Deletion of RAI1 noncoding exons 1-2 causes Smith-Magenis syndrome

Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by developmental delay and a typical behavioral phenotype. Interstitial 17p11.2 deletions, which include the RAI1 gene are detected in >90% of patients, while single nucleotide variants (SNVs) are detected in the rest. The RAI1 gene is encoded from exons 3 onwards, while exons 1-2 are noncoding. It is unclear whether genetic variants preceding exon 3 cause SMS. We evaluated a 15-month-old infant for developmental delay and infantile spasms who was found to carry a deletion encompassing exons 1-2 of RAI. To determine whether the deletion of the noncoding exons 1-2 of the RAI1 gene is associated with SMS and to elucidate the underlying mechanism of this association. A singleton exome-based gene panel was performed, followed by chromosomal-microarray (CMA) to confirm the results. Real time quantitative PCR (RT-qPCR) analysis was conducted to evaluate RAI1 mRNA expression. CMA confirmed a de novo 737.8 kbp deletion on 17p11.2, which includes exons 1-2 of RAI1 but spares exons 3 onwards. RT-qPCR analysis on RNA extracted from the patient, father and three unrelated controls revealed that the patient has RAI1 haploinsufficiency. We show that deletion of the RAI1 noncoding exons 1-2, which spares the gene's coding region, causes RAI1 haploinsufficiency by eliminating regulatory elements, including the gene promoter, thus causing SMS and expanding the mutational spectrum of SMS.