ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000017.10) (NC_000017.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
12652298 Slager et al. (2003) reported 3 patients with clinical diagnoses of Smith Magenis syndrome (SMS) but without 17p11.2 deletions detectable by standard fluorescence in situ hybridization techniques. Mutation analysis identified 3 dominant frameshift variants leading to protein truncation in RAI1. These variants are a 29bp deletion in exon 3 of the RAI1 gene, a 1 bp deletion in exon 3 (1308delC aka 1449delC), and another 1bp deletion (4929delC aka 5265delC). The authors propose that haploinsufficiency of RAI1 is thought to be responsible for the behavioral, neurological, otolaryngological and craniofacial aspects of this syndrome, but more variable features such as heart and renal defects are probably due to hemizygosity of other genes in the 17p11.2 region. The polyC tract exon 3 may be a preferential target for frameshift mutations.
15565467 Bi et al. (2004) reported 2 new RAI1 mutations, [Q1035fsX30/c.3130insC) and one nonsense mutation (R960X/c.2878C>T) [NP_109590.3:p.Arg960Ter], in SMS patients without FISH-detectable deletions. Comparisons of the clinical features in these two patients, three of the reported in Slager et al in 2003, and the patients with a common deletion suggest that the majority of the clinical features in SMS. No mutation analysis on parents was reported. The polyC tract exon 3 may be a preferential target for frameshift mutations.
15788730 Girirajan al. (2005) report two small deletions [NM_030665.4(RAI1):c.3801del (p.Thr1268fs)] and [RAI1, 19-BP DEL] (in addition to two missense variants, which will not be counted as evidence in this dosage evaluation). The two small deletions in RAI1 result in frameshift and premature termination of the protein. All patients had developmental delay, reduced motor and cognitive skills, craniofacial and behavioral anomalies, and sleep disturbance. Seizures, not previously thought to be associated with RAI1 variants, were observed in 1 patient. The authors concluded that haploinsufficiency of the RAI1 gene is associated with most features of SMS, including craniofacial, behavioral, and neurologic signs and symptoms.

Haploinsufficiency phenotype comments:

Additional evidence includes: Giriajan et al. (2006) (PMID:16845274) report three SMS patients with de novo heterozygous variants in RAI1. These de novo variants are 1119delC (misincorporation of 65 amino acids), 4649delC (misincorporation of 36 amino acids) and 4933delGCCG (misincorporation of 35 amino acids). Genotype and phenotype comparison between individuals with deletions involving RAI1 and individuals with point variation within RAI1 showed that RAI1 is the primary gene responsible for most features of SMS, though other genes within 17p11.2 contribute to the variable features and overall severity of the syndrome. Bi et al. (2006) (PMID: 17041942) report a de novo frameshift variant, c.3103delC, in RAI1 in a 9-year-old boy with SMS features. The deletion of a single cytosine occurs in a heptameric C-tract (CCCCCCC), the longest mononucleotide repeat in the RAI1 coding region. Truong et al. (2010) (PMID:20932317) report a male with the same deletion of a single cytosine, c.3103delC, located within the heptameric C-tract in exon 3 of RAI1. This frameshift mutation predicts the misincorporation of 28 amino acids before a premature stop codon is introduced. The resulting truncated protein is predicted to be non-functional, contributing to the haploinsufficiency of RAI1. A female was also reported with a insertion, c.3103insC, located within the same heptameric C-tract in exon 3 of RAI1. Both cases are phenotypically consistent with SMS, but also have other anomalies not previously reported in SMS, including spontaneous pneumothoraces. Vilboux et al. (2011) (PMID:21857958) reported an extensive genetic and clinical analyses of 36 patients with SMS-like features, but without the 17p11.2 microdeletion. Ten of these patients had RAI1 variants, including 4 with de novo deleterious loss of function variants, and 6 with novel missense variants, 5 of which were familial. The reported 4 de novo heterozygous variants are, c.1973G.A/p.W658X, c.1449delC/p.E484KfsX35, c.3103insC/p.Q1034PfsX31, c.548delT/p.L183RfsX69. RAI1 mRNA expression was significantly decreased in cells of patients with the common 17p11.2 deletion, as well as in those with de novo RAI1 variants. RAI1 expression emerged as a genetic target for development of therapeutic interventions for SMS. Yeetong et al. (2016) (PMID: 27311559) report a 25-year-old female SMS patient with a de novo RAI1 variant (c.5536C>T; p.Q1846X). The diagnosis of SMS in this patient was initially suspected at age 12 years, but cytogenetic fluorescence in situ hybridization studies failed to confirm an interstitial deletion of 17p11.2. Re-evaluation for suspected SMS was pursued with RAI1 sequencing analysis in response to urgent parental concerns of escalating behaviors and aggression with subsequent incarceration of the subject for assault of a health professional. Acquaviva et al. (2017) (PMID:27683195) report a 1 bp deletion in RAI1 (NM_030665.3:c.1194delC_p.Ser399Profs*40) in a mother and a daughter; both have a diagnosis of SMS. This frameshift variant is de novo in the mother, and transmitted to her daughter. No other family members carried this mutation. This is the first report of an SMS patient having offspring.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Duplications of 17p11.2 including RAI1 are associated with Potocki-Lupski syndrome (PTLS); see ISCA-37418 for a full description of evidence supporting this region. Zhang et al. (2010) analyze 74 patients with PTLS. They identified 8 novel non-recurrent duplications that helped them refine the smallest region of overlap to a 125 kb that only includes RAI1. However, no duplication cases that include only RAI1 were observed in the study (PMID: 20188345).