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

Abstract

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a disorder of sex development which affects 1 in 4,500 females and is characterized by agenesis of müllerian structures, including the uterus, cervix, and upper vagina. It can occur in isolation (type 1) or in conjunction with various anomalies (type 2), with a subset of these comprising müllerian, renal, and cervicothoracic abnormalities (MURCS) association. The genetic causes of MRKH have been investigated previously yielding limited results, with massive parallel sequencing becoming increasingly utilized. We sought to identify genetic contributions to MRKH using a combination of microarray and whole exome sequencing (WES) on a cohort of 8 unrelated women with MRKH and MURCS. WES data were analysed using a candidate gene approach to identify potential contributing variants. Microarray analysis identified a 0.6-Mb deletion in the previously implicated 16p11.2 region in a patient with MRKH type 2. WES revealed 16 rare nonsynonymous variants in MRKH candidate genes across the cohort. These included variants in several genes, such as LRP10 and DOCK4, associated with disorders with müllerian anomalies. Further functional studies of these variants will help to delineate their biological significance and expand the genotypic spectrum of MRKH.

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

“…Recently, Pan et al performed whole-genome sequencing (WGS) analysis of nine MRKH syndrome trios (patient and both parents) demonstrating the capacity of WGS in unbiased detection of de novo genomic variation [77]. Other recent studies also used NGS technology in genomic searches for genetic variation [24,64,78,79]. However, it remains a challenge to interpret the pathogenicity of these findings and investigations of larger cohorts will likely be needed in order to identify recurrent genetic variation.…”

Recurrent constellations of embryonic malformations re‐conceptualized as an overlapping group of disorders with shared pathogenesis

“…The advent of the genome era of human genetics has seen a dramatic increase in the pace of gene discovery, especially for more common and recognizable syndromes. Yet many well‐characterized human malformation syndromes and associations remain unsolved despite extensive investigations (Boycott, Dyment, & Innes, 2018), including chromosome microarray analysis, exome sequencing, and deep sequencing of single genes to detect mosaic mutations (Backhouse et al, 2019; Hartsfield, 2007; Keppler‐Noreuil, Gorton, Foo, Yankowitz, & Keegan, 2007; Solomon, 2018; Solomon et al, 2013). Among these are several syndromes or associations reported to occur more frequently than expected in monozygotic discordant twins and other multiple births (Chen et al, 2018; Bartels et al, 2012; Wieczorek et al, 2007).…”

“…Each of these associations or syndromes share an early embryonic origin, no (or extremely rare) reports of familial recurrence (Backhouse et al, 2019;Chen et al, 2018;Solomon, 2018), and an excess of reported discordant twins and other multiple births (Bartels et al, 2012;Wieczorek et al, 2007). They share other common features as well.…”

“…Survivors typically have normal intelligence, excluding those with evidence for an acquired cause such as brain injury during cardiac bypass. The increase in reported twinning includes discordant monozygotic (MZ) twins, and when noted, genetic testing has uniformly been negative (Backhouse et al, 2019;Chen et al, 2018;Wieczorek et al, 2007). Further, there are individuals reported who have major features associated with two RCEM (Balusamy, Kumar, & Subrahamian, 2009;McKinlay Gardner, Umstad, & Hale, 2007).…”

Studying Müllerian duct anomalies – from cataloguing phenotypes to discovering causation

“…WES also found a rare homozygous variant in CDC42BPB in three sisters with septate uterus ( Luo et al, 2020 ). Backhouse et al (2019) used WES in combination with microarrays in patients with MRKH and found damaging variants of several genes: LRP10 , encoding a lipoprotein receptor; FRAS1 , encoding an extracellular matrix protein previously described as essential for metanephros organogenesis ( Pitera et al, 2008 ); RSPO4 , involved in the WNT pathway; NPHP3 , which was previously linked to kidney development ( Olbrich et al, 2003 ); DYNC2H1 , a cilium-related dynein; and NAALADL2 , which encodes an enzyme not yet linked to MDAs. This study also identified MKKS , the gene that triggers McKusick–Kaufman syndrome (OMIM 236700), presenting reproductive effects related to vaginal maldevelopment ( Backhouse et al, 2019 ).…”