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TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype.
Eur J Hum Genet. 2012 Aug; 20(8):863-9.EJ

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.

Authors+Show Affiliations

Department of Clinical Genetics, Birmingham Women's NHS Foundation Trust, Birmingham, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

22333898

Citation

Patel, Chirag, et al. "TBX5 Intragenic Duplication: a Family With an Atypical Holt-Oram Syndrome Phenotype." European Journal of Human Genetics : EJHG, vol. 20, no. 8, 2012, pp. 863-9.
Patel C, Silcock L, McMullan D, et al. TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype. Eur J Hum Genet. 2012;20(8):863-9.
Patel, C., Silcock, L., McMullan, D., Brueton, L., & Cox, H. (2012). TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype. European Journal of Human Genetics : EJHG, 20(8), 863-9. https://doi.org/10.1038/ejhg.2012.16
Patel C, et al. TBX5 Intragenic Duplication: a Family With an Atypical Holt-Oram Syndrome Phenotype. Eur J Hum Genet. 2012;20(8):863-9. PubMed PMID: 22333898.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype. AU - Patel,Chirag, AU - Silcock,Lee, AU - McMullan,Dominic, AU - Brueton,Louise, AU - Cox,Helen, Y1 - 2012/02/15/ PY - 2012/2/16/entrez PY - 2012/2/16/pubmed PY - 2012/12/10/medline SP - 863 EP - 9 JF - European journal of human genetics : EJHG JO - Eur. J. Hum. Genet. VL - 20 IS - 8 N2 - 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. SN - 1476-5438 UR - https://www.unboundmedicine.com/medline/citation/22333898/TBX5_intragenic_duplication:_a_family_with_an_atypical_Holt_Oram_syndrome_phenotype_ L2 - http://dx.doi.org/10.1038/ejhg.2012.16 DB - PRIME DP - Unbound Medicine ER -