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. 2018 Feb 3:11:13.
doi: 10.1186/s13039-018-0359-3. eCollection 2018.

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

Durkadin Demir Eksi #  1 , Yiping Shen #  2   3   4   5 , Munire Erman  6 , Lynn P Chorich  7   8 , Megan E Sullivan  7   8 , Meric Bilekdemir  6 , Elanur Yılmaz  9 , Guven Luleci  9 , Hyung-Goo Kim  7   8 , Ozgul M Alper  9 , Lawrence C Layman  7   8
Affiliations

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

Durkadin Demir Eksi et al. Mol Cytogenet. .

Abstract

Background: Little 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.

Results: 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.

Conclusions: 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.

Keywords: CNV; Candidate gene; Congenital absence of the uterus and vagina; Copy number variant; MRKH; Mayer-Rokitansky-Küster-Hauser syndrome; Müllerian aplasia; ROH; Regions of homozygosity.

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Conflict of interest statement

All patients consented to have blood drawn for molecular analysis and signed a consent approved by the Human Assurance Committee of the Medical College of Georgia at Augusta University or Akdeniz University Faculty of Medicine, Turkey.Not applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
The 42 regions of homozygosity shared by at least two different Turkish MRKH patients are indicated to the left of each chromosome as a vertical bar
See this image and copyright information in PMC

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