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• W2039180361 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. 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. Floating-Harbor syndrome (FHS [MIM 136140]) is a rare condition characterized by short stature, delayed osseous maturation, language deficits, and a distinctive facial appearance. The dysmorphic features typical of this disorder include a triangular face, short philtrum, wide mouth with a thin vermilion border of the upper lip, and long nose with a narrow bridge, broad base, full tip, and low-hanging columella.1Pelletier G. Feingold M. Case report 1.in: Bergsma D. Syndrome Identification. National Foundation-March of Dimes, White Plains, NY1973: 8-9Google Scholar, 2Leisti J. Hollister D.W. Rimoin D.L. The Floating-Harbor syndrome.Birth Defects Orig. Artic. Ser. 1975; 11: 305PubMed Google Scholar, 3Robinson P.L. Shohat M. Winter R.M. Conte W.J. Gordon-Nesbitt D. Feingold M. Laron Z. Rimoin D.L. A unique association of short stature, dysmorphic features, and speech impairment (Floating-Harbor syndrome).J. Pediatr. 1988; 113: 703-706Abstract Full Text PDF PubMed Scopus (55) Google Scholar, 4White S.M. Morgan A. Da Costa A. Lacombe D. Knight S.J. Houlston R. Whiteford M.L. Newbury-Ecob R.A. Hurst J.A. The phenotype of Floating-Harbor syndrome in 10 patients.Am. J. Med. Genet. A. 2010; 152A: 821-829Crossref PubMed Scopus (40) Google Scholar Some degree of intellectual or learning disability is present in most individuals, and language (both receptive and expressive) is typically more severely affected. The name “Floating Harbor” is a portmanteau of Boston Floating Hospital and Harbor General Hospital (Torrance, CA), the two institutions from which the initial case reports originated.1Pelletier G. Feingold M. Case report 1.in: Bergsma D. Syndrome Identification. National Foundation-March of Dimes, White Plains, NY1973: 8-9Google Scholar, 2Leisti J. Hollister D.W. Rimoin D.L. The Floating-Harbor syndrome.Birth Defects Orig. Artic. Ser. 1975; 11: 305PubMed Google Scholar Of the 50 or so cases of FHS in the literature, the majority are sporadic, although four reported instances of parent-to-child transmission suggest that this is an autosomal-dominant disorder in at least some instances.4White S.M. Morgan A. Da Costa A. Lacombe D. Knight S.J. Houlston R. Whiteford M.L. Newbury-Ecob R.A. Hurst J.A. The phenotype of Floating-Harbor syndrome in 10 patients.Am. J. Med. Genet. A. 2010; 152A: 821-829Crossref PubMed Scopus (40) Google Scholar, 5Lacombe D. Patton M.A. Elleau C. Battin J. Floating-Harbor syndrome: Description of a further patient, review of the literature, and suggestion of autosomal dominant inheritance.Eur. J. Pediatr. 1995; 154: 658-661Crossref PubMed Scopus (39) Google Scholar, 6Peñaloza J.M. García-Cruz D. Dávalos I.P. Dávalos N.O. García-Cruz M.O. Pérez-Rulfo D. Sánchez-Corona J. A variant example of familial Floating-Harbor syndrome?.Genet. Couns. 2003; 14: 31-37PubMed Google Scholar, 7Arpin S. Afenjar A. Dubern B. Toutain A. Cabrol S. Héron D. Floating-Harbor Syndrome: Report on a case in a mother and daughter, further evidence of autosomal dominant inheritance.Clin. Dysmorphol. 2012; 21: 11-14Crossref PubMed Scopus (12) Google Scholar Some authors have highlighted the clinical overlap between FHS and Rubinstein-Taybi syndrome (RTS [MIM 180849]), which shares several key features (short stature, a long nose with low-hanging columella, a thin vermilion border of the upper lip, and anomalous thumbs).3Robinson P.L. Shohat M. Winter R.M. Conte W.J. Gordon-Nesbitt D. Feingold M. Laron Z. Rimoin D.L. A unique association of short stature, dysmorphic features, and speech impairment (Floating-Harbor syndrome).J. Pediatr. 1988; 113: 703-706Abstract Full Text PDF PubMed Scopus (55) Google Scholar, 7Arpin S. Afenjar A. Dubern B. Toutain A. Cabrol S. Héron D. Floating-Harbor Syndrome: Report on a case in a mother and daughter, further evidence of autosomal dominant inheritance.Clin. Dysmorphol. 2012; 21: 11-14Crossref PubMed Scopus (12) Google Scholar Despite the recognition of FHS as a distinct clinical entity more than 25 years ago, no causative mutations have been identified to date. To identify the genetic basis of FHS, we assembled a cohort of 13 unrelated probands, three of whom were previously reported.4White S.M. Morgan A. Da Costa A. Lacombe D. Knight S.J. Houlston R. Whiteford M.L. Newbury-Ecob R.A. Hurst J.A. The phenotype of Floating-Harbor syndrome in 10 patients.Am. J. Med. Genet. A. 2010; 152A: 821-829Crossref PubMed Scopus (40) Google Scholar The clinical details of these individuals are presented in Table 1 and Figure 1. To identify FHS-causing mutations, we performed exome capture and high-throughput sequencing of five unrelated affected persons (probands 1–5). Approval of the study design was obtained from the institutional research ethics board (Children's Hospital of Eastern Ontario), and free and informed consent was obtained from each study subject (or parent, if appropriate) prior to enrollment. We performed exome target enrichment by using the Agilent SureSelect 50 Mb All Exon Kit, and sequencing (Illumina HiSeq) generated 35–40 Gbp of 100 bp paired-end reads per sample. Reads were preprocessed (trimmed) and aligned to hg19 (see Web Resources for list of tools). We used an in-house annotation pipeline to identify coding and splice-site variants that met a minimum quality threshold (i.e., ≥20% of reads supported the variant). Next, we filtered the variants to exclude common polymorphisms (>1% minor-allele frequency) represented in dbSNP131, in the 1000 Genomes pilot release, or in 270 exomes sequenced for individuals with unrelated disorders at our center.Table 1Phenotype of Floating-Harbor Syndrome Probands with SRCAP MutationsaThis table summarizes the clinical findings in all study participants. Five participants (discovery cohort; individuals 1–5) underwent exome sequencing. Mutations in individuals 6–13 (validation cohort) were identified with Sanger sequencing.Proband12345678910111213Mutation (cDNA)c.7330C>Tc.7330C>Tc.7330C>Tc.730C>Tc.7549delCc.7330C>Tc.7330C>Tc.7330C>Tc.7303C>Tc.7303C>Tc.7303C>Tc.7218_7219delTCc.7316dupCAlteration (protein)p.Arg2444∗p.Arg2444∗p.Arg2444∗p.Arg2435∗p.Gln2517fs∗5p.Arg2444∗p.Arg2444∗p.Arg2444∗p.Arg2435∗p.Arg2435∗p.Arg2435∗p.Gln2407fs∗35p.Ala2440fs∗3Inheritanceunknownunknownunknownde novode novode novode novounknownunknownunknownunknownde novode novoSexMFMMMMMFMMMMMEthnicityFrenchmixed Europeanmixed EuropeanFinnishGerman and MexicanBrazilianGermanCaucasianCaucasianBrazilianBrazilianChinesePolishPaternal age (year)28432935393244403441404035Gestation (weeks)40403837394039314139404041Birth weight (g)3,040 (−0.7 SD)3,060 (−0.6 SD)2,400 (−1.7 SD)2,620 (−0.5 SD)2,515 (−2.2 SD)2,555 (−1.8 SD)2,430 (−2.4 SD)1,655 (0 SD)2,900 (−1.0 SD)2,550 (−1.8 SD)2,030 (−3.1 SD)2,800 (−1.1 SD)2,730 (−1.5 SD)Age at diagnosis3 years10 years15 months11 years4 years, 3 months3 years, 3 months4 years, 4 months4 years11 months7 years, 5 months8 years10 years35 monthsALA8 years12 years12 years11 years4 years, 3 months4 years4 years, 4 months10 years, 5 months11 years19 years19 years, 7 months11 years7 years, 5 monthsHead circumference (cm) ALA54 (+1 SD)0 SD53 (−1 SD)53.5 (0 SD)48.5 (−1.7 SD)48 (−2 SD)50 (+0.7 SD)49.5 (−1 SD)50.5 (−2 SD)52 (−2.5 SD)56 (0 SD)53 (0 SD)51.5 (−0.5 SD)Weight (kg) ALA25.5 (0 SD)35.6 (−0.8 SD)N/R22.4 (−3.2 SD)11 (−3.4 SD)12 (−2.5 SD)12.5 (−2.4 SD)19.3 (−3.3 SD)20 (−4.2 SD)37.6 (−5.3 SD)62.1 (−0.7 SD)35 (0 SD)20 (−1.4 SD)Height (cm) ALA123 (−0.8 SD)133.5 (−2.2 SD)134.8 (−2.0 SD)122 (−3.1 SD)86.5 (−4.3 SD)89.8 (−3.2 SD)90 (−3.6 SD)118.5 (−3.5 SD)116.8 (−3.9 SD)145.5 (−4.1 SD)148 (−3.8 SD)139 (−0.6 SD)111 (−2.5 SD)Age at pubertyN/A12 yearsN/AN/AN/AN/AN/AN/APubertal age 14 years at CA 11 yearsN/RN/R10 yearsN/APrepubertal height−0.8 SD−2.2 SD−2.0 SD−3.1 SD−4.4 SD−3.2 SD−3.6 SD−3.5 SDN/RN/RN/R−3 SD−2.5 SDBA versus CABA 2.5 years at CA 7.5 yearsBA 2 years, 6 months at CA 5 years,7 months; BA 11 years at CA 9 years, 9 monthsBA 8 years at CA 11 yearsBA 2 years at CA 4 years, 8 months; BA 9 years at CA10 years, 8 monthsBA 1 year at CA 2 years, 11 monthsBA 1 year at CA 3 yearsBA 3 years at CA 4 yearsBA 1 year at CA 5 yearsBA 3–6 months at CA 1 yearBA 2 years, 8 months at CA 7 yearsBA 3 years at CA 7 yearsBA 10 years, 6 months at CA 11 years, 4 monthsBA 8 months at CA 2 years, 8 monthsTriangular face+++++N/R-++++++Distinctive nose+++++++++++++Low-hanging columella+++++++++++++Short philtrum+++++++++-+-+Thin upper vermilion border++++--+++--++Wide mouth+-+++/−++++++++Low-set ears++-++-+++--++Broad thumbs-+-+++-N/RN/RN/R+++Broad fingertips-+++N/RN/R-N/R+N/R+++Brachydactyly-+++-fifth toes-+-N/R+++Clinodactyly-N/Rradial deviation fifth distal phalanx++--++N/R+++Other skeletalN/RN/Rdislocated radial head, 11 rib pairsN/Rshort fifth metacarpalN/Rclavicular hypoplasiakyphoscoliosisdysplastic hips11 rib pairs, ivory epiphyses in distal phalangesshort middle phalanges of second and fifth fingersshort first metacarpalshort fifth metacarpalDental issuesN/RN/Rmaxillary retrusion, underbitecaries, microdontiaN/RN/RN/Rcaries, delayed loss of primary teethN/RN/Rnormalcaries, microdontia, underbiteN/ROther health issueshypospadias, celiac diseasehydronephrosis, nephrocalcinosis, recurrent otitis mediaaortic coarctation (mild)cryptorchidism, hyperopia, conductive hearing losshyperopiaASD, hyperopia, unilateral renal pelviectasismesocardia, persistent left superior vena cava, conductive hearing lossconstipationbilateral inguinal hernia, cryptorchidism, VPI, hearing lossposterior urethral valves, umbilical herniastrabismusbilateral epididymal cysts, left varicoceleunilateral cleft lip, cryptorchidismIntellectual developmentborderline normalnormalborderline normalborderline normalnormalmoderate delayborderline normalmild intellectual disabilitymoderately severe learning disabilitysignificant intellectual disabilityintellectual disabilityborderline normalmild intellectual disabilityExpressive language delaydelaymoderate delaymoderate delayimpairmentborderline normal, bilingualmoderate delaymoderate delaysevere delaymoderate delaysome wordsmoderate delaymoderate delaymoderate delayEducationmainstream with supportmainstream with supportmainstream with supportspecial schoolmainstreamN/Amainstream with supportmodified classroomspecial schoolspecial schoolspecial schoolmodified classroommainstream with supportMicroarray findings and (type)normal (44K)normal (Affymetrix 2.7M)normal (180K Agilent)normal (105K)7q31dup (paternally inherited)Xp22.31dup (maternally inherited)N/AN/AN/AN/Anormal 22q11normal (Agilent 6.1)normal (244K Agilent)ReferenceWhite et al,4White S.M. Morgan A. Da Costa A. Lacombe D. Knight S.J. Houlston R. Whiteford M.L. Newbury-Ecob R.A. Hurst J.A. The phenotype of Floating-Harbor syndrome in 10 patients.Am. J. Med. Genet. A. 2010; 152A: 821-829Crossref PubMed Scopus (40) Google Scholar person 10White et al,4White S.M. Morgan A. Da Costa A. Lacombe D. Knight S.J. Houlston R. Whiteford M.L. Newbury-Ecob R.A. Hurst J.A. The phenotype of Floating-Harbor syndrome in 10 patients.Am. J. Med. Genet. A. 2010; 152A: 821-829Crossref PubMed Scopus (40) Google Scholar person 9this reportthis reportthis reportthis reportthis reportthis reportWhite et al,4White S.M. Morgan A. Da Costa A. Lacombe D. Knight S.J. Houlston R. Whiteford M.L. Newbury-Ecob R.A. Hurst J.A. The phenotype of Floating-Harbor syndrome in 10 patients.Am. J. Med. Genet. A. 2010; 152A: 821-829Crossref PubMed Scopus (40) Google Scholar person 8this reportthis reportthis reportthis reportNumbering of mutations is relative to NM_006662.2 (gene) and NP_006653 (protein). Abbreviations are as follows: ALA, at last assessment; N/A, Not Applicable; N/R, Not Reported; +, Feature Present; -, Feature Absent; SD, standard deviations; BA, bone age; CA, chronological age; ASD, atrial septal defect; and VPI, velopharyngeal incompetence.a This table summarizes the clinical findings in all study participants. Five participants (discovery cohort; individuals 1–5) underwent exome sequencing. Mutations in individuals 6–13 (validation cohort) were identified with Sanger sequencing. Open table in a new tab Numbering of mutations is relative to NM_006662.2 (gene) and NP_006653 (protein). Abbreviations are as follows: ALA, at last assessment; N/A, Not Applicable; N/R, Not Reported; +, Feature Present; -, Feature Absent; SD, standard deviations; BA, bone age; CA, chronological age; ASD, atrial septal defect; and VPI, velopharyngeal incompetence. Presuming FHS to be an autosomal-dominant condition, we identified genes containing a single rare variant in each of several probands in a combinatorial fashion. Table 2 lists the numbers of potential candidate genes containing rare variants in any n probands as n is increased. Of five sequenced individuals with classic FHS, we noted that all contained heterozygous truncating variants clustered in the final (34th) exon of a single gene, SRCAP (encoding SNF2-related CREBBP activator protein). To confirm SRCAP as the gene mutated in FHS, we identified SRCAP exon 34 mutations with Sanger sequencing in a validation cohort of eight more unrelated probands (Table 1 and Figure 2; Figure S1, available online). All of these mutations are truncating (nonsense or frameshift) alleles, tightly clustered between codons 2,407 and 2,517; none are represented in dbSNP131, 1000 Genomes, or the National Heart, Lung, and Blood Institute (NHLBI) Exome Variant Server (see Web Resources). Two mutations in particular, c.7330C>T (NM_006662.2) (p.Arg2444∗ [NP_006653]) in six individuals and c.7303C>T (p.Arg2435∗) in four individuals, accounted for the large majority of mutations. FHS-causing mutations were shown to be de novo in all six instances in which parental DNA samples were available.Table 2Variant Analysis in Floating-Harbor Syndrome ProbandsAny X of five individuals12345Number of genes containing missense, nonsense, insertion, deletion, or splice-site variants2,3753074882Allele frequency ≤1% in dbSNP131 and 1000 Genomes; not represented in 270 local exomes1,178703SRCAPSRCAP Open table in a new tab SRCAP encodes a switch/sucrose nonfermentable (SWI/SNF)-type chromatin-remodeling ATPase identified in a two-hybrid screen for interacting partners of CREB-binding protein (CREBBP, hereafter called CBP).8Johnston H. Kneer J. Chackalaparampil I. Yaciuk P. Chrivia J. Identification of a novel SNF2/SWI2 protein family member, SRCAP, which interacts with CREB-binding protein.J. Biol. Chem. 1999; 274: 16370-16376Crossref PubMed Scopus (73) Google Scholar In reporter assays, SRCAP is a potent coactivator for CREB and CBP-mediated transcription.8Johnston H. Kneer J. Chackalaparampil I. Yaciuk P. Chrivia J. Identification of a novel SNF2/SWI2 protein family member, SRCAP, which interacts with CREB-binding protein.J. Biol. Chem. 1999; 274: 16370-16376Crossref PubMed Scopus (73) Google Scholar, 9Monroy M.A. Ruhl D.D. Xu X. Granner D.K. Yaciuk P. Chrivia J.C. Regulation of cAMP-responsive element-binding protein-mediated transcription by the SNF2/SWI-related protein, SRCAP.J. Biol. Chem. 2001; 276: 40721-40726Crossref PubMed Scopus (34) Google Scholar In transgenic Drosophila, exogenous SRCAP colocalizes with transcriptionally active chromatin and augments CBP's presence at these sites.10Eissenberg J.C. Wong M. Chrivia J.C. Human SRCAP and Drosophila melanogaster DOM are homologs that function in the notch signaling pathway.Mol. Cell. Biol. 2005; 25: 6559-6569Crossref PubMed Scopus (47) Google Scholar Affinity-purified SRCAP precipitates as a large complex that catalyzes ATP-dependent substitution of the variant histone H2A.Z into nucleosomes.11Ruhl D.D. Jin J. Cai Y. Swanson S. Florens L. Washburn M.P. Conaway R.C. Conaway J.W. Chrivia J.C. Purification of a human SRCAP complex that remodels chromatin by incorporating the histone variant H2A.Z into nucleosomes.Biochemistry. 2006; 45: 5671-5677Crossref PubMed Scopus (187) Google Scholar This activity has been confirmed by knockdown experiments with natural promoters, and it is correlated with in vivo target-gene expression.12Wong M.M. Cox L.K. Chrivia J.C. The chromatin remodeling protein, SRCAP, is critical for deposition of the histone variant H2A.Z at promoters.J. Biol. Chem. 2007; 282: 26132-26139Crossref PubMed Scopus (126) Google Scholar Separately, SRCAP has also been shown to transduce signals belonging to the nuclear (steroid) hormone receptor and Notch pathways, indicating that it has diverse roles in gene expression.10Eissenberg J.C. Wong M. Chrivia J.C. Human SRCAP and Drosophila melanogaster DOM are homologs that function in the notch signaling pathway.Mol. Cell. Biol. 2005; 25: 6559-6569Crossref PubMed Scopus (47) Google Scholar, 13Monroy M.A. Schott N.M. Cox L. Chen J.D. Ruh M. Chrivia J.C. SNF2-related CBP activator protein (SRCAP) functions as a coactivator of steroid receptor-mediated transcription through synergistic interactions with CARM-1 and GRIP-1.Mol. Endocrinol. 2003; 17: 2519-2528Crossref PubMed Scopus (36) Google Scholar In keeping with its multiple coactivator roles, SRCAP contains several discrete functional domains.8Johnston H. Kneer J. Chackalaparampil I. Yaciuk P. Chrivia J. Identification of a novel SNF2/SWI2 protein family member, SRCAP, which interacts with CREB-binding protein.J. Biol. Chem. 1999; 274: 16370-16376Crossref PubMed Scopus (73) Google Scholar, 9Monroy M.A. Ruhl D.D. Xu X. Granner D.K. Yaciuk P. Chrivia J.C. Regulation of cAMP-responsive element-binding protein-mediated transcription by the SNF2/SWI-related protein, SRCAP.J. Biol. Chem. 2001; 276: 40721-40726Crossref PubMed Scopus (34) Google Scholar, 10Eissenberg J.C. Wong M. Chrivia J.C. Human SRCAP and Drosophila melanogaster DOM are homologs that function in the notch signaling pathway.Mol. Cell. Biol. 2005; 25: 6559-6569Crossref PubMed Scopus (47) Google Scholar These domains include an SNF2-like ATPase, an N-terminal HSA (Helicase-SANT-associated) domain, and three C-terminal AT-hook DNA-binding motifs; the CBP interaction domain of SRCAP is located centrally (Figure 2). Given the structure of SRCAP, the nonrandom clustering of truncating mutations seen in our study participants is strongly suggestive of a dominant-negative disease mechanism due to loss of one or more critical domain(s), for instance the three C-terminal AT-hook motifs. Several more arguments support this. First, in reporter assays, the major transactivation function of SRCAP is located in a 655 residue C-terminal fragment abolished by FHS-causing truncations.9Monroy M.A. Ruhl D.D. Xu X. Granner D.K. Yaciuk P. Chrivia J.C. Regulation of cAMP-responsive element-binding protein-mediated transcription by the SNF2/SWI-related protein, SRCAP.J. Biol. Chem. 2001; 276: 40721-40726Crossref PubMed Scopus (34) Google Scholar Second, expression of a construct solely consisting of the CBP interaction domain of SRCAP strongly inhibits CREB-mediated transactivation in a dominant-negative fashion.9Monroy M.A. Ruhl D.D. Xu X. Granner D.K. Yaciuk P. Chrivia J.C. Regulation of cAMP-responsive element-binding protein-mediated transcription by the SNF2/SWI-related protein, SRCAP.J. Biol. Chem. 2001; 276: 40721-40726Crossref PubMed Scopus (34) Google Scholar Third, the Database of Genomic Variants (see Web Resources) contains two HapMap control individuals who bear a 208 kb deletion copy-number variation (#2,209) containing SRCAP and nine adjacent genes and who have no reported phenotype. In general, the phenotype of persons with SRCAP mutations is concordant with earlier clinical descriptions of FHS (Table 1 and Figure 1), and nearly all individuals have short stature and expressive-language impairment. Despite the remarkable similarity among mutations seen in our study subjects, cognitive outcomes ranging from “normal” to “significant intellectual disability” were reported. It is unclear whether genetic modifier(s) and/or currently unidentified environmental factors are responsible. Many of our study subjects had additional systemic malformations, particularly genitourinary (eight individuals) and cardiac (three individuals) malformations. Again, genotype-phenotype correlations explaining these features are lacking. Given that FHS is a dominant condition exhibiting a high de novo mutation rate, one might expect a paternal age effect to be present, and indeed the mean paternal age of the affected individuals was advanced (36.9 years; range: 29–44 years). Importantly, our findings suggest a basis for the long-recognized phenotypic overlap between FHS and RTS, the latter of which is caused by alterations in CBP or its homolog, p300.14Petrij F. Giles R.H. Dauwerse H.G. Saris J.J. Hennekam R.C. Masuno M. Tommerup N. van Ommen G.J. Goodman R.H. Peters D.J. et al.Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.Nature. 1995; 376: 348-351Crossref PubMed Scopus (1022) Google Scholar, 15Roelfsema J.H. White S.J. Ariyürek Y. Bartholdi D. Niedrist D. Papadia F. Bacino C.A. den Dunnen J.T. van Ommen G.J. Breuning M.H. et al.Genetic heterogeneity in Rubinstein-Taybi syndrome: Mutations in both the CBP and EP300 genes cause disease.Am. J. Hum. Genet. 2005; 76: 572-580Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar, 16Stevens C.A. Rubinstein-Taybi Syndrome.in: Pagon R.A. GeneReviews. University of Washington, Seattle2002Google Scholar Because alterations in both CBP and SRCAP are expected to produce widespread target-gene dysregulation, further studies are needed before we can determine which transcriptional targets are primarily responsible for each phenotype and whether any of these might be valid therapeutic targets. The availability of a molecular test for FHS will greatly improve the reliability of a formerly challenging clinical diagnosis. Historically, a diagnosis of FHS has relied upon the presence of typical facial features because many other key findings (e.g., short stature and language impairment) are nonspecific. The advent of molecular diagnosis for this condition will allow us to gain a better appreciation of the true prevalence and phenotypic spectrum of FHS. The authors would first like to thank the study participants and their families, without whose participation and cooperation this work would not have been possible. This work was funded by the government of Canada through Genome Canada, the Canadian Institutes of Health Research (CIHR), and the Ontario Genomics Institute (OGI-049). Additional funding was provided by Genome Québec and Genome British Columbia. K.M.B. is supported by a Clinical Investigatorship Award from the CIHR Institute of Genetics. This work was selected for study by the FORGE Canada Steering Committee, consisting of K. Boycott (University of Ottawa), J. Friedman (University of British Columbia), J. Michaud (University of Montreal), F. Bernier (University of Calgary), M. Brudno (University of Toronto), B. Fernandez (Memorial University), B. Knoppers (McGill University), M. Samuels (Université de Montreal), and S. Scherer (University of Toronto). Download .pdf (.18 MB) Help with pdf files Document S1. Figure S1 The URLs for data presented herein are as follows:Database of Genomic Variants, http://projects.tcag.ca/variation/FASTX-Toolkit, http://hannonlab.cshl.edu/fastx_toolkit/NHLBI Exome Variant Server, http://evs.gs.washington.edu/EVS/Online Mendelian Inheritance in Man (OMIM), http://www.omim.orgPicard, http://picard.sourceforge.net/SAMtools, http://samtools.sourceforge.net/ The NCBI accession number for the SRCAP sequence reported in this paper is NM_006662.2 and local identifiers are as follows:NM_006662.2: c.7330C>T (NCBI ss477606270)NM_006662.2: c.7303C>T (NCBI ss477606271)NM_006662.2: c.7549delC (NCBI ss477606272)NM_006662.2: c.7218_7219delTC (NCBI ss477606273)NM_006662.2: c.7316dupC (NCBI ss477606274)" @default.
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• W2039180361 title "Mutations in SRCAP, Encoding SNF2-Related CREBBP Activator Protein, Cause Floating-Harbor Syndrome" @default.
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