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.
Highlights
7–10% of women have uterovaginal anomalies [1], but perhaps the most severe is Müllerian aplasia, which is known as Mayer-RokitanskyKüster-Hauser (MRKH) syndrome—the name patients prefer [2]
One was the previously described 16p11.2 in MRKH, which was a 746 kb deletion, for which a similar sized copy number variants (CNVs) was seen in DGV six times, but not in Decipher
CNVs were identified in approximately 20% of Turkish MRKH patients, but it is unknown if they are causative
Summary
7–10% of women have uterovaginal anomalies [1], but perhaps the most severe is Müllerian aplasia, which is known as Mayer-RokitanskyKüster-Hauser (MRKH) syndrome—the name patients prefer [2]. These patients have congenital absence of the uterus and vagina (type I; MIM# 277000), or they may have associated anomalies such as renal agenesis, skeletal abnormalities, cardiac anomalies, or deafness (type II; MIM# 601076) [3]. There is evidence for genetic transmission, as there are some families with more than one affected MRKH individual [6, 7]. We utilized SNP/CGH microarrays to identify CNVs and define regions of homozygosity (ROH) in Anatolian Turkish MRKH patients
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