Malformation syndrome of duplication 12q24.1→qter

Melnyk, Andrew R.; Weiss, Lester; Dyke, Daniel L. Van; Jarvi, P

doi:10.1002/ajmg.1320100408

Cited by 39 publications

(30 citation statements)

References 13 publications

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“…[37][38][39][40] Patients with whole or partial chromosome 12q duplications (including the 12q24.21 region and TBX5 gene) have been described to have some of the cardiac features of HOS (mainly septal defects), other congenital anomalies and dysmorphism, but hardly any of the skeletal features. [41][42][43][44][45][46][47][48][49] This partially conforms to the prominent cardiac defects and milder limb defects seen in this family with the TBX5 duplication, therefore it seems expression of TBX5 must be finely regulated for normal cardiac and limb development. Postma et al 50 described a HOS family with predominantly cardiac defects and mild limb defects, with a novel gain-of-function missense mutation (Gly125Arg) in TBX5.…”

Section: Discussionsupporting

confidence: 73%

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

Patel

Silcock²,

McMullan³

et al. 2012

Eur J Hum Genet

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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.

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Section: Discussionsupporting

confidence: 73%

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

Patel

Silcock²,

McMullan³

et al. 2012

Eur J Hum Genet

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“…Of these mutations, the vast majority are nonsense/frameshift mutations, splice mutations, or chromosomal rearrangements, which are postulated to produce disease through TBX5 haploinsuf®ciency. A number of cases of 12q duplication also show features of HoltOram syndrome consistent with a more generalized effect of TBX5 gene dosage, both under-and overexpression, in disease causation [Melnyk et al, 1981;McCorquodale et al, 1986;Dixon et al, 1993]. The mechanisms of action of lesscommon TBX5 missense mutations are unknown.…”

Section: Atrial and Ventricular Septal Defects Holt-oram Syndromementioning

confidence: 94%

Molecular determinants of atrial and ventricular septal defects and patent ductus arteriosus

Vaughan

Basson

2000

Am. J. Med. Genet.

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Septation defects and patent ductus arteriosus are the most common human cardiovascular malformations (CVMs). Genetic factors play a major part in the origin of these malformations. Recent molecular analyses have shed light on several mendelian forms. In the autosomal dominant Holt-Oram syndrome, both atrial and ventricular septal defects are inherited in association with limb deformity as a result of mutations in the gene encoding the TBX5 transcription factor. Mutations in the NKX2.5 transcription factor gene cause autosomal dominant familial atrial septal defects in association with progressive atrioventricular block as well as complex congenital heart disease. Common atrial syndromes in autosomal dominant Ellis-van Creveld syndrome arise in the context of axial skeletal and limb malformation as a result of mutations in the EVC gene, whose function is unknown. Patent ductus arteriosus occurs in several syndromic forms of congenital heart disease, including Holt-Oram syndrome. Recent analyses of autosomal dominant Char syndrome, which includes, with variable penetrance, patent ductus arteriosus as well as craniofacial and hand malformations, have shown that the syndrome is caused by mutations in the TFAP2B transcription factor gene. Ongoing analyses are poised to determine the contribution of these genes as well as others yet to be identified to common, sporadic forms of congenital heart disease.

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“…The resulting embryonic lethal nature, despite the expression of Hic-5 and leupaxin, revealed the lack of compensation by these paralogs and thus the specific requirement for paxillin. Although no definitive human diseases thus far have been linked to the expression of a mutant paxillin, chromosome 12q24 duplications (the location of paxillin and PKL) have been reported which result in severe musculoskeletal, cardiovascular, and central nervous system malformation syndromes (162,179,214). In addition, amplification of 12q24 was found in many bladder tumors in a comparative genomic hybridization and cytogenetic analysis screen (130), whereas chromosome 12q24 was identified as containing tumor suppressors, in a micro cell-mediated chromosome transfer screen in prostate cancer cells (105).…”

Section: B Potential Roles In Diseasementioning

confidence: 99%

Paxillin: Adapting to Change

Brown¹,

Turner²

2004

Physiological Reviews

550

728

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Molecular scaffold or adaptor proteins facilitate precise spatiotemporal regulation and integration of multiple signaling pathways to effect the optimal cellular response to changes in the immediate environment. Paxillin is a multidomain adaptor that recruits both structural and signaling molecules to focal adhesions, sites of integrin engagement with the extracellular matrix, where it performs a critical role in transducing adhesion and growth factor signals to elicit changes in cell migration and gene expression.

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Malformation syndrome of duplication 12q24.1→qter

Cited by 39 publications

References 13 publications

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

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

Molecular determinants of atrial and ventricular septal defects and patent ductus arteriosus

Paxillin: Adapting to Change

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