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

Sandbacka, Maria; Laivuori, Hannele; Freitas, Edmílson Dias de; Halttunen, Mervi; Jokimaa, Varpu; Morin‐Papunen, Laure; Rosenberg, Carla; Aittomäki, Kristiina

doi:10.1186/1750-1172-8-125

Cited by 82 publications

(101 citation statements)

References 51 publications

(65 reference statements)

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“…There are several well-documented cases in the literature, including the 1q21 deletions associated with TAR syndrome (47) or the 16p12 deletions associated with autism (48) and Mullerian aplasia (49). Additionally, it is important to be aware that the aCGH technique does not detect uniparental disomy, a known cause for children being born SGA (14).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

Canton

Costa

Rodrigues

et al. 2014

European Journal of Endocrinology

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Background: The etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders. Objective: To analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause. Patients and methods: A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature. Results: In 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation. Conclusion: Pathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.

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Section: Discussionmentioning

confidence: 99%

Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

Canton

Costa

Rodrigues

et al. 2014

European Journal of Endocrinology

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“…Furthermore, we and other groups found microdeletions and -duplications in patients with müllerian aplasia using array-CGH [Ledig et al, 2011;Nik-Zainal et al, 2011;Sandbacka et al, 2013]. Very recently we could show that patients affected by fusion anomalies of the müllerian ducts are partly carriers of the same microdeletions and -duplications as patients affected by MRKHS [Ledig et al, 2018].…”

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confidence: 53%

Sequence Variants in <b><i>TBX6</i></b> Are Associated with Disorders of the Müllerian Ducts: An Update

Tewes¹,

Hucke²,

Römer³

et al. 2019

Sex Dev

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Müllerian anomalies comprise the Mayer-Rokitansky-Küster-Hauser syndrome as well as fusion defects of the müllerian ducts. Recurrent micro-aberrations like deletions in 16p11.2 encompassing TBX6 were found to be causative in these patients. TBX6 encodes a transcription factor which plays a role in paraxial mesoderm differentiation/specification. In previous studies, we and other groups found possibly pathogenic variants in TBX6 in patients with müllerian anomalies. Since we suggested TBX6 as a strong candidate, we performed sequential analysis of the TBX6 gene in additional 125 patients with müllerian anomalies, and 2 possibly pathogenic missense variants and 1 nonsense substitution in TBX6 in 4/125 patients were found. The missense variant c.484G>A, which we have described in a previous study, was reidentified but with no higher frequency as in our controls. We detected 3 possibly pathogenic variants in TBX6 and could show that the variant c.484G>A is not causative for disorders of the müllerian ducts in the non-Finnish European population. In summary, we present increasing evidence for association of variants in TBX6 with malformations of the müllerian ducts.

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“…Recurrent deletions of this region have previously been reported in both MRKH type 1 and 2 as well as in MURCS [Nik-Zainal et al, 2011] and are reported to contribute to around 1% of MRKH patients [Morcel et al, 2012]. In addition to this, splice site variants of TBX6 , a gene within this region, have been identified in individuals with MRKH [Nik-Zainal et al, 2011;Sandbacka et al, 2013]. Individual MRKH6 also has a VWF variant (c.7390C>T, p.Arg2464Cys), which has previously been reported in a patient with von Willebrand disease with functional validation [Lester et al, 2007].…”

Section: Discussionmentioning

confidence: 82%

Identification of Candidate Genes for Mayer-Rokitansky-Küster-Hauser Syndrome Using Genomic Approaches

Backhouse

Hanna

Robevska

et al. 2018

Sex Dev

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Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a disorder of sex development which affects 1 in 4,500 females and is characterized by agenesis of müllerian structures, including the uterus, cervix, and upper vagina. It can occur in isolation (type 1) or in conjunction with various anomalies (type 2), with a subset of these comprising müllerian, renal, and cervicothoracic abnormalities (MURCS) association. The genetic causes of MRKH have been investigated previously yielding limited results, with massive parallel sequencing becoming increasingly utilized. We sought to identify genetic contributions to MRKH using a combination of microarray and whole exome sequencing (WES) on a cohort of 8 unrelated women with MRKH and MURCS. WES data were analysed using a candidate gene approach to identify potential contributing variants. Microarray analysis identified a 0.6-Mb deletion in the previously implicated 16p11.2 region in a patient with MRKH type 2. WES revealed 16 rare nonsynonymous variants in MRKH candidate genes across the cohort. These included variants in several genes, such as LRP10 and DOCK4, associated with disorders with müllerian anomalies. Further functional studies of these variants will help to delineate their biological significance and expand the genotypic spectrum of MRKH.

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

Cited by 82 publications

References 51 publications

Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

Sequence Variants in <b><i>TBX6</i></b> Are Associated with Disorders of the Müllerian Ducts: An Update

Identification of Candidate Genes for Mayer-Rokitansky-Küster-Hauser Syndrome Using Genomic Approaches

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