TBX3 and TBX5 duplication: A family with an atypical overlapping Holt-Oram/ulnar-mammary syndrome phenotype

TY - JOUR

T1 - TBX3 and TBX5 duplication: A family with an atypical overlapping Holt-Oram/ulnar-mammary syndrome phenotype

AU - Cenni, Camille

AU - Andres, Stephanie

AU - Hempel, Maja

AU - Strom, Tim M

AU - Thomas, Ellen

AU - Davies, Angela

AU - Timoney, Norma

AU - Frigiola, Alessandra

AU - Logan, Malcolm

AU - Holder-Espinasse, Muriel

N1 - Copyright © 2021 Elsevier Masson SAS. All rights reserved.

PY - 2021/7

Y1 - 2021/7

N2 - Holt-Oram syndrome (HOS) is a rare, autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. A wide spectrum of TBX5 mutations have been reported previously, most resulting in a null allele leading to haploinsufficiency. TBX5 gene duplications have been previously reported in association with typical and atypical HOS phenotypes. Ulnar-Mammary syndrome (UMS) is a distinct rare, autosomal dominant condition caused by mutations in the TBX3 gene. TBX5 and TBX3 are physically linked in cis on human chromosome 12 and contiguous chromosome 12q24 deletions comprising both TBX5 and TBX3 genes have been previously reported but to our knowledge, duplications have never been described. We report on a large German family with at least 17 affected individuals over 6 generations bearing a duplication at 12q24.21 identified on array-CGH comprising both TBX5 and TBX3 genes. Affected patients are presenting with HOS and UMS symptoms, consisting of variable limb anomalies involving the radial and the ulnar rays and cardiac findings such as congenital heart defects, persistent arterial duct or aortic stenosis, and non-classical symptoms, such as supernumerary nipples and cardiomyopathy. Fluorescence in situ hybridisation confirmed a tandem duplication at the 12q24.21 locus. This is the first report of a contiguous TBX3/TBX5 duplication associated with HOS/UMS phenotype.

AB - Holt-Oram syndrome (HOS) is a rare, autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. A wide spectrum of TBX5 mutations have been reported previously, most resulting in a null allele leading to haploinsufficiency. TBX5 gene duplications have been previously reported in association with typical and atypical HOS phenotypes. Ulnar-Mammary syndrome (UMS) is a distinct rare, autosomal dominant condition caused by mutations in the TBX3 gene. TBX5 and TBX3 are physically linked in cis on human chromosome 12 and contiguous chromosome 12q24 deletions comprising both TBX5 and TBX3 genes have been previously reported but to our knowledge, duplications have never been described. We report on a large German family with at least 17 affected individuals over 6 generations bearing a duplication at 12q24.21 identified on array-CGH comprising both TBX5 and TBX3 genes. Affected patients are presenting with HOS and UMS symptoms, consisting of variable limb anomalies involving the radial and the ulnar rays and cardiac findings such as congenital heart defects, persistent arterial duct or aortic stenosis, and non-classical symptoms, such as supernumerary nipples and cardiomyopathy. Fluorescence in situ hybridisation confirmed a tandem duplication at the 12q24.21 locus. This is the first report of a contiguous TBX3/TBX5 duplication associated with HOS/UMS phenotype.

KW - Abnormalities, Multiple/genetics

KW - Breast Diseases/complications

KW - Female

KW - Gene Duplication

KW - Heart Defects, Congenital/complications

KW - Heart Septal Defects, Atrial/complications

KW - Humans

KW - Lower Extremity Deformities, Congenital/complications

KW - Male

KW - Pedigree

KW - Phenotype

KW - T-Box Domain Proteins/genetics

KW - Ulna/abnormalities

KW - Upper Extremity Deformities, Congenital/complications

U2 - 10.1016/j.ejmg.2021.104213

DO - 10.1016/j.ejmg.2021.104213

M3 - SCORING: Journal article

C2 - 33930582

VL - 64

JO - EUR J MED GENET

JF - EUR J MED GENET

SN - 1769-7212

IS - 7

M1 - 104213

ER -