Copy number variation and regions of homozygosity analysis in patients with MÜLLERIAN aplasia

Abstract

BackgroundLittle is known about the genetic contribution to Müllerian aplasia, better known to patients as Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Mutations in two genes (WNT4 and HNF1B) account for a small number of patients, but heterozygous copy number variants (CNVs) have been described. However, the significance of these CNVs in the pathogenesis of MRKH is unknown, but suggests possible autosomal dominant inheritance. We are not aware of CNV studies in consanguineous patients, which could pinpoint genes important in autosomal recessive MRKH. We therefore utilized SNP/CGH microarrays to identify CNVs and define regions of homozygosity (ROH) in Anatolian Turkish MRKH patients.Result(s)Five different CNVs were detected in 4/19 patients (21%), one of which is a previously reported 16p11.2 deletion containing 32 genes, while four involved smaller regions each containing only one gene. Fourteen of 19 (74%) of patients had parents that were third degree relatives or closer. There were 42 regions of homozygosity shared by at least two MRKH patients which was spread throughout most chromosomes. Of interest, eight candidate genes suggested by human or animal studies (RBM8A, CMTM7, CCR4, TRIM71, CNOT10, TP63, EMX2, and CFTR) reside within these ROH.Conclusion(s)CNVs were found in about 20% of Turkish MRKH patients, and as in other studies, proof of causation is lacking. The 16p11.2 deletion seen in mixed populations is also identified in Turkish MRKH patients. Turkish MRKH patients have a higher likelihood of being consanguineous than the general Anatolian Turkish population. Although identified single gene mutations and heterozygous CNVs suggest autosomal dominant inheritance for MRKH in much of the western world, regions of homozygosity, which could contain shared mutant alleles, make it more likely that autosomal recessively inherited causes will be manifested in Turkish women with MRKH.

The Endometrial Transcription Landscape of MRKH Syndrome

“…The combined approach of differential and co-expression analyses highlighted candidate genes that can explain large parts of the altered expression landscape in context of the MRKH syndrome. These novel candidates together with previously associated genes like FOXO1 ( Demir Eksi et al, 2018 ) and pathways like WNT signaling ( Ledig and Wieacker, 2018 ) share direct links into the TGFB1 regulatory neighborhood ( Attisano and Wrana, 2013 ) and reached into disease-associated co-expression modules.…”

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update

“…Chromosomal microarray analysis can be considered for the detection of copy number variations but is not obligate for the diagnosis. Overall test positive rate for imbalances has been reported at ~ 16–20% but the interpretation of the pathogenicity of these findings remains a challenge [ 20 , 61 , 63 ]. Other relevant laboratory tests include FSH, LH, androgens and estradiol, which are generally considered to be normal in MRKH syndrome [ 3 , 83 ].…”

Studying Müllerian duct anomalies – from cataloguing phenotypes to discovering causation

“…Some patients suffering from DiGeorge syndrome (22q11.2 deletion syndrome; Box 1 ) additionally display congenital MDA/MRKH phenotypes, although the causative genes related to the urogenital anomalies within this chromosome are currently unknown ( Cheroki et al, 2007 ; Sundaram et al, 2007 ; Devriendt et al, 1997 ; Ledig et al, 2011 ; Morcel et al, 2011 ; Nik-Zainal et al, 2011 ). Aberrations in chromosome 1 in patients with MDAs include deletions/duplications of variable size, mainly at 1q21.1 ( Ledig et al, 2011 ; McGowan et al, 2015 ; Demir Eksi et al, 2018 ; Chen et al, 2015 ). This region contains the candidate MDA gene RBM8A ( Box 1 ), as four variants were found to be associated with MDAs ( Tewes et al, 2015 ).…”