Fig. 3

Genetic heterogeneity, phenotypic variance, and misdiagnosis. a RAI1 and gene A are associated with Smith-Magenis syndrome (SMS) and syndrome A, respectively, and variants (yellow “lightning bolts”) in those genes cause the green and blue phenotypes, respectively. b The phenotypic spectra of these diseases could be more variable than anticipated and result in overlapping features. Such overlap could be due to a broader phenotypic variability of syndrome A, of SMS or of both syndromes (right panels). The rare variants in Rai1-associated genes identified in individuals with SMS-like features and reported here (red “lightning bolts”) could be explained by a combination of genetic heterogeneity of SMS and allelic heterogeneity of gene A (c), an increased variance of syndrome A (d), or a misdiagnosis of SMS (e)