Whole-Exome Sequencing Identified a TBX6 Loss of Function Mutation in a Patient with Distal Vaginal Atresia

Chu, Chunfang; Li, Lin; Lü, Dan; Duan, Aihong; Luo, Liqun; Li, Shenghui; Yin, Chenghong

doi:10.1016/j.jpag.2019.06.006

Cited by 6 publications

(10 citation statements)

References 32 publications

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“…Since TBX6 is the only identified pathogenic gene of distal vaginal atresia by now [ 12 ] and TBX3 is belonging to the same conserved family, we detected a frameshift deletion on this gene in patient I36. Moreover, similar phenotypes of Tbx3 mutated mouse were reported, including imperforate vaginas of female mice [ 14 ] and failure of vaginal opening [ 13 ].…”

Section: Resultsmentioning

confidence: 94%

“…Both kinds of studies have helped to identify key genes that regulate the vaginal development. To date, only one study has reported TBX6 as a candidate causing distal vaginal atresia by exome sequencing [ 12 ], while further investigations are needed to elucidate its role in the development of the vagina. A small portion of female mice with heterozygous variants on Tbx3 showed a failure of vaginal opening or imperforate vagina [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Clinical and Genetic Characteristics of a Cohort with Distal Vaginal Atresia

Kang

Zhou

Chen

et al. 2022

IJMS

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Distal vaginal atresia is a rare abnormality of female reproductive tract in which the vagina is closed or absent. The distal vagina may be replaced by fibrous tissue and the condition is often not diagnosed until a girl fails to begin having periods at puberty. Although it is a congenital disorder, potential genetic causes of distal vaginal atresia are still unknown. We recruited a cohort of 39 patients with distal vaginal atresia and analyzed their phenotypic and genetic features. In addition to the complaint of distal vaginal atresia, approximately 17.9% (7/39) of the patients had other Müllerian anomalies, and 17.9% (7/39) of the patients had other structural abnormalities, including renal-tract, skeletal and cardiac anomalies. Using genome sequencing, we identified two fragment duplications on 17q12 encompassing HNF1B and LHX1, two dosage-sensitive genes with candidate pathogenic variants, in two unrelated patients. A large fragment of uniparental disomy was detected in another patient, affecting genes involved in cell morphogenesis and connective tissue development. Additionally, we reported two variants on TBX3 and AXL, leading to distal vaginal atresia in mutated mouse model, in our clinical subjects for the first time. Essential biological functions of these detected genes with pathogenic variants included regulating reproductive development and cell fate and patterning during embryogenesis. We displayed the comprehensive clinical and genetic characteristic of a cohort with distal vaginal atresia and they were highly heterogeneous both phenotypically and genetically. The duplication of 17q12 in our cohort could help to expand its phenotypic spectrum and potential contribution to the distal vaginal atresia. Our findings of pathogenic genetic variants and associated phenotypes in our cohort could provide evidence and new insight for further research attempting to reveal genetic causes of distal vaginal atresia.

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Section: Resultsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Characteristics of a Cohort with Distal Vaginal Atresia

Kang

Zhou

Chen

et al. 2022

IJMS

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“…The TBX6 gene, which is located in this region, encodes a transcription factor that affects the embryogenetic development and, more specifically, the differentiation of the mesoderm. Therefore, it is suggested to be a putative candidate for MRKH syndrome [ 9 , 12 , 27 , 28 , 30 , 34 , 36 , 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…Autism spectrum disorders, neurological disorders, unaffected persons [28] Mouse models: Deletion of TBX6 presents skeletal (mainly vertebral) and urinary tract malformations [31,32] Type I + II [27,30,[33][34][35][36][37][38] 17q12…”

Section: Chromosome Locationmentioning

confidence: 99%

Identification of Genetic Causes in Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome: A Systematic Review of the Literature

et al. 2022

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Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital condition characterizing females with absence of the uterus and part of the vagina. Several genetic defects have been correlated with the presence of MRKH; however, the exact etiology is still unknown due to the complexity of the genetic pathways implicated during the embryogenetic development of the Müllerian ducts. A systematic review (SR) of the literature was conducted to investigate the genetic causes associated with MRKH syndrome and Congenital Uterine Anomalies (CUAs). This study aimed to identify the most affected chromosomal areas and genes along with their associated clinical features in order to aid clinicians in distinguishing and identifying the possible genetic cause in each patient offering better genetic counseling. We identified 76 studies describing multiple genetic defects potentially contributing to the pathogenetic mechanism of MRKH syndrome. The most reported chromosomal regions and the possible genes implicated were: 1q21.1 (RBM8A gene), 1p31-1p35 (WNT4 gene), 7p15.3 (HOXA gene), 16p11 (TBX6 gene), 17q12 (LHX1 and HNF1B genes), 22q11.21, and Xp22. Although the etiology of MRKH syndrome is complex, associated clinical features can aid in the identification of a specific genetic defect.

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“…That indicates the role of genetic factors in the pathogenesis of MDAs, but the pathogenic genes are still unclear. Previous studies have found that mutations or copy number variations (CNVs) in the genes, including TBX6 , HNF1B , HOXA13 , HOXA10 , LHX1 , PBX1 , WNT9B , EMX2 , CRKL and TP63 , are associated with MDAs.…”

Section: Introductionmentioning

confidence: 99%

Sequence variant in the CDC42BPB gene is potentially associated with Mullerian duct anomalies

Luo

Feng

et al. 2020

J of Obstet and Gynaecol

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Aim: Mullerian duct anomalies (MDA) are common female genital tract malformations. Genetic and environmental factors are important causes of MDA in women. Although many genes and mutations have been found to be associated with the pathogenesis of MDA, in most cases, the genetic pathogenic factors of MDA are still unknown. Methods: We first analyzed the three sisters using low coverage whole-genome sequencing. Then wholeexome sequencing was carried out in each patient. The identified sequence variant was confirmed by Sanger sequencing. In silico pathogenicity analysis and conservative analysis of the mutation site were also performed. Protein structural modeling was used to analyze the effect of the mutated amino acid. Results: We first analyzed the three sisters with septate uterus using low coverage whole-genome sequencing, but no possible pathogenic copy number variation was found. Then whole-exome sequencing was performed on the three sisters, and a rare homozygous variant, CDC42BPB:c.2012G>A:p.R671Q, was identified. All three patients were found with this variant. Sanger sequencing validated that this variant was segregated within the family. In silico pathogenicity analysis and conservative analysis of the mutation site suggested that the variant might be damaging. Protein structural analysis suggested that R671Q might weaken the electrostatic potential of this region, which may be a significant regulation target or protein interaction surface of CDC42BPB. Conclusion: We demonstrated that CDC42BPB genetic variant might be potentially associated with the pathogenesis of MDA.

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Whole-Exome Sequencing Identified a TBX6 Loss of Function Mutation in a Patient with Distal Vaginal Atresia

Cited by 6 publications

References 32 publications

Clinical and Genetic Characteristics of a Cohort with Distal Vaginal Atresia

Clinical and Genetic Characteristics of a Cohort with Distal Vaginal Atresia

Identification of Genetic Causes in Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome: A Systematic Review of the Literature

Sequence variant in the CDC42BPB gene is potentially associated with Mullerian duct anomalies

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