Abstract
BackgroundMayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, or the congenital absence of uterus and vagina, is the most severe anomaly of the female reproductive tract. It affects 1 in 5,000 females, and is the second most common cause of primary amenorrhea. The etiology remains unknown in most patients, although four single gene defects and some repetitive copy number variants (CNVs) have been identified. Translocations in MRKH patients are very rare, and reported only in three patients previously without breakpoint mapping. We have identified the fourth MRKH translocation patient and are the first to characterize the breakpoints mapped by molecular methods.ResultsThe proband is a 17- year old white female with agenesis of the uterus and vagina who had a peripheral blood karyotype revealing a de novo balanced translocation 46,XX,t(3;16)(p22.3;p13.3)dn. There were no known related anomalies present in the proband or her family. No CNVs were found by chromosomal microarray analysis, and no genes were directly disrupted by the translocation. DNA sequencing of six nearby candidate genes—TRIM71, CNOT10, ZNF200, OR1F1, ZNF205, and ZNF213—did not reveal any mutations. RT-qPCR of proband lymphoblast RNA for 20 genes near the breakpoints of 3p22.3 and 16p13.3 showed significantly altered expression levels for four genes in the proband compared to three white female controls, after correction for multiple comparisons. Reduced expression was seen for CMTM7 and CCR4 on 3p22.3, while increased expression was observed for IL32 and MEFV on 16p13.3.ConclusionWe have mapped the breakpoints of our t(3;16)(p22.3;p13.3) translocation patient using molecular methods to within 13.6 kb at 3p22.3 and within 1.9 kb for 16p13.3 and have suggested 10 nearby genes that become plausible candidate genes for future study.
Highlights
Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, or the congenital absence of uterus and vagina, is the most severe anomaly of the female reproductive tract
Mayer-RokitanskyKuster-Hauser (MRKH) syndrome, known as congenital absence of the uterus and vagina or mullerian aplasia, is the most severe anomaly of the female reproductive tract in which the uterus and vagina are absent from birth [1]
In this study we present an MRKH patient with a de novo balanced translocation of 46,XX,t(3;16)(p22.3;p13.3)dn with the purpose to: 1) identify the molecular breakpoints of 3p22 and 16p13; 2) propose candidate genes for MRKH; and 3) compare the proband to other MRKH patients with balanced translocations presented in the literature
Summary
Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, or the congenital absence of uterus and vagina, is the most severe anomaly of the female reproductive tract. It affects 1 in 5,000 females, and is the second most common cause of primary amenorrhea. MRKH (the name patients prefer) affects approximately 1 in 5,000 females, and is the second most common cause of primary amenorrhea [1]. These women are 46,XX females that lack the vagina and most of the uterus, fallopian tubes may be present [2]. Women with MRKH may present with deafness, inguinal hernia, or abnormalities of the cardiac or nervous systems [3]
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