Smith-Magenis syndrome in monozygotic twin fetuses presenting with discordant phenotypes and uteroplacental insufficiency

Abstract

Smith-Magenis syndrome (SMS) is a rare condition with multiple congenital malformations caused by the haploinsufficiency of RAI1 (deletion or mutation of RAI1). However, the correlation between genotype and phenotype is not well understood. The present study describes the prenatal diagnosis of monozygotic twins with a 17p11.2 deletion, which is indicative of SMS, who presented with discordant phenotypes and uteroplacental insufficiency. A high-resolution genome-wide single nucleotide polymorphism array revealed a 3.7-Mb deletion in the 17p11.2 chromosome region. Accurate breakpoints of the deletion in these patients were used to identify correlations between SMS and the concomitant phenotypes, particularly uteroplacental insufficiency, which has rarely been investigated in SMS. In addition, no exonic mutations were identified in or affected known disease-associated loci that could explain the congenital anomalies, according to a model that accounts for the possibility of incomplete penetrance. Furthermore, a novel benign copy number variation (a duplication of 195 kb at 13q12.13) was identified but was unlikely to be clinically significant in the discordant phenotypes of the twins. The present study showed that multiple interacting genetic and environmental factors are involved in determining the variance of the SMS phenotype.