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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2013

Open Access 01-12-2013 | Research

TBX6, LHX1 and copy number variations in the complex genetics of Müllerian aplasia

Authors: Maria Sandbacka, Hannele Laivuori, Érika Freitas, Mervi Halttunen, Varpu Jokimaa, Laure Morin-Papunen, Carla Rosenberg, Kristiina Aittomäki

Published in: Orphanet Journal of Rare Diseases | Issue 1/2013

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Abstract

Background

Müllerian aplasia (MA) is a congenital disorder of the female reproductive tract with absence of uterus and vagina with paramount impact on a woman’s life. Despite intense research, no major genes have been found to explain the complex genetic etiology.

Methods and Results

We have used several genetic methods to study 112 patients with MA. aCGH identified CNVs in 8/50 patients (16%), including 16p11.2 and 17q12 deletions previously associated with MA. Subsequently, another four patients were shown to carry the ~0.53 Mb deletion in 16p11.2. More importantly, sequencing of TBX6, residing within 16p11.2, revealed two patients carrying a splice site mutation. Two previously reported TBX6 variants in exon 4 and 6 were shown to have a significantly higher frequency in patients (8% and 5%, respectively) than in controls (2% each). We also sequenced LHX1 and found three apparently pathogenic missense variants in 5/112 patients. Altogether, we identified either CNVs or variations in TBX6 or LHX1 in 30/112 (26.8%) MA patients. CNVs were found in 12/112 (10.7%), patients, novel variants in TBX6 or LHX1 in 7/112 (6.3%), and rare variants in TBX6 in 15/112 (13.4%) patients. Furthermore, four of our patients (4/112, 3.6%) were shown to carry variants in both TBX6 and LHX1 or a CNV in combination with TBX6 variants lending support to the complex genetic etiology of MA.

Conclusions

We have identified TBX6 as a new gene associated with MA. Our results also support the relevance of LHX1 and CNVs in the development of this congenital malformation.
Appendix
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Metadata
Title
TBX6, LHX1 and copy number variations in the complex genetics of Müllerian aplasia
Authors
Maria Sandbacka
Hannele Laivuori
Érika Freitas
Mervi Halttunen
Varpu Jokimaa
Laure Morin-Papunen
Carla Rosenberg
Kristiina Aittomäki
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2013
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/1750-1172-8-125

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