Variants in genes related to development of the urinary system are associated with Mayer–Rokitansky–Küster–Hauser syndrome

Abstract

Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome, also known as Müllerian agenesis, is characterized by uterovaginal aplasia in an otherwise phenotypically normal female with a normal 46,XX karyotype. Previous studies have associated sequence variants of PAX8, TBX6, GEN1, WNT4, WNT9B, BMP4, BMP7, HOXA10, EMX2, LHX1, GREB1L, LAMC1, and other genes with MRKH syndrome. The purpose of this study was to identify the novel genetic causes of MRKH syndrome. Ten patients with MRKH syndrome were recruited at Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China. Whole-exome sequencing was performed for each patient. Sanger sequencing confirmed the potential causative genetic variants in each patient. In silico analysis and American College of Medical Genetics and Genomics (ACMG) guidelines helped to classify the pathogenicity of each variant. The Robetta online protein structure prediction tool determined whether the variants affected protein structures. Eleven variants were identified in 90% (9/10) of the patients and were considered a molecular genetic diagnosis of MRKH syndrome. These 11 variants were related to nine genes: TBC1D1, KMT2D, HOXD3, DLG5, GLI3, HIRA, GATA3, LIFR, and CLIP1. Sequence variants of TBC1D1 were found in two unrelated patients. All variants were heterozygous. These changes included one frameshift variant, one stop-codon variant, and nine missense variants. All identified variants were absent or rare in gnomAD East Asian populations. Two of the 11 variants (18.2%) were classified as pathogenic according to the ACMG guidelines, and the remaining nine (81.8%) were classified as variants of uncertain significance. Robetta online protein structure prediction analysis suggested that missense variants in TBC1D1 (p.E357Q), HOXD3 (p.P192R), and GLI3 (p.L299V) proteins caused significant structural changes compared to those in wild-type proteins, which in turn may lead to changes in protein function. This study identified many novel genes, especially TBC1D1, related to the pathogenesis of MRKH syndrome. The identification of these variants provides new insights into the etiology of MRKH syndrome and a new molecular genetic reference for the development of the reproductive tract.

Maximizing the Benefits of WES Data for Clinical Diagnosis of individuals with Differences/Variations of Sex Development

“…Following a thorough literature review, the subjects were further screened for the presence of the mutations in the following genes: PAX8, TBX6, GEN1, WNT9B, BMP4, BMP7, HOXA10, GREB1L, LAMC1, TBC1D1, KMT2D, HOXD3, DLG5, HIRA, GATA3, LIFR, CLIP1, SHOX, HNF1B, ITIH5, RBM8A, and NR1B1. (Michael Finkel and Vinod Misra 2023;Williams et al 2017;Gervasini et al 2010;Renard et al 2019;Chu et al 2022;Triantafyllidi et al 2022;Herlin, Petersen, and Brännström 2020;N. Chen et al 2022) Variations were identified in three out of the ten individuals.…”

“…TBX6 has previously been associated with MRKH syndrome due to a substantial mutation burden in a Chinese MRKH cohort (Ma et al 2022). The third variant was a heterozygous missense mutation in the DLG5 gene, where a nonsense mutation has previously been implicated as the underlying cause of the patient's MRKH syndrome (Table 3) (Chu et al 2022).…”

Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications

“…Optical genome mapping is a newer cytogenomic method with higher resolution for the detection of both imbalanced and balanced structural variation and has recently been applied in a study by Brakta et al (73). In more recent years, whole-exome and wholegenome sequencing analyses have been applied for genome-wide detection of genetic variation at the nucleotide level (74,75,(96)(97)(98)(99)(100)(101)(102)(103)(104)(105). Investigations have included both extended familial cases and larger patient cohorts identifying variants of interesting genes, most notably GREB1L (99, 101, 102) and PAX8 (75).…”