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Background <p><i>LHX8</i> 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 <i>LHX8</i>.</p> Results <p>Whole exome sequencing identified heterozygous loss-of-function variants in <i>LHX8</i> (NM_001001933.1) in both patients: c.778&#xa0;C &gt; T (p.Gln260Ter) in family 1 and c.581-1G &gt; 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.</p> Conclusions <p>These findings expand the phenotypic spectrum of <i>LHX8</i> related infertility and provide mechanistic evidence that partial reduction of <i>LHX8</i> activity compromises oocyte quality. Recognition of the characteristic morphology may guide genetic testing and counseling in cases of unexplained infertility.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月21日

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  • Yusuke Sako,
  • Hidehito Inagaki,
  • Akira Yanagihara,
  • Koichi Kinoshita,
  • Kaname Nakayama,
  • Yasuyuki Mio,
  • Keitaro Yumoto,
  • Rei Hirata,
  • Toshihiro Habara,
  • Haruki Nishizawa,
  • Hiroki Kurahashi

摘要

Background

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.

Results

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.

Conclusions

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.