Evaluation of SHOX copy number variations in patients with Müllerian aplasia

Abstract

BackgroundMüllerian aplasia (MA) characterized by congenital loss of functional uterus and vagina is one of the most difficult disorders of female reproductive health. Despite of growing interest in this research field, the cause of the disorder for the majority of patients is still unknown. A recent report of partial SHOX duplications in five patients with MA has motivated us to further evaluate their role in the disorder. Therefore we have studied SHOX copy number variations (CNVs) in a cohort of 101 Finnish patients with MA and in 115 healthy controls.MethodsWe used multiplex ligation-dependent probe amplification (MLPA) to study SHOX CNVs.ResultsAll patients showed normal amplification of SHOX. Several aberrations, duplications and deletions, were found downstream of the gene in five patients and seven controls, but these were all copy number polymorphisms.ConclusionsOur study in an extensive cohort of patients with MA does not support a role for SHOX CNVs in the aetiology of the disorder. Further studies in the field are important for both patients looking for answers as well as for the scientific community for better understanding the regulation of the female reproductive duct development.

Mayer-Rokitansky-Küster-Hauser syndrome discordance in monozygotic twins: matrix metalloproteinase 14, low-density lipoprotein receptor–related protein 10, extracellular matrix, and neoangiogenesis genes identified as candidate genes in a tissue-specific mosaicism

“…Recently described recurrent CNVs in patients with isolated or syndromic m€ ullerian aplasia (30)(31)(32)(33)(34)(35)(36) were not detected in our patients or their unaffected co-twins (Supplemental Table 1, available online at www.fertstert.org). Moreover, no relevant CNVs were found in the chromosomal regions containing genes relevant to the embryonic development of the genital tract, such as the HOXA genes, or genes coding for hormone receptors, such as the estrogen receptors and the progesterone receptor (Supplemental Table 2, available online at www.fertstert.org).…”

“…Moreover, no relevant CNVs were found in the chromosomal regions containing genes relevant to the embryonic development of the genital tract, such as the HOXA genes, or genes coding for hormone receptors, such as the estrogen receptors and the progesterone receptor (Supplemental Table 2, available online at www.fertstert.org). Regions containing other candidate genes as described in previous studies, such as Lim homeobox gene 1 (LHX1), hepatocyte nuclear factor 1b (HNF1B), and WNT4, were also screened without detecting any relevant CNV (Supplemental Table 2) (8,(30)(31)(32)(33)(34)(35)(36). Furthermore, no relevant genomic rearrangements were identified in chromosomal regions of candidate genes such as homeobox A5 (HOXA5) and homeobox A9 (HOXA9) or the estrogen and progesterone receptor found in our previous combined whole-genome expression and methylation analysis (Supplemental Table 2) (2).…”

“…Recently, several recurrent copy number variants (CNVs) have been reported in patients with isolated and syndromic m€ ullerian aplasia and other disorders of sexual development (30)(31)(32)(33)(34)(35)(36). With the use of array comparative genomic hybridization (array CGH), different chromosomal regions have been found to be associated with MRKHS.…”

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

“…However, studies have failed to find evidence for this hypothesis [32][33][34]. Several other candidate genes based on developmental pathways and associated diseases have disproved to cause MRKH syndrome [35][36][37][38][39][40][41][42][43][44][45][46][47][48]. Mutations in WNT4 were detected in patients with Müllerian aplasia and virilization/hyperandrogenism [49][50][51].…”

Protein–protein interaction network analysis applied to DNA copy number profiling suggests new perspectives on the aetiology of Mayer–Rokitansky–Küster–Hauser syndrome

“…2 A–C). CRLF2 duplication has been classified as a benign CNV 35 and was no further considered. Moreover, MLPA assay detected a novel duplication of CNE-2 SHOX enhancer in Patient 64 (Fig.…”