TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

Abstract

Holt-Oram syndrome (HOS) is a rare autosomal dominant heart-hand syndrome due to mutations in the TBX5 transcription factor. Affected individuals can have structural cardiac defects and/or conduction abnormalities, and exclusively upper limb defects (typically bilateral, asymmetrical radial ray defects). TBX5 mutations reported include nonsense, missense, splicing mutations and exon deletions. Most result in a null allele and haploinsufficiency, but some impair nuclear localisation of TBX5 protein or disrupt its interaction with co-factors and downstream targets. We present a five generation family of nine affected individuals with an atypical HOS phenotype, consisting of ulnar ray defects (ulnar hypoplasia, short fifth fingers with clinodactyly) and very mild radial ray defects (short thumbs, bowing of the radius and dislocation of the radial head). The cardiac defects seen are those more rarely reported in HOS (atrioventricular septal defect, hypoplastic left heart syndrome, mitral valve disease and pulmonary stenosis). Conduction abnormalities include atrial fibrillation, atrial flutter and sick sinus syndrome. TBX5 mutation screening (exons 3-10) identified no mutations. Array comparative genomic hybridisation (CGH) revealed a 48 kb duplication at 12q24.21, encompassing exons 2-9 of the TBX5 gene, with breakpoints within introns 1-2 and 9-10. The duplication segregates with the phenotype in the family, and is likely to be pathogenic. This is the first known report of an intragenic duplication of TBX5 and its clinical effects; an atypical HOS phenotype. Further functional studies are needed to establish the effects of the duplication and pathogenic mechanism. All typical/atypical HOS cases should be screened for TBX5 exon duplications.

An Inheritance of Idiopathic Cardiac Conduction Disorders

“…Наиболее часто мута-ции гена TBX5 ассоциируются с так называемым Холт-Орам синдромом (Holt-Oram syndrome, HOS). Данный синдром наследуется по аутосомно-доми-нантному типу и характеризуется структурным пора-жением сердца, в т. ч. нарушениями сердечного ритма и проводимости, и дефектами развития верхних конечностей [3][4][5][6]. В литературе также описаны слу-чаи сочетания синдрома HOS с врожденным дефек-том атриовентрикулярного соединения [7].…”

Insights into the Genetic Structure of Congenital Heart Disease from Human and Murine Studies on Monogenic Disorders

“…ASDs and VSDs are the most commonly described heart lesions. Occasionally, other forms of CHD have been reported, including hypoplastic left heart, persistence of the left superior vena cava, mitral valve prolapse, pulmonary stenosis, tetralogy of Fallot, truncus arteriosus, coarctation of the aorta, total anomalous pulmonary venous return, patent ductus arteriosus, tricuspid atresia, and AVSDs (Smith et al 1979;Ruzic et al 1981;Sahn et al 1981;Glauser et al 1989;Basson et al 1994;Newbury-Ecob et al 1996;Bruneau et al 2001;Patel et al 2012;Thal et al 2012). Missense, insertion, deletion, and chromosomal translocation mutations have all been reported.…”

Early frameshift alleles of zebrafish <em>tbx5a</em> that fail to develop the heartstrings phenotype

“…Mutations in the human TBX5 gene cause Holt-Oram Syndrome (HOS) with concomitant heart and arm malformations [4] [5] that Tbx5-mutant mice recapitulate [2] [3]. Zebrafish homozygous for the tbx5a allele heartstrings (hst m21 , or short hst) and morpholino-mediated tbx5a knockdown mimic HOS phenotypes with defects in heart and pectoral fin formation [6] [7].…”