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

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.

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

“…The gene associated with Floating-Harbor syndrome (SRCAP) encodes a component of SWI/SNF chromatin remodelling complexes (174,175).…”

Floating Harbor Syndrome

“…Additional features described in different reports include gluten intolerance, conductive hearing loss and polycystic kidney disease [3,4]. Most of the mutations described are truncating and appear to be clustered in the last (34th) exon as seen in this case also [2]. Mutation detection helps in counseling about prognosis which is usually satisfactory and no significant risk of recurrence in the siblings.…”

“…This may explain the phenotypic overlap with Rubinstein Taybi syndrome. The facial features, short stature and delayed bone age are constant features [2]. Some developmental delay, especially in speech is common though great variability in intellect is reported.…”

When chromatin organisation floats astray: theSrcapgene and Floating–Harbor syndrome

“…Notably, the CBP encoding gene was found to be mutated in half of patients affected by the Rubinstein–Taybi syndrome (RTS) 42. It has been suggested that disrupted interaction between these two proteins likely explains some of the clinical overlap between FHS and RTS 33. As shown in figure 2B, in addition to the CBP-binding domain (1639-1988), SRCAP carries other functional domains, located at the C-terminal end (2316–2971), which activate transcription independently of CBP;41 one such domain may correspond to the portion containing the AT-hook motifs.…”

“…It is conceivable that the dominant effect underlying FHS is due to the loss of the C-terminal portion of SRCAP protein, including the AT-hook motifs 31 33. In Srcap + /ΔSrcap heterozygous FHS patients, where both the wild-type SRCAP and the truncated SRCAP variant (ΔSRCAP) are expressed, ΔSRCAP may disrupt the binding of wild-type SRCAP to both DNA and chromatin targets, thus affecting the expression levels of genes controlling the onset of differentiation and developmental processes 31 33. However, how could this effect be produced?…”