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

Wenke Seifert,Wolfram Heinritz,Denise Horn,Peter Meinecke,Gabriele Krüger,Eva Rossier,Achim Wüsthof

doi:10.1186/s12881-014-0127-0

Abstract

BackgroundFloating-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.MethodsHere 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.ResultsTwo 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.ConclusionsOur 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.

Highlights

Floating-Harbor syndrome is a rare autosomal dominant short stature syndrome with retarded speech development, intellectual disability and dysmorphic facial features
Floating-Harbor syndrome (FHS, OMIM: #136140) is a genetic disorder characterized by short stature, delayed bone age, retarded speech development and intellectual disability (ID) as well as characteristic facial dysmorphisms (Figure 1)
Mutations located in exon 34 of the Snf2-related CREBBP activator protein (SRCAP) gene, encoding the core catalytic component of the multiprotein chromatinremodeling SRCAP complex, were found to cause FHS in about 50 patients [1,2,3,4]

Summary

Introduction

Floating-Harbor syndrome is a rare autosomal dominant short stature syndrome with retarded speech development, intellectual disability and dysmorphic facial features. Dominant mutations almost exclusively located in exon 34 of the Snf2-related CREBBP activator protein gene were identified to cause FHS. Floating-Harbor syndrome (FHS, OMIM: #136140) is a genetic disorder characterized by short stature, delayed bone age, retarded speech development and intellectual disability (ID) as well as characteristic facial dysmorphisms (Figure 1). Mutations located in exon 34 of the Snf2-related CREBBP activator protein (SRCAP) gene, encoding the core catalytic component of the multiprotein chromatinremodeling SRCAP complex, were found to cause FHS in about 50 patients [1,2,3,4]. Mutations in the SRCAP gene may result in an altered protein that interferes with normal activation of the CREBBP gene, leading to a disturbed development. Rubinstein-Taybi syndrome, an autosomal dominant inherited disorder with some phenotypic overlap, is caused by mutations in the CREBBP gene itself [6]

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