Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome

Abstract

Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS.

Figure 1

Floating-Harbor Syndrome Due to SRCAP Mutations Clinical photos depicting 9 of 13 unrelated FHS probands with a confirmed SRCAP mutation are shown with the characteristically triangular face, long eyelashes, typical nose (long and narrow nasal bridge, broad base, full tip, and low-hanging columella), short philtrum, wide mouth, thin vermilion border of the upper lip, short chin, and low-set, posteriorly rotated ears. Clinical details concerning all study participants are presented in Table 1. (A) Individual 1. Age 3 years; age 8 years. (B) Individual 3. Age 3 years, 7 months; age 11 years, 5 months. (C) Individual 4. Age 4 years, 6 months. (D) Individual 8. Age 4 years; age 10 years, 5 months. (E) Individual 9. Age 11 years. (F) Individual 10. Age 15 months; age 19 years. (G) Individual 11. Age 19 years, 7 months. (H) Individual 12. Age 4 years. (I) Individual 13. Age 3 years; age 7 years, 5 months.

Figure 2

Locations of FHS-Causing Mutations within SRCAP (A) Intron-exon structure of SRCAP. Exon 34 mutation cluster is indicated by a red bar. (B) Domain architecture of SRCAP indicates amino acid positions of recognized domains and FHS-causing mutations. All probands are heterozygous for truncating mutations at the positions shown. The ATPase domain of SRCAP is divided into two sections, one containing conserved motifs I-IV and one containing V-VI. The following abbreviation is used: HSA, Helicase-SANT-associated domain.