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. 2014 Nov 30:15:127.
doi: 10.1186/s12881-014-0127-0.

Expanded spectrum of exon 33 and 34 mutations in SRCAP and follow-up in patients with Floating-Harbor syndrome

Wenke Seifert  1 , Peter Meinecke  2 , Gabriele Krüger  3 , Eva Rossier  4 , Wolfram Heinritz  5 , Achim Wüsthof  6 , Denise Horn  7
Affiliations

Expanded spectrum of exon 33 and 34 mutations in SRCAP and follow-up in patients with Floating-Harbor syndrome

Wenke Seifert et al. BMC Med Genet. .

Abstract

Background: Floating-Harbor syndrome is a rare autosomal dominant short stature syndrome with retarded speech development, intellectual disability and dysmorphic facial features. Recently dominant mutations almost exclusively located in exon 34 of the Snf2-related CREBBP activator protein gene were identified to cause FHS.

Methods: Here we report the genetic analysis of 5 patients fulfilling the diagnostic criteria of FHS obtained by Sanger sequencing. All of them presented with short stature, speech delay as well as psychomotor delay and typical facial dysmorphism. Three patients showed a good response to growth hormone treatment.

Results: Two patients demonstrate novel, heterozygous de novo frameshift mutations in exon 34 (c.7396delA and c.7218dupT) leading to premature stop mutations in SRCAP (p.Val2466Tyrfs*9 and p.Gln2407Serfs*36, respectively). In two further patients we found already known SRCAP mutations in exon 34, c.7330C > T and c.7303C > T, respectively, which also lead to premature stop codons: p.Arg2444* and p.Arg2435*. In one patient, we identified a novel de novo stop mutation in exon 33 (c.6985C > T, p.Arg2329*) demonstrating that not all FHS cases are caused by mutations in exon 34 of SRCAP.

Conclusions: Our data confirm a mutational hot spot in the final exon of SRCAP in the majority of FHS patients but also show that exon 33 of this gene can be affected.

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Figures

Figure 1
Figure 1
Photographs of patients, showing facial characteristics of Floating-Harbor syndrome. A - Patient A at age 5 years. B - Patient B at 22 years. C - Patient C at 5.5 years. D - Patient D at 7 years. E - Patient E at age of 5.5 years. Note overlapping facial dysmorphisms such as long-hanging columella, short philtrum, and thin lips.
Figure 2
Figure 2
Schematic representation of the SRCAP gene and positions of known SRCAP mutations. A - In this study, five de novo mutations have been identified to cause FHS (red frame – novel mutations, red-gray dashed frame – recurrent mutations). B - Expanded SRCAP protein network predicted functional links to several proteins involved in transcriptional regulation of selected genes by chromatin remodeling including CREBBP.
See this image and copyright information in PMC

References

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