RT Journal Article
SR Electronic
T1 Reduced expression by <em>SETBP1</em> haploinsufficiency causes developmental and expressive language delay indicating a phenotype distinct from Schinzel–Giedion syndrome
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 117
OP 122
DO 10.1136/jmg.2010.084582
VO 48
IS 2
A1 Isabel Filges
A1 Keiko Shimojima
A1 Nobuhiko Okamoto
A1 Benno Röthlisberger
A1 Peter Weber
A1 Andreas R Huber
A1 Tsutomu Nishizawa
A1 Alexandre N Datta
A1 Peter Miny
A1 Toshiyuki Yamamoto
YR 2011
UL http://jmg.bmj.com/content/48/2/117.abstract
AB Background Mutations of the SET binding protein 1 gene (SETBP1) on 18q12.3 have recently been reported to cause Schinzel–Giedion syndrome (SGS). As rare 18q interstitial deletions affecting multiple genes including SETBP1 correlate with a milder phenotype, including minor physical anomalies and developmental and expressive speech delay, mutations in SETBP1 are thought to result in a gain-of-function or a dominant-negative effect. However, the consequence of the SETBP1 loss-of-function has not yet been well described.Methods Microarray-based comparative genomic hybridisation (aCGH) analyses were performed to identify genetic causes for developmental and expressive speech delay in two patients. SETBP1 expression in fibroblasts obtained from one of the patients was analysed by real-time RT-PCR and western blotting. A cohort study to identify nucleotide changes in SETBP1 was performed in 142 Japanese patients with developmental delay.Results aCGH analyses identified submicroscopic deletions of less than 1 Mb exclusively containing SETBP1. Both patients show global developmental, expressive language delay and minor facial anomalies. Decreased expression of SETBP1 was identified in the patient's skin fibroblasts. No pathogenic mutation of SETBP1 was identified in the cohort study.Conclusion SETBP1 expression was reduced in a patient with SETBP1 haploinsufficiency, indicating that the SETBP1 deletion phenotype is allele dose sensitive. In correlation with the exclusive deletion of SETBP1, this study delimits a milder phenotype distinct from SGS overlapping with the previously described phenotype of del(18)(q12.2q21.1) syndrome including global developmental, expressive language delay and distinctive facial features. These findings support the hypothesis that mutations in SETBP1 causing SGS may have a gain-of-function or a dominant-negative effect, whereas haploinsufficiency or loss-of-function mutations in SETBP1 cause a milder phenotype.