Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith–Magenis syndrome

Abstract

Smith-Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of B139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS. European Journal of Human Genetics (2012) 20, 148-154; doi:10.1038/ejhg.2011.167; published online 7 September 2011Keywords: Smith-Magenis syndrome; 17p11.2; RAI1; arrayCGH; mutation; deletion INTRODUCTION Smith-Magenis syndrome (SMS, MIM 182290) is a multiple congenital anomalies and intellectual disability syndrome associated with a deletion of chromosome 17p11. 2. The incidence of SMS is estimated to be B1:15 000-1:25 000 births. 1 SMS is most commonly characterized by a variable degree of intellectual disability including speech and motor delay, craniofacial and skeletal anomalies, sleep disturbance, self-injurious and attention-seeking behaviors. 1,2 Craniofacial features include brachycephaly, midface hypoplasia, tented upper lip, relative prognathism with age and deep-set and hypoteloric eyes. 3,4 Skeletal features include brachydactyly, short stature and short/ broad hands. 3,4 The behavioral phenotype includes onychotillomania, polyembolokoilamania, 'hand licking and page flipping' , 'self-hugging' and hyperactivity. 5 Sleep disturbance is present in 88% of SMS patients and is characterized by difficulty getting to sleep, frequent nocturnal awakenings, early sleep offset and daytime sleepiness with a need for daytime naps. 6,7 SMS clinical features overlap with other intellectual disability syndromes such as Prader-Willi, Williams and Down's syndromes, which often complicate its clinical diagnosis.A majority, B90%, of SMS patients have a deletion of chromosome 17p11.2 that includes the RAI1 gene. 3 The classical SMS deletions span B3.5 Mb of 17p11.2 and are present in B70% of affected individuals.

Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

“…High-density 17p11.2 aCGH and Sanger sequencing of RAI1 showed that 134 out of 149 individuals presented a genetic or genomic alteration of the RAI1 gene [9, 11, 17, 49–52], 96/134 (72 %) individuals carried the classic recurrent 3.7 Mb SMS deletion, ten (7.5 %) contained an uncommon recurrent 1 (UR1) or UR2 rearrangement, 24 (18 %) a non-recurrent RAI1 deletion, and four (3 %) had a de novo variant in RAI1 [9, 11, 49, 52, 53] (Additional file 2 Table S1). Whereas these proportions are similar to published results [12, 54], it is likely that some clinicians did not refer individuals with SMS features who were negative for SMS molecular diagnosis (via aCGH or fluorescence in situ hybridization, FISH) or who were positive for another potentially causative CNV, for example 1p36 deletion syndrome [15, 55, 56] that shares multiple similarities with SMS. Indeed, many individuals were molecularly diagnosed prior to sample submission.…”

“…Indeed, many individuals were molecularly diagnosed prior to sample submission. Consistent with this hypothesis, a separate study identified mutations affecting RAI1 in only 30 % of participants with a suspected diagnosis of SMS [12]. …”

“…Whereas SMS is classically associated with a deletion within cytogenetic G-band 17p11.2 that includes the RAI1 gene (about 90 % of individuals) or a nucleotide variant in that gene (about 5 %) [1, 9–12], some reports suggested genetic heterogeneity as SMS-like individuals were found to recurrently harbor deletions of the 2q37.3 or 2q23.1 cytobands encompassing HDAC4 and MBD5 , respectively [13–15]. Similarly, PITX3 was proposed to be responsible for the SMS-like neurobehavioral abnormalities observed in an individual [16].…”

Intellectual and Behavioral Disabilities in Smith — Magenis Syndrome

“…A deletion of chromosome 17p11.2 was identified as the cause of this condition in approximately 90% of cases, and thus this disorder belongs to the group of contiguous-gene syndromes, currently referred to as genome diseases [3][4][5]. SMS patients without deletions 17p11.2 may carry a point mutation in the gene RAI1 [6][7][8][9][10], which codes a transcription factor acting in several different biological pathways. RAI1 dosage is crucial for normal regulation of circadian rhythm, lipid metabolism, and melatonin function.…”

Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions

“…More recently, point mutations in the RAI1 (retinoic acid induced 1) gene have been identified in less than 10% of SMS patients [Slager et al, 2003;Bi et al, 2004Bi et al, , 2006Girirajan et al, 2005Girirajan et al, , 2006Vilboux et al, 2011;Vieira et al, 2012]. This gene maps in the SMS critical region [Bi et al, 2002;Vlangos et al, 2003].…”