SRCAP – Floating-Harbor syndrome

Floating-Harbor syndrome (FHS) is a rare autosomal dominant neurodevelopmental disorder characterized by proportionate short stature, delayed bone maturation, expressive and receptive speech impairment, and a distinctive triangular facial gestalt. FHS is caused by heterozygous truncating mutations in the SRCAP gene, which encodes the SNF2-related CREBBP activator protein, a chromatin remodeler that interfaces with histone acetyltransferase complexes. Genetic sequencing studies across multiple cohorts have consistently identified de novo truncating variants clustered in exons 33 and 34 of SRCAP, defining a mutational hotspot responsible for FHS pathogenesis.

Inheritance is autosomal dominant, with most pathogenic alleles arising de novo; parental transmission has been documented in at least two families, confirming vertical segregation of heterozygous truncating mutations. In the initial exome-based cohort, 13 unrelated probands harbored heterozygous truncating SRCAP variants ([PMID:22265015]). Subsequent reports and case series have expanded this to over 100 molecularly confirmed cases worldwide ([PMID:35664296]).

Pathogenic variants are overwhelmingly loss-of-function alleles—nonsense and frameshift mutations—that truncate the C-terminal AT-hook motifs while preserving ATPase and CREBBP-binding domains. Two recurrent hotspots, c.7303C>T (p.Arg2435Ter) and c.7330C>T (p.Arg2444Ter), account for a large fraction of cases and have been observed across diverse ethnicities. One representative variant is c.7303C>T (p.Arg2435Ter), a de novo nonsense change validated by Sanger sequencing in multiple studies.

Functional assays support a dominant-negative mechanism: FHS-associated truncations disrupt SRCAP nuclear localization, perturb incorporation of the histone variant H2A.Z at AT-rich enhancers, and alter neural crest gene programs in human iPSC-derived models and Xenopus embryos, recapitulating key craniofacial defects of FHS ([PMID:31491386]). Patient-derived iPSC lines carrying heterozygous exon 34 truncations exhibit abnormal pluripotency marker expression and impaired differentiation, reinforcing the pathogenic role of C-terminal loss.

Clinically, FHS patients require multidisciplinary monitoring: growth hormone therapy produces modest height gains in some individuals, while renal ultrasound screening is advised given reports of hypertension and adult-onset polycystic kidneys. Regular blood pressure assessment and neurodevelopmental evaluation are critical, as are ophthalmologic exams following reports of chorioretinal colobomas.

In summary, the definitive association between heterozygous truncating SRCAP variants and Floating-Harbor syndrome underpins genetic testing for early diagnosis and tailored surveillance. Identification of SRCAP mutations informs prognosis, guides endocrine and renal management, and enables accurate genetic counseling.

References

• American Journal of Human Genetics • 2012 • Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome. PMID:22265015
• Frontiers in Genetics • 2022 • Molecular Genetics and Pathogenesis of the Floating Harbor Syndrome: Case Report of Long-Term Growth Hormone Treatment and a Literature Review. PMID:35664296
• Cell • 2019 • Single Amino Acid Change Underlies Distinct Roles of H2A.Z Subtypes in Human Syndrome. PMID:31491386
• Journal of Medical Genetics • 2016 • When chromatin organisation floats astray: the Srcap gene and Floating-Harbor syndrome. PMID:27208210

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