# Novel LHX8 variants associated with distinctive oocyte morphological abnormalities and maturation arrest in primary infertility

## TL;DR

This study identifies new LHX8 gene variants linked to infertility by causing oocyte abnormalities and maturation issues in two unrelated women.

## Contribution

The study reports novel LHX8 variants and their association with distinct oocyte morphological defects and infertility.

## Key findings

- Two patients with primary infertility had likely pathogenic LHX8 variants causing oocyte abnormalities.
- Oocyte defects included cytoplasmic vacuoles, impaired zona pellucida function, and poor embryo development.
- A splice site variant showed incomplete penetrance and was confirmed to cause loss of LHX8 function.

## Abstract

LHX8 gene encodes a germ cell specific transcription factor that is required for oocyte development. We evaluated two unrelated women with primary infertility who showed reproducible oocyte abnormalities across in vitro fertilization cycles, and we performed genomic and functional assays to clarify the role of LHX8.

Whole exome sequencing identified heterozygous loss-of-function variants in LHX8 (NM_001001933.1) in both patients: c.778 C > T (p.Gln260Ter) in family 1 and c.581-1G > A in family 2. Both variants met the American College of Medical Genetics and Genomics criteria for likely pathogenicity. The two patients had high proportions of degenerated or immature oocytes and showed consistent morphologic features, including multiple cytoplasmic vacuoles, impaired zona pellucida function with accumulation of sperm in the perivitelline space, and poor embryo development. The splice site variant was inherited from a fertile mother, which indicates incomplete penetrance. A minigene assay confirmed the use of a cryptic acceptor site that produced a one nucleotide deletion and a frameshift, consistent with loss of function.

These findings expand the phenotypic spectrum of LHX8 related infertility and provide mechanistic evidence that partial reduction of LHX8 activity compromises oocyte quality. Recognition of the characteristic morphology may guide genetic testing and counseling in cases of unexplained infertility.

The online version contains supplementary material available at 10.1186/s13048-026-01978-2.