Genome Sequencing and Transcriptome Profiling in Twins Discordant for Mayer-Rokitansky-Küster-Hauser Syndrome

Abstract

To identify potential genetic causes for Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), we analyzed blood and rudimentary uterine tissue of 5 MRKH discordant monozygotic twin pairs. Assuming that a variant solely identified in the affected twin or affected tissue could cause the phenotype, we identified a mosaic variant in ACTR3B with high allele frequency in the affected tissue, low allele frequency in the blood of the affected twin, and almost absent in blood of the unaffected twin. Focusing on MRKH candidate genes, we detected a pathogenic variant in GREB1L in one twin pair and their unaffected mother showing a reduced phenotypic penetrance. Furthermore, two variants of unknown clinical significance in PAX8 and WNT9B were identified. In addition, we conducted transcriptome analysis of affected tissue and observed perturbations largely similar to those in sporadic cases. These shared transcriptional changes were enriched for terms associated with estrogen and its receptors pointing at a role of estrogen in MRKH pathology. Our genome sequencing approach of blood and uterine tissue of discordant twins is the most extensive study performed on twins discordant for MRKH so far. As no clear pathogenic differences were detected, research to evaluate other regulatory layers are required to better understand the complex etiology of MRKH.

The expanded spectrum of human disease associated with GREB1L likely includes complex congenital heart disease

“…Variants were then manually re‐annotated using diagnostic criteria of the ACMG 17 . Only individuals with pathogenic or likely pathogenic variants were included, which were present in 23 articles 1,2,4–6,8–12,18–30 . We also characterized the ascertainment criteria with which these studies identified individuals.…”

“…17 Only individuals with pathogenic or likely pathogenic variants were included, which were present in 23 articles. 1,2,[4][5][6][8][9][10][11][12][18][19][20][21][22][23][24][25][26][27][28][29][30] We also characterized the ascertainment criteria with which these studies identified individuals.…”

“…1,2 Subsequent investigation focused on individuals with Mayer-Rokitanksy-Küster-Hauser syndrome (MIM 277000: characterized by uterine-vaginal atresia, variably accompanied by cardiac, skeletal, auditory, and renal anomalies) demonstrated that variants in GREB1L also caused this disease presentation. [9][10][11] These cohorts included individuals with isolated uterine anomalies in the absence of other urogenital findings. Rare, putatively deleterious GREB1L variants are more common in cohorts of individuals with scoliosis.…”

“…The GREB1L discovery cohorts also included individuals with uterine malformations 1,2 . Subsequent investigation focused on individuals with Mayer‐Rokitanksy‐Küster‐Hauser syndrome (MIM 277000: characterized by uterine‐vaginal atresia, variably accompanied by cardiac, skeletal, auditory, and renal anomalies) demonstrated that variants in GREB1L also caused this disease presentation 9–11 . These cohorts included individuals with isolated uterine anomalies in the absence of other urogenital findings.…”

Recurrent human 16p11.2 microdeletions in type I Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome patients in Chinese Han population

“…It is also reported carrying variants in both TBX6 and LHX1 or a CNV in combination with TBX6 variants might play a role in the etiology of Mullerian aplasia (Sandbacka et al, 2013). Interestingly, since only some of the cases have been attributed to genetic anomalies, other presumption of pathologic mechanisms such as epigenetics and somatic mutations have been suggested to play a role in Mullerian aplasia (Buchert et al, 2022; Hentrich et al, 2020). And the application of techniques including whole genome sequencing (WGS) and RNA‐seq is expected to provide new clues hopefully (Buchert et al, 2022; Hentrich et al, 2020; Pan et al, 2019).…”