Novel Biallelic DNHD1 Variants Associated with Male Infertility with Severe MMAF Phenotype

Two siblings share novel homozygous DNHD1 mutations causing severe flagellar defects and near-total sperm immotility

Journal: Asian Journal of Andrology | Published: 2025-11-11 | Type: Case Report / Journal Article | PMID: 41214471 Authors: Islam U, Zafar I, Xu CL, et al. (Center for Reproduction and Genetics, Dept. of Obstetrics and Gynecology, First Affiliated Hospital — institution name truncated in source data); Khan MI (University of Agriculture, Faisalabad) Funding/COI: Not listed

Summary

Two brothers from a consanguineous Pakistani family were found to carry two novel homozygous variants in DNHD1 — a missense variant (p.K1486R) and a nonsense variant (p.R3542*) — identified via whole-exome sequencing. Both presented with severe multiple morphological abnormalities of the sperm flagella (MMAF): absent, short, coiled, and irregular flagella with extreme asthenoteratozoospermia. Electron microscopy confirmed structural axonemal disintegration, including missing central microtubule pairs and severe mitochondrial sheath damage.

Claims

• Both affected siblings exhibited low progressive sperm motility and severe MMAF morphology on semen analysis
• WES identified two novel homozygous DNHD1 variants: a missense variant (c.A4457G; p.K1486R) and a nonsense/stop-gain variant (c.C10624T; p.R3542*)
• Transmission electron microscopy revealed missing central pairs of the axoneme, disorganized microtubule doublets, and severe mitochondrial sheath defects
• Immunofluorescence and H&E staining corroborated structural flagellar pathology
• Authors position these as novel variants expanding the known mutation spectrum of DNHD1 in asthenoteratozoospermia

Study Quality

This is a case report of two individuals — brothers from a single consanguineous family. There is no control group, no functional rescue experiment (e.g., introducing wild-type DNHD1 to confirm pathogenicity), and no population-level frequency data for these variants in South Asian cohorts. WES is an appropriate discovery tool here, and the multimodal structural characterization (electron microscopy + immunofluorescence + H&E) is solid for a case-level description. However, the consanguineous family design means co-segregation of variants with phenotype is expected by default — it cannot establish causality on its own.

The nonsense variant (p.R3542*) is biologically plausible as a loss-of-function allele; the missense variant (p.K1486R) requires more evidence to confirm pathogenicity versus being an incidental finding in a highly inbred pedigree.

Red Flags

• Sample size of two (2) individuals — no statistical inference is possible
• No functional validation; pathogenicity of the missense variant is asserted, not demonstrated
• Consanguineous family pedigree increases probability of multiple co-inherited variants unrelated to phenotype
• Funding and conflict of interest not declared — unusual for a 2025 publication in a peer-reviewed andrology journal
• No comparison to existing DNHD1 variant carriers to contextualize phenotype severity
• Institutional affiliations are truncated in the source metadata, making it difficult to assess author independence

Strengths

• Multimodal structural workup (TEM, immunofluorescence, H&E) provides detailed phenotypic characterization beyond semen analysis alone
• WES is appropriate methodology for rare monogenic infertility investigation
• Adds to the growing catalog of DNHD1 variants linked to MMAF, which is clinically relevant for genetic counseling in affected families
• Reports from an underrepresented population (Pakistani consanguineous families), where recessive infertility variants are enriched

Verdict

Two patients do not make a discovery — they make a hypothesis. This case report is useful scaffolding for future functional studies and population screens, and the structural TEM data is genuinely informative about how DNHD1 loss manifests in sperm ultrastructure. But the missing functional validation, undeclared funding, and two-person sample size place this firmly in the "preliminary signal, not confirmed gene" category. Worth filing under the DNHD1 literature for anyone tracking MMAF genetics; not worth citing as evidence of causality.