ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.