Microduplication of 3p25.2 encompassing RAF1 associated with congenital heart disease suggestive of Noonan syndrome

Abstract

Noonan syndrome (NS) is a clinically variable and genetically heterogeneous disorder with congenital heart defects (CHD), short stature, and craniofacial dysmorphisms. Gain-of-function mutations in RAF1 can cause NS and the highly related NS with multiple lentigines (previously known as LEOPARD syndrome). Here we report on a 15-year-old male with NS phenotype: short stature, heart defects, low posterior hairline, facial malformations, malformed left ear with sensorineural hearing loss, widely spaced nipples, and unilateral upper limb anomaly. Using high-resolution SNP array technology, we identified in this patient a 0.25 Mb microduplication at 3p25.2 in which RAF1 is located. Sequence analysis did not identify mutations in genes associated with Holt-Oram syndrome. These findings suggest that duplications of genomic regions encompassing RAF1 could cause NS and are consistent with the notion that rare copy number variations encompassing causative genes may underlie a small percentage of patients with syndromic CHD like NS.