Genetic variants analysis of 17 female patients with idiopathic hypogonadotropic hypogonadism

Only 4 of 17 sequenced female IHH patients (23.5%) had an identifiable pathogenic variant; the majority remain genetically undiagnosed

Journal: Beijing da xue xue bao / Journal of Peking University Health Sciences | Published: 2026-04-18 | Type: Journal Article (English Abstract) | PMID: 41978403 Authors: Chen Qiqi, Wang Haining, Liu Ye, Zhi Xu — Department of Obstetrics/Gynecology and Endocrinology, Peking University Third Hospital Funding/COI: Not listed for either

Summary

This single-center case series used whole exome sequencing on 17 female patients with idiopathic hypogonadotropic hypogonadism (IHH), a condition where the brain fails to signal the gonads to produce sex hormones. Pathogenic variants in known genes (FGFR1, PROKR2) were found in fewer than a quarter of patients. A novel missense variant in PLXNA1 — a PLEXIN pathway gene not previously established as IHH-causative — was identified in two Kallmann syndrome patients and modeled with AlphaFold2, showing a hydrophobicity change at amino acid 1134.

Claims

• 4/17 sequenced patients (23.5%) carried pathogenic variants in FGFR1 or PROKR2
• 13/17 patients received no specific genetic diagnosis
• Two Kallmann syndrome patients shared the same heterozygous variant PLXNA1 c.3401G>A, found in no other PLEXIN pathway gene in those patients
• AlphaFold2 structural modeling showed the PLXNA1 missense mutation alters hydrophobicity at amino acid position 1134
• Four patients with family history carried variants in FGFR1, CHD7, and POLR3B, but pathogenicity reached only VUS (variant of unknown significance) per ACMG criteria, and genotype-phenotype co-segregation was inconsistent within families
• Normosmic IHH and Kallmann syndrome subgroups showed no significant difference in baseline clinical data

Study Quality

This is a small, single-center case series from one Chinese academic hospital. Twenty-one patients were recruited; only 17 and their family members provided samples for sequencing — the paper does not clearly account for why 4 were excluded from the genetic analysis. Whole exome sequencing plus Sanger confirmation is methodologically appropriate, and applying ACMG guidelines for variant classification is the correct standard. AlphaFold2-based protein structure prediction for the PLXNA1 variant is a reasonable exploratory step but is not functional validation — it identifies a structural change, not a disease mechanism.

The PLXNA1 finding, the paper's main novel claim, rests on exactly two patients sharing one heterozygous variant with no other PLEXIN pathway hit. That is insufficient to establish pathogenicity. The authors acknowledge this, calling it a "potential risk variant," but this caveat should be prominent, not buried in the conclusion.

Red Flags

• N=17 for sequencing — far too small to draw population-level conclusions about inheritance patterns or variant frequency
• 76.5% diagnostic yield failure — most patients leave with no genetic answer, which limits the paper's clinical utility
• PLXNA1 novelty claim based on 2 patients — no functional studies, no replication cohort, no population frequency comparison with gnomAD or similar databases reported
• Funding and COI not disclosed — a basic transparency failure
• Paper published in Chinese with English abstract only — full methodology, statistical approach, and patient characteristics are not accessible to most readers
• No control group for variant frequency comparison
• Genotype-phenotype co-segregation inconsistent in family cases — the authors acknowledge this undermines VUS reclassification for those variants

Strengths

• Applies appropriate gold-standard sequencing methodology (WES + Sanger confirmation)
• Uses ACMG guidelines for variant classification rather than ad hoc pathogenicity calls
• Collects family member samples for co-segregation analysis — a necessary step most small case series skip
• Honestly reports the high proportion of genetically undiagnosed patients rather than overselling findings
• AlphaFold2 structural prediction adds mechanistic hypothesis generation for the PLXNA1 variant

Verdict

A small, honest case series that documents how difficult female IHH genetics remain — most patients go undiagnosed even with whole exome sequencing. The PLXNA1 finding is hypothesis-generating at best; two patients sharing a single heterozygous variant with no functional validation is a lead for future research, not a reportable result. The undisclosed funding and COI, combined with Chinese-language-only full text, limit external scrutiny. Worth filing as background on IHH genetic complexity; not worth citing as evidence that PLXNA1 is a KS risk gene.