Array‐comparative genomic hybridization analysis in patients with Müllerian fusion anomalies

Abstract

Fusion anomalies of the Müllerian ducts are associated with an increased risk for miscarriage and premature labor. In most cases polygenic-multifactorial inheritance can be assumed but autosomal-dominant inheritance with reduced penetrance and variable manifestation should be considered. We performed array-comparative genomic hybridization (CGH) analysis in a cohort of 103 patients with Müllerian fusion anomalies. In 8 patients we detected microdeletions and microduplications in chromosomal regions 17q12, 22q11.21, 9q33.1, 3q26.11 and 7q31.1. The rearrangement in 17q12 including LHX1 and HNF1β as well as in 22q11.21 have already been observed in MRKHS (Mayer-Rokitansky-Küster-Hauser syndrome). In summary, we (1) detected causative micro-rearrangements in patients with Müllerian fusion anomalies, (2) show that Müllerian fusion anomalies and MRKHS may have a common etiology, and (3) identified new candidate genes for Müllerian fusion anomalies.

Identification of Candidate Genes for Mayer-Rokitansky-Küster-Hauser Syndrome Using Genomic Approaches

“…Recently, another report has found 2 patients with either partial septate uterus or uterus didelphys, with small duplications within this gene [Ledig et al, 2018]. Our patient had right unicornuate uterus, vaginal agenesis and hydronephrosis in addition to fused vertebrae (C2-3, C6-7, L3-4), butterfly vertebra (L3), lumbar scoliosis, dislocated radial head bilaterally, imperforate anus, and an atrial septal defect.…”

“…A patient with Herlyn-Werner-Wunderlich syndrome and a partial duplication of RSPO4 [Ledig et al, 2018] has been described previously, although homozygous mutations of RSPO4 are associated with congenital anonychia (OMIM 206800), suggesting that heterozygous missense mutations in this gene may be tolerated or have a different mechanism of action to that previously reported.…”

“…Finally, this patient also had a single nucleotide variant in the DOCK4 candidate gene. This is the second report of a patient carrying an aberration in this gene, the first was a patient with partial septate uterus who carried a 218-kb gain partly affecting DOCK4 [Ledig et al, 2018]. DOCK4 is a guanine nucleotide exchange factor (GEF), involved in the regulation of adherens junctions between cells and thought to play a role in cell migration.…”

“…Most studies have employed microarrays or small gene panels/Sanger sequencing to investigate the causes of MRKH [Ledig et al, 2011;Ma et al, 2015;McGowan et al, 2015;Murry et al, 2015;Brucker et al, 2017;Williams et al, 2017;Ledig et al, 2018]. The development of massively parallel sequencing, including whole exome sequencing (WES), has broadened the scope for a more comprehensive genomic approach to identify genetic contributors to MRKH.…”

Sequence Variants in <b><i>TBX6</i></b> Are Associated with Disorders of the Müllerian Ducts: An Update

“…Very recently we could show that patients affected by fusion anomalies of the müllerian ducts are partly carriers of the same microdeletions and -duplications as patients affected by MRKHS [Ledig et al, 2018]. Recurrent aberrations in 16p11.2 were identified by array-CGH in 1% of patients with müllerian aplasia [Morcel et al, 2007].…”