Genotype-phenotype correlation in Smith-Magenis syndrome: Evidence that multiple genes in 17p11.2 contribute to the clinical spectrum

University of Toronto, Toronto, Ontario, Canada
Genetics in Medicine (Impact Factor: 7.33). 07/2006; 8(7):417-27. DOI: 10.1097/01.gim.0000228215.32110.89
Source: PubMed


Smith-Magenis syndrome (SMS) is a complex disorder that includes mental retardation, craniofacial and skeletal anomalies, and behavioral abnormalities. We report the molecular and genotype-phenotype analyses of 31 patients with SMS who carry 17p11.2 deletions or mutations in the RAI1 gene.
Patients with SMS were evaluated by fluorescence in situ hybridization and/or sequencing of RAI1 to identify 17p11.2 deletions or intragenic mutations, respectively, and were compared for 30 characteristic features of this disorder by the Fisher exact test.
In our cohort, 8 of 31 individuals carried a common 3.5 Mb deletion, whereas 10 of 31 individuals carried smaller deletions, two individuals carried larger deletions, and one individual carried an atypical 17p11.2 deletion. Ten patients with nondeletion harbored a heterozygous mutation in RAI1. Phenotypic comparison between patients with deletions and patients with RAI1 mutations show that 21 of 30 SMS features are the result of haploinsufficiency of RAI1, whereas cardiac anomalies, speech and motor delay, hypotonia, short stature, and hearing loss are associated with 17p11.2 deletions rather than RAI1 mutations (P<.05). Further, patients with smaller deletions show features similar to those with RAI1 mutations.
Although RAI1 is the primary gene responsible for most features of SMS, other genes within 17p11.2 contribute to the variable features and overall severity of the syndrome.

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Available from: Sarah H Elsea, Mar 11, 2014
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    • "Phenotypic variability is observed across a variety of genomic disorders including SMS, Potocki-Lupski syndrome (OMIM 610883), Angelman syndrome (OMIM 105830), and brachydactyly-mental retardation syndrome (OMIM 600430) [5], [18]. Individual differences in the genome that act to modify phenotypic outcomes of these particular disorders are likely one of many factors contributing to the range of clinical findings. "
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    ABSTRACT: Smith-Magenis syndrome is a complex genomic disorder in which a majority of individuals are obese by adolescence. While an interstitial deletion of chromosome 17p11.2 is the leading cause, mutation or deletion of the RAI1 gene alone results in most features of the disorder. Previous studies have shown that heterozygous knockout of Rai1 results in an obese phenotype in mice and that Smith-Magenis syndrome mouse models have a significantly reduced fecundity and an altered transmission pattern of the mutant Rai1 allele, complicating large, extended studies in these models. In this study, we show that breeding C57Bl/6J Rai1+/- mice with FVB/NJ to create F1 Rai1+/- offspring in a mixed genetic background ameliorates both fecundity and Rai1 allele transmission phenotypes. These findings suggest that the mixed background provides a more robust platform for breeding and larger phenotypic studies. We also characterized the effect of dietary intake on Rai1+/- mouse growth during adolescent and early adulthood developmental stages. Animals fed a high carbohydrate or a high fat diet gained weight at a significantly faster rate than their wild type littermates. Both high fat and high carbohydrate fed Rai1+/- mice also had an increase in body fat and altered fat distribution patterns. Interestingly, Rai1+/- mice fed different diets did not display altered fasting blood glucose levels. These results suggest that dietary regimens are extremely important for individuals with Smith- Magenis syndrome and that food high in fat and carbohydrates may exacerbate obesity outcomes.
    PLoS ONE 08/2014; 9(8):e105077. DOI:10.1371/journal.pone.0105077 · 3.23 Impact Factor
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    • "SMS has a reported prevalence of between 1 in 25,000 live births (Greenberg et al., 1996), and 1 in 15,000 (Laje et al., 2010). Typically, the syndrome results from a de novo deletion on chromosome 17 (17p11.2) (Girirajan et al., 2006) but for approximately 10% of cases, a mutation of the retinoic acid-induced 1 (RAI1) gene on the same chromosome has been implicated (Elsea & Girirajan, 2008). Self-injurious behavior has been noted frequently (e.g. "
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    ABSTRACT: Research into behavioural phenotypes identifies both environmental and organic factors as influencing aggression in children and adults with genetic disorders associated with intellectual disability. However, in contrast to self-injury there is a paucity of research that compares aggression across relevant syndromes. The primary aim of this review is to examine the association between aggression and genetic syndromes by analysis of prevalence studies. The review also examines the literature on the form of the behaviour and influence of environmental factors. Results imply that certain syndrome groups (Cri du Chat, Smith-Magenis, Prader-Willi, Angelman, Cornelia de Lange, and Fragile X syndromes; estimates over 70%) evidence a stronger association with aggression than others (e.g. Williams and Down syndromes; estimates below 15%). However, the strength of association is difficult to quantify due to methodological differences between studies. The results from examining form and environmental influences highlight the importance of phenotype–environment interactions. Research employing group comparison designs is warranted and future work on the assessment and intervention of aggression in genetic syndromes should consider the importance of phenotype–environment interactions.
    Research in developmental disabilities 05/2014; 35(5). DOI:10.1016/j.ridd.2014.01.033 · 4.41 Impact Factor
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    • "To date more than twenty patients with SMS have been related to a heterozygous mutation within the RAI1 coding region [3]–[6], [9], [22]–[24] (figure 1A). We had defined two functional domains in the RAI1 protein, the N-terminal one that has the transactivational activity and the C-terminal that presents the signals for nuclear localization [10]. "
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    ABSTRACT: Smith-Magenis Syndrome (SMS) is a complex genomic disorder mostly caused by the haploinsufficiency of the Retinoic Acid Induced 1 gene (RAI1), located in the chromosomal region 17p11.2. In a subset of SMS patients, heterozygous mutations in RAI1 are found. Here we investigate the molecular properties of these mutated forms and their relationship with the resulting phenotype. We compared the clinical phenotype of SMS patients carrying a mutation in RAI1 coding region either in the N-terminal or the C-terminal half of the protein and no significant differences were found. In order to study the molecular mechanism related to these two groups of RAI1 mutations first we analyzed those mutations that result in the truncated protein corresponding to the N-terminal half of RAI1 finding that they have cytoplasmic localization (in contrast to full length RAI1) and no ability to activate the transcription through an endogenous target: the BDNF enhancer. Similar results were found in lymphoblastoid cells derived from a SMS patient carrying RAI1 c.3103insC, where both mutant and wild type products of RAI1 were detected. The wild type form of RAI1 was found in the chromatin bound and nuclear matrix subcellular fractions while the mutant product was mainly cytoplasmic. In addition, missense mutations at the C-terminal half of RAI1 presented a correct nuclear localization but no activation of the endogenous target. Our results showed for the first time a correlation between RAI1 mutations and abnormal protein function plus they suggest that a reduction of total RAI1 transcription factor activity is at the heart of the SMS clinical presentation.
    PLoS ONE 09/2012; 7(9):e45155. DOI:10.1371/journal.pone.0045155 · 3.23 Impact Factor
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