Mosaic variants in the LIM homeobox 1 (LHX1) gene contribute to Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome.

Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome presents as the congenital absence of the uterus and vagina and affects approximately 1 in 4500 women. Affected individuals have normal breast development, primary amenorrhea, and a 46,XX karyotype. Müllerian aplasia may be isolated (type 1) or associated with renal, skeletal, cardiac, and auditory anomalies (type 2). The pathogenesis of MRKH largely remains unknown, but the LHX1 gene, which encodes a transcription factor, is an attractive candidate. LHX1 has been extensively studied in animals but less studied in humans. The Lhx1-null mouse model is embryonic lethal, but conditional knockout models found it important for urogenital system development. Although several possible deleterious variants have been reported in humans, LHX1 has not been established as a cause of MRKH in OMIM. In this study, we identified heterozygous intragenic LHX1 deletions by qPCR in 3/134 (2.2%) individuals with MRKH, which were confirmed by RT-PCR of lymphoblast RNA. This 166 bp frameshift deletion produces a premature stop codon (c.676_841del;p.V226Ifs*120) and is predicted to disrupt the DNA-binding domain essential for function. Mapping of the variant in genomic DNA revealed an 1864 bp deletion encompassing intron 3, exon 4, and intron 4, with allele frequencies of 3.4, 6.2, and 1%, respectively, in the three patients. Our findings provide supportive evidence that a low-level mosaic likely pathogenic variant in LHX1 could contribute to the pathogenesis of MRKH with or without nonreproductive anomalies.