) specifications. Standardized US biometry (percentiles and Z-scores) was used to characterize fetal abnormalities, and the correlation between prenatal US phenotypes and genotypes was analyzed. Results: The principal standardized US abnormalities identified across the 5 fetuses included nuchal cystic hygroma (1/5, 20%), choroid plexus cyst (2/5, 40%), macrocephaly (>95th percentile, 2/5, 40%), polyhydramnios (>95th percentile, 4/5, 80%), and fetal growth restriction (FGR; <10th percentile, 1/5, 20%), with all fetuses presenting multiple US abnormalities. Pathogenic or likely pathogenic missense variants were detected in all cases via WES, achieving a 100% diagnostic rate (5/5); pathogenic variants accounted for 60% (3/5), and the likely pathogenic variant detection rate was 40% (2/5). Four core rat sarcoma‑mitogen‑activated protein kinase (RAS‑MAPK) pathway genes were involved (PTPN11, KRAS, SOS1, RAF1), corresponding to NS types 1, 3, 4, and 5, respectively. PTPN11 exhibited the highest variant frequency in this cohort (2/5, 40%, 95% confidence interval [CI]: 5.2%–94.8%). Familial co-segregation analysis confirmed 4 cases (80%) as de novo mutations and 1 case (20%) as maternally inherited from an asymptomatic mother. Specific US-genotype correlations were observed in this regional cohort. Conclusions: In fetuses from the Jiaxing region with prenatal US abnormalities such as nuchal cystic hygroma, macrocephaly, and polyhydramnios (per International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) 2020 guidelines), as well as negative SNP-array results, NS should be highly suspected. WES was able to successfully identify the genetic etiology and variant inheritance pattern of prenatal NS in this small cohort, and the tiered diagnostic workflow of SNP-array combined with WES and Sanger sequencing has important etiological diagnostic value for such fetuses. This study clarifies the regional US and genetic characteristics of prenatal NS in the Jiaxing region, providing a clinical reference for local prenatal screening, genetic diagnosis, and genetic counseling. Due to the small sample size, the results are exploratory and descriptive in nature, and future large-sample multicenter studies are warranted for validation.