Floating-Harbor syndrome is a rare genetic disorder characterized by proportionate short stature, delayed bone age, delayed speech development, and typical facial features. The face is triangular with deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, and ... Floating-Harbor syndrome is a rare genetic disorder characterized by proportionate short stature, delayed bone age, delayed speech development, and typical facial features. The face is triangular with deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, and thin lips (Lacombe et al., 1995). Rubinstein-Taybi syndrome (see 180849), which shows phenotypic overlap with Floating-Harbor syndrome, is caused by mutation in the CREBBP gene (600140), for which SRCAP is a coactivator.
Robinson et al. (1988) used the designation Floating-Harbor syndrome for a syndrome that was first described by Pelletier and Feingold (1973) in a boy seen at the Boston Floating Hospital and by Leisti et al. (1975) in a ... Robinson et al. (1988) used the designation Floating-Harbor syndrome for a syndrome that was first described by Pelletier and Feingold (1973) in a boy seen at the Boston Floating Hospital and by Leisti et al. (1975) in a patient at the Harbor General Hospital in Torrance, California. The syndrome is characterized by a triad of short stature with significantly delayed bone age; expressive language delay, usually in the presence of normal motor development; and a triangular face with a prominent nose and deep-set eyes. Feingold (2006) provided a 32-year clinical follow-up of the first patient with Floating-Harbor syndrome reported by Pelletier and Feingold (1973). At 37 years of age, the patient was in good health except for arthritis and hypertension. His facial appearance remained fairly characteristic with low hairline, broad nasal tip, short nasal labial distance, depressed columella, thin lips, and posteriorly positioned ears. His stature remained short, and he had mild to moderate mental retardation. Feingold (2006) emphasized that the correct diagnosis of the syndrome should be based on the characteristic facial features. Patton et al. (1991) reviewed 7 families, each with a single affected patient. Two of the 7 were male. The chromosome studies were normal. Only one of the cases was the product of a consanguineous marriage, a third-cousin Iranian union. No information on parental age was provided. It is possible that this represents a new dominant mutation. Chudley and Moroz (1991) reported the case of a 17-year-old girl with celiac disease and features consistent with Floating-Harbor syndrome. Celiac disease had been reported in 1 of 6 previously reported cases. Majewski and Lenard (1991) reported the presumed seventh case. Lacombe et al. (1995) reported a case and reviewed 16 cases from the literature. The father was 54 years old and the mother 41. Growth and speech development were delayed throughout infancy, although motor development was normal. Proportionate short stature and characteristic face, which was triangular with broad and bulbous nose with a prominent nasal bridge, large nares, and a wide columella below the level of the nares, were described. Other facial features included glabella angioma, short philtrum, and thin upper and lower lips. There was brachyphalangy and bilateral fifth finger clinodactyly. At the age of 7 years and 9 months, she had the bone age of a 3-year-old. Dominant inheritance was suggested by the fact that the patient's mother had short stature (138 cm), mild mental retardation, and facial appearance resembling her daughter with a bulbous nose, thin lips, and brachyphalangy of hands and feet. Smeets et al. (1996) reported a girl with typical manifestations of the syndrome. The authors noted that marked speech delay and odd and hyperkinetic behavior may also be found in small children with Shprintzen velocardiofacial syndrome (192430). Ala-Mello and Peippo (1996) described a 6-year-old boy of Finnish origin who, in addition to typical manifestations of the syndrome, had unusual high-pitched voice and supernumerary upper incisor, 2 features that had not been reported in other patients. Abnormal high titers of gliadin antibodies suggesting celiac disease were also found in this boy. Celiac disease had been described in at least 3 other patients with Floating-Harbor syndrome. Ala-Mello and Peippo (1996) suggested that all patients with this syndrome should be examined for celiac disease. Ala-Mello and Peippo (2004) reported follow-up on the Finnish patient they reported in 1996. Reexamination at age 14 years showed classic facial features of the syndrome, with a more pronounced nose, prognathism, and hypoplasia of the maxilla. He had also had recurrent middle ear infections. Growth rate had accelerated (height at -0.7 SD), hands and feet were small (less than third percentile), and his pubertal stage was Tanner P3G3 with normal testicular size and normal bone age. His high-pitched voice described earlier was no longer so pronounced. Reticulin and gliadin antibody titers were normal. Davalos et al. (1996) described a 6-year-old Mexican girl whose clinical picture (short stature with delayed bone age, language difficulties, and triangular face with prominent nose) was compatible with the diagnosis of Floating-Harbor syndrome. Neuropsychologic evaluation disclosed mild mental retardation, constructive apraxia, and comprehensive and expressive language impairment. Sixteen previously described patients were reviewed. Midro et al. (1997) reported this syndrome in a 9-year-old girl who showed short stature, delayed bone age, mild mental retardation, speech problems, and specific craniofacial features. A girl with Floating-Harbor syndrome reported by Hersh et al. (1998) showed trigonocephaly due to metopic suture synostosis, preauricular pit, hypoplastic thumb, subluxated radial head, and Sprengel deformity. From a review of other cases they suggested that trigonocephaly may be an important craniofacial manifestation recognizable in infancy but becoming less noticeable later when the face develops a triangular shape, accentuated by a broad and bulbous nose. Wieczorek et al. (2001) reported 2 female patients, aged 11 and 8 years, with clinical findings consistent with Floating-Harbor syndrome. The first patient presented with characteristic facial features (large nose with wide columella and hypoplastic alae nasi, short philtrum, and prominent chin), brachydactyly, broad thumbs, and delayed speech development, but less pronounced short stature than previously reported. The second patient presented with short stature, characteristic facial features, brachydactyly, and delayed speech as well as mental development; she was successfully treated with growth hormone. Wieczorek et al. (2001) commented on the facial similarity of their 2 patients with the patient reported by Houlston et al. (1994) and reproduced pictures for comparison. They also commented on a similarity of the metacarpal phalangeal pattern profiles (MCPP) in their patients and in previously reported patients. Penaloza et al. (2003) suggested Floating-Harbor syndrome as the diagnosis in a 2-year-old boy with short stature, retarded speech development, delayed bone age, a bulbous nose, wide columella, and thin lips. Intestinal biopsy revealed villous atrophy compatible with celiac disease. The mother was thought to have minor phenotypic characteristics, supporting the possibility of dominant inheritance. She had a triangular face, deep-set eyes, a wide columella, and thin lips. Ioan and Fryns (2003) described 2 sisters with clinical histories and physical findings most compatible with the diagnosis of Floating-Harbor syndrome. Family data favored autosomal recessive inheritance, although germinal mosaicism for an autosomal dominant mutation could not be excluded. Both sisters had microcephaly and developmental delay, with expressive language being severely retarded. Both were of short stature and had distinct craniofacial appearance: triangular face with deeply-set eyes, large and bulbous nose with wide columella, short philtrum, high-arched palate, and low-set ears. Wiltshire et al. (2005) reported a patient with Floating-Harbor syndrome complicated by a tethered spinal cord. She had typical facies, delayed bone age, delay in expressive speech, and short stature treated with growth hormone. At age 6 years, she developed daytime enuresis, gait disturbance, hyperreflexia of the lower limbs, and extensor plantar responses. Spinal MRI showed tethered cord with a small lipoma. Surgical repair was successful. Wiltshire et al. (2005) suggested that increased growth velocity associated with growth hormone therapy may have unmasked the tethered cord in this patient. Karaer et al. (2006) reported an 8-year-old Turkish girl with microcephaly, normal psychomotor development with speech delay and a high-pitched voice, triangular face with temporal narrowing and posteriorly angulated ears, upslanting palpebral fissures, deep-set eyes with long eyelashes, large and protruding nose with wide columella and hypoplastic alae nasi, high-arched palate, and supernumerary incisor. She had short stature with delayed bone age, small hands and feet with hypermobile and hyperextensible fingers, and hirsutism, especially on the upper arms and shoulders. Her intellectual abilities were in the average range, but she had hyperactivity disorder and learning disabilities. She had constipation but no evidence of celiac disease. Karaer et al. (2006) stated that this was the first female Turkish patient with Floating-Harbor syndrome. Paluzzi et al. (2008) reported a woman who was diagnosed at 4.5 years of age with Floating-Harbor syndrome based on dysmorphic facial features involving a prominent nose with broad nares, short upper lip with a wide mouth, and a small jaw, in association with good perceptive language but delayed expressive speech, a petit mal seizure disorder, and short stature with delayed bone age. At 22 years of age, the patient presented with severe headache, vomiting, and neck stiffness and was found to have a ruptured aneurysm of the left internal carotid artery by CT angiography, which was successfully embolized. Fenestration of the distal internal carotid artery was also noted on the angiogram. White et al. (2010) reported 10 patients with a diagnosis of Floating-Harbor syndrome (FHS), including 1 previously studied patient ('patient 5' of Robinson et al., 1988). Serial photographs of the patients demonstrated that the dysmorphic facial features of FHS are age-related. In infancy and early childhood, deep-set eyes with relatively short palpebral fissures, a triangular configuration to the nasal tip, and a thin upper lip vermilion are seen; however, in later childhood, the classic facial appearance alters substantially, with widening of the palpebral fissures, which makes the eyes appear less deep-set, and increasing prominence of the nasal tip. In addition, bone age data in this study indicated that it is a reliable diagnostic feature under the age of 6 years, but may be normal in otherwise typical patients from 6 years to puberty. White et al. (2010) argued that the disorder of speech and language is more severe than previously recognized, noting that children with FHS have difficulties with all facets of motor speech production and that language, literacy, and social aspects of communication are severely impaired. Consistent with previous reports, most patients in this study were rated as having borderline normal intellectual function or a mild intellectual disability, and noted as having abnormal hands, albeit with variable features. Nelson et al. (2009) described a 5-year-old boy with short stature, delayed bone age, expressive language delay, developmental delay, and facial anomalies consistent with Floating-Harbor syndrome, who also developed an intramedullary ganglioglioma extending from T7 to the conus. The authors stated that this was the first report of a tumor associated with FHS. In a 9-year-old Turkish girl with Floating-Harbor syndrome who was being evaluated for hearing loss that showed only minimal improvement after the placement of grommets, Hendrickx et al. (2010) performed high-resolution CT of the temporal bone and observed bilateral prominent soft-tissue thickening between the head of the malleus and the anterior wall of the atticus. In addition, on the right, there was fusion of the head of the malleus with the body of the incus, whereas on the left, narrowing of the articulation between malleus and incus was seen. Hendrickx et al. (2010) stated that this was the first reported abnormal middle ear anatomy in a patient with FLHS.
Hood et al. (2012) performed exome capture and high-throughput sequencing in 5 unrelated probands with Floating-Harbor syndrome, including 2 patients (patients 9 and 10) previously studied by White et al. (2010), and identified heterozygosity in all 5 probands ... Hood et al. (2012) performed exome capture and high-throughput sequencing in 5 unrelated probands with Floating-Harbor syndrome, including 2 patients (patients 9 and 10) previously studied by White et al. (2010), and identified heterozygosity in all 5 probands for 3 truncating variants in the SRCAP gene (611421.0001-611421.0003, respectively). Analysis of SRCAP in an additional 8 probands, including 'patient 8' of White et al. (2010), identified 6 with heterozygosity for 2 of the previously identified mutations, respectively (611421.0001; 611421.0002), as well as 2 with heterozygosity for 2 more frameshift mutations. The mutations were shown to be de novo in all 6 instances in which parental DNA was available, and none were represented in dbSNP131, the 1000 Genomes Project, or the National Heart, Lung, and Blood Institute Exome Variant Server. The authors stated that the phenotype of mutation-positive individuals was concordant with earlier descriptions of FLHS, and that nearly all individuals had short stature and expressive language impairment. However, despite the remarkable similarity among mutations in these patients, all of which were truncating mutations tightly clustered in the last exon of the SRCAP gene, cognitive outcomes ranging from 'normal' to 'significant intellectual disability' were reported, suggesting that genetic modifiers and/or environmental factors might be involved. By whole-exome sequencing followed by Sanger sequencing, Le Goff et al. (2013) identified heterozygous mutations in the SRCAP gene in 6 of 9 patients with Floating-Harbor syndrome (see, e.g., 611421.0001, 611421.0002, and 611421.0004). There were no major clinical differences between the mutation-positive patients and those in whom no mutation was found. Le Goff et al. (2013) concluded that Floating-Harbor syndrome is a clinically homogeneous but genetically heterogeneous condition, although they noted that partial intragenic deletions or mutations in the introns or promoter region could not be excluded in the mutation-negative patients.
The diagnosis of Floating-Harbor syndrome (FHS) is suspected in those with typical clinical findings (especially facial features) and confirmed by the presence of a heterozygous SRCAP mutation. ...
DiagnosisThe diagnosis of Floating-Harbor syndrome (FHS) is suspected in those with typical clinical findings (especially facial features) and confirmed by the presence of a heterozygous SRCAP mutation. Craniofacial appearance (see Figure 1)FigureFigure 1. Facial appearance of an 11-year-old girl with FHS (SRCAP mutation p.Arg2444*) A. Note triangular face with deep-set eyes; short philtrum; long nose with narrow bridge and broad base with low hanging columella; and thin upper (more...)Triangular faceDeep-set eyesShort philtrum Wide mouth with a thin vermilion border of the upper lipLong nose with a narrow bridge, broad base, full tip and low-hanging columellaLow-set earsOther featuresSignificant delay in bone age (-2 SD or greater) with normalization between ages six and 12 years Skeletal anomalies: brachydactyly, broad fingertips that give the appearance of clubbing, clinodactyly, short thumbs, prominent joints, clavicular abnormalities (see Figure 2) Short adult stature: 140-155 cm (see Figure 3)FigureFigure 2. Dorsal (A) and palmar (B) view of the hands of the girl in Figure 1. Note clinodactyly, widened fingertips, and prominent joints. FigureFigure 3. Frontal view of the girl in Figure 1. She has proportionate short stature with height <3rd centile. Speech and languageDysarthria and verbal dyspraxia with phoneme imprecisionHypernasalityHigh-pitched voiceSevere receptive and expressive language impairment across all domains of functionIntellectual disability. All individuals have some degree of intellectual impairment and/or learning disability ranging from borderline normal to moderate intellectual disability.Molecular Genetic TestingGene. SRCAP is the only gene in which mutations are known to cause Floating-Harbor syndrome.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Floating-Harbor Syndrome View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySRCAPSequence analysisSequence variants 2Unknown 3Clinical Sequence analysis of select exons 4Sequence variants in exon 34Observed in 19 patients reported to date 3, 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Hood et al [2012]4. Exons may vary by laboratory.5. Goff et al [2012]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. The diagnosis of FHS is suspected in those with characteristic clinical findings and confirmed in those with a heterozygous SRCAP mutation.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this GeneReview chapter are known to be associated with mutations in SRCAP.
Prior to the molecular characterization of Floating-Harbor syndrome (FHS) by Hood et al [2012], a number of reports included descriptions of individuals in whom the diagnosis of FHS could be questioned. This GeneReview chapter only includes information on those 19 individuals with molecularly confirmed FHS (i.e., presence of a heterozygous SRCAP mutation) [Goff et al 2012, Hood et al 2012]. The six females and 13 males range in age from 11 months to 32 years....
Natural History Prior to the molecular characterization of Floating-Harbor syndrome (FHS) by Hood et al [2012], a number of reports included descriptions of individuals in whom the diagnosis of FHS could be questioned. This GeneReview chapter only includes information on those 19 individuals with molecularly confirmed FHS (i.e., presence of a heterozygous SRCAP mutation) [Goff et al 2012, Hood et al 2012]. The six females and 13 males range in age from 11 months to 32 years.FHS is frequently recognized in early childhood because of the characteristic facial features (Figure 1). Infants and younger children are often referred for assessment of poor growth or developmental (predominantly speech and language) delay.Intellect. Although gross motor and fine motor milestones are within normal limits, affected individuals typically have mild to moderate intellectual disability. A disorder of speech and language is the most severe disability. Most aspects of communication are affected; expressive language is most consistently and severely affected. Speech is absent in some.The majority of affected children receive mainstream education with individualized educational plans. Regression of skills is not typical of FHS. Behavior. Many individuals with FHS have temperament and behavior differences and difficulties: temper tantrums in infancy and attention deficit-hyperactivity disorder (ADHD) spectrum with impulsivity, inattention, and restlessness at school age. Aggressive and violent outbursts can occur. Obsessive compulsive disorder (OCD) and anxiety have been observed. Behavioral problems are reported to improve in adulthood. Growth. Short stature is a cardinal sign of FHS.The majority of individuals with FHS have low birth weight (from -3 SD to 0 SD) and normal head circumference (-2 SD to 0 SD). In the first years of life weight gain and linear growth are poor. Average adult height is 140-155 cm. Puberty. Early puberty has been reported; data are insufficient to determine the incidence in either gender.Eye. Three of 19 patients have been reported with hyperopia and one of 13 with strabismus. One patient had anterior chamber abnormalities.Hearing. Conductive hearing loss has been seen in three of 19 individuals with FHS. Cochlear abnormality has been observed in one of 19.Neurologic. Seizures have been observed in three of 19 patients. Gastrointestinal. Reflux can be severe, requiring G-tube feeding in some. Constipation and colonic strictures have been observed. One of 19 patients had celiac disease; two had transient gluten intolerance. Genitourinary. Renal and genitourinary anomalies can occur and include hypospadias and undescended testes, epididymal cysts, varicocele, and posterior urethral valves in boys. Hydronephrosis/renal pelviectasis and nephrocalcinosis, renal cysts, and renal agenesis have been observed. One adult of the 19 reported individuals developed polycystic kidney disease and end-stage renal disease (ESRD).Orthopedic. The body habitus is often stocky with a broad chest and short neck. Additional features include hand anomalies such as clinodactyly, brachydactyly, short thumbs, and broad fingertips that give the appearance of clubbing (Figure 2). Clavicular anomalies including pseudarthrosis and clavicular hypoplasia have been observed, as have short metacarpals, 11 pairs of ribs, kyphoscoliosis, dysplastic hips, and dislocated radial heads. Dental. A number of individuals with FHS have dental problems (e.g., caries, microdontia, delayed loss of primary teeth) and orthodontic problems (e.g., maxillary retrusion, underbite).Cardiac. Cardiac malformations are not usually a feature of FHS. Of 19 affected individuals one had mild aortic coarctation, one mesocardia with persistent left superior vena cava, and one atrial septal defect.
The distinctive facial features, bone age delay, and characteristic speech disability that make the diagnosis of Floating-Harbor syndrome (FHS) straightforward in early childhood become less distinct with age. The following conditions should be considered in children in whom the diagnosis of FHS is suspected....
Differential DiagnosisThe distinctive facial features, bone age delay, and characteristic speech disability that make the diagnosis of Floating-Harbor syndrome (FHS) straightforward in early childhood become less distinct with age. The following conditions should be considered in children in whom the diagnosis of FHS is suspected.Broad or angulated thumbs and low hanging columella are typically seen in Rubinstein-Taybi syndrome(RSTS). RSTS is characterized by distinctive facial features that include downward-slanting palpebral fissures, low-hanging columella, high palate, grimacing smile, and talon cusps. The clinical diagnosis of RSTS can be confirmed by identification of a heterozygous mutation in either CREBBP or EP300, the only genes in which mutation is known to cause RSTS. Mode of inheritance is autosomal dominant, with most affected individuals having a de novo mutation.Russell-Silver syndrome (RSS) is characterized by intrauterine growth retardation accompanied by postnatal growth deficiency. Affected individuals typically have proportionately short stature, normal head circumference, fifth-finger clinodactyly, typical facial features with triangular facies characterized by broad forehead and narrow chin, and limb-length asymmetry that may result from hemihypotrophy with diminished growth of the affected side. Growth velocity is normal in children with RSS. The average adult height of males is 151.2 cm and that of females is 139.9 cm. Individuals with RSS are at significant risk for developmental delay (both motor and cognitive) and learning disabilities. RSS is a genetically heterogeneous condition and for most affected individuals represents a phenotype rather than a specific disorder.3-M syndrome is characterized by severe pre- and postnatal growth retardation (final height 5-6 SD below the mean; i.e., 120-130 cm), characteristic facies with relatively large head, triangular face, hypoplastic midface, full eyebrows, fleshy nasal tip, long philtrum, prominent mouth and lips, pointed chin, and normal intelligence. Additional features of 3-M syndrome include short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, short fifth fingers, prominent heels, and loose joints. The bone age may be slightly delayed. Males with 3-M syndrome have hypogonadism and, occasionally, hypospadias. Characteristic radiologic findings differentiate 3M syndrome from Floating-Harbor syndrome. Biallelic mutations in one of three genes – CUL7, OBSL1, and CCDC8 – are now known to cause 3-M syndrome. Mode of inheritance is autosomal recessive.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with Floating-Harbor syndrome (FHS), the following evaluations are recommended: ...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with Floating-Harbor syndrome (FHS), the following evaluations are recommended: Multidisciplinary developmental evaluation including assessment of gross and fine motor skills, speech/language, cognitive abilities, and vocational skills with special attention to speech delay and anomaliesMeasurement of growth and plotting of growth parameters Note: Syndrome-specific charts are currently not available for children with a SRCAP mutation.Ophthalmologic examinationHearing evaluation (See Deafness and Hereditary Hearing Loss Overview for details of evaluation.)Renal ultrasound examination and blood pressure assessmentAssessment for cryptorchidism in malesOrthopedic assessment of hip dysplasia and clavicular anomaliesDental evaluationMedical genetics consultationTreatment of ManifestationsTreatment includes the following:Early intervention programs, special education, and vocational training to address developmental disabilitiesCommunication rehabilitation with sign languages or alternative means of communicationBehavior management strategies including referral to a behavioral specialist/psychologist and consideration of medication if neededReferral of the family to support groups and other resourcesStandard treatment for any of the following if identified:Refractive errors and strabismusHearing lossSeizuresRenal diseaseCryptorchidismOrthopedic complicationsDental problemsReferral to an endocrinologist for consideration of human growth hormone (HGH) therapy. HGH therapy with modest response has been reported in three children with FHS. Caution is indicated as limited information about HGH therapy in FHS is available.Investigation for celiac disease if indicated by clinical featuresSurveillanceSurveillance includes the following:Close monitoring of growth, especially in the first year of life. Annual: Ophthalmologic evaluationAudiologic screening; more frequent evaluation if there is a history of multiple episodes of otitis mediaBlood pressure measurement and assessment of renal functionStandard monitoring for renal anomaliesMonitoring of bone age and for early puberty especially in cases of growth hormone useSonographic evaluation for renal cysts in teenage/adult years as indicated by abnormalities on the renal function tests and/or blood pressure measurementEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management No specific pregnancy complications for the mother or the fetus have been observed in the two women with a SRCAP mutation who had children with FHS.Therapies Under InvestigationSearch Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Floating-Harbor Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSRCAP16p11.2Helicase SRCAPSRCAP @ LOVDSRCAPData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Floating-Harbor Syndrome (View All in OMIM) View in own window 136140FLOATING-HARBOR SYNDROME; FLHS 611421SNF2-RELATED CBP ACTIVATOR PROTEIN; SRCAPNormal allelic variants. SRCAP encodes the core catalytic component of the multi-protein chromatin-remodeling SRCAP complex (NM_006662.2 ). SRCAP is 154 kb in length and comprises 34 exons; exons 1 and 2 are noncoding. Pathologic allelic variants. In 13 individuals with FHS reported by Hood et al [2012] all SRCAP mutations were observed in exon 34. All pathogenic allelic variants (frameshift or nonsense) predict a truncated protein and are clustered between codons 2,407 and 2,517. The two observed recurrent mutations are described in Table 2 [Hood et al 2012]. Table 2. Selected SRCAP Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.7303C>Tp.Arg2435*NM_006662.2 NP_006653.2c.7330C>Tp.Arg2444*See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). Normal gene product. Helicase SRCAP, a 400-kd nuclear protein of 3230 amino acids, mediates different intracellular signaling pathways as well as chromatin remodeling. The encoded protein is an ATPase that is necessary for the incorporation of the histone variant H2A.Z into nucleosomes. It is an interacting partner of CREB binding protein (CREBBP, also known as CBP). SRCAP is a potent coactivator for CREB and CBP-mediated transcription. It also functions as a transcriptional activator in Notch-mediated and steroid receptor-mediated transcription. Abnormal gene product. Germline mutations in SRCAP associated with FHS may lead to a gene product with abolished transactivation function located in the 655-residue C-terminal fragment. These mutations may result in a dominant-negative disease mechanism.