The phenotype of Floating-Harbor syndrome: clinical characterization of 52 individuals with mutations in exon 34 of SRCAP

Sarah M Nikkel ,Usha Kini,Neeti Ghali,Alessandra Renieri,Francesca Forzano,Murray Feingold,Isabel Cordeiro,Alexandra Afenjar,Nine V A M Knoers,Bruna Santos Da Cunha,Alexander Hoischen,Connie Fung On Yee,Ineke Van Der Burgt,Louisa A Delaney,Anne Destrée,Ivan F M Lo,Francesco Brancati,Joaquim Sá,Kate Pope,Didier Lacombe,Jeroen Schoots,Katerina Harwood,Sonja De Munnik,Andrew Dauber,Claire M Jacob,Sanne Traasdahl Møller,Delphine Héron,Paolo Balestri,Anne Slavotinek,Oana Caluseriu,Dagmar Wierczorek,Francesca Mari,Chung Lee,Meghan Connolly,Susan Price,Beate Albrecht,Greta Gillies,Lies H Hoefsloot ,Elizabeth Lemos Silveira ,Johan Afendi Ibrahim ,Edwin P Kirk ,Sarina G Kant ,Engela Honey ,Rebecca L Hood ,David R Fitzpatrick ,Dennis E Bulman ,Ernie M.h.f Bongers ,Sue White ,Chandree L Beaulieu ,Bert B.a De Vries ,Chong Kim ,Daniela T Pilz ,Yvonne Hendriks ,Jane A Hurst ,Jan M Wit ,Judith Allanson ,Han G Brunner ,Margo Whiteford ,Małgorzata J.m Nowaczyk ,Verónica Mericq ,Tawfeg Ben‐Omran ,James D Weisfeld-Adams ,Marleen Simon ,Jukka S Moilanen ,I Karen Temple ,Luiza Silveira Lucas ,Stéphanie Moortgat ,Kym M Boycott

doi:10.1186/1750-1172-8-63

Abstract

BackgroundFloating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome.Methods and resultsClinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations.ConclusionsThis large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.

Highlights

Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance
Floating-Harbor syndrome (FHS [MIM 136140]) is a rare disorder characterized by short stature with delayed bone age, deficits in expressive language and a distinctive facial appearance
The mechanism of disease in FHS is suspected to be dominant-negative [3] due to the non-random clustering of truncating mutations in the final exon that result in the loss of the major transactivation function of SNF2-related CREB-binding protein (CBP) activator protein (SRCAP) located in a 655 residue C-terminal fragment, evidence that expression of a construct solely consisting of the CBP interaction domain of SRCAP strongly inhibits CREBmediated transactivation in a dominant-negative fashion [5], and the existence of patients with haploinsufficiency of SRCAP who do not have features of FHS [3]

Summary

Introduction

Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Floating-Harbor syndrome (FHS [MIM 136140]) is a rare disorder characterized by short stature with delayed bone age, deficits in expressive language and a distinctive facial appearance. The mechanism of disease in FHS is suspected to be dominant-negative [3] due to the non-random clustering of truncating mutations in the final exon that result in the loss of the major transactivation function of SRCAP located in a 655 residue C-terminal fragment, evidence that expression of a construct solely consisting of the CBP interaction domain of SRCAP strongly inhibits CREBmediated transactivation in a dominant-negative fashion [5], and the existence of patients with haploinsufficiency of SRCAP who do not have features of FHS [3]

Methods

Results

Conclusion