HYDIN – Primary Ciliary Dyskinesia

Autosomal recessive primary ciliary dyskinesia (PCD) is characterized by impaired motile cilia function leading to chronic respiratory disease, bronchiectasis, laterality defects, and infertility. HYDIN encodes a central pair apparatus protein essential for the C2b projection within motile cilia. Biallelic HYDIN variants disrupt axonemal structure and mucociliary clearance, establishing HYDIN as a PCD gene.

Multiple independent cohorts (n ≥ 35 probands [PMID:23022101], [PMID:39317196], [PMID:39291810]) and several multiplex families exhibit autosomal recessive inheritance of HYDIN variants. Founder analysis in the Faroe Islands identified homozygous c.922A>T (p.Lys308Ter) in six individuals from three families, and three affected siblings with homozygous splice-site variants were reported in Germany ([PMID:23022101]). Segregation analysis in German and cis‐mutation siblings confirms pathogenicity in 6 additional relatives ([PMID:23022101], [PMID:39317196]).

The variant spectrum includes >30 distinct alleles: nonsense (e.g., c.922A>T (p.Lys308Ter)), splice‐site, frameshift, and missense changes. A recurrent founder c.922A>T variant and multiple private loss-of-function alleles have been reported across diverse populations, including Finnish ([PMID:39291810]), Chinese, Indian ([PMID:39004944]), and Turkish cohorts. HYDIN2 pseudogene interference necessitates long-read sequencing to detect copy number variants.

Functional assays demonstrate that HYDIN deficiency abolishes the central pair C2b projection, as shown by transmission electron microscopy and electron tomography in patient respiratory cells. High‐speed video microscopy reveals stiff or static ciliary beating, and immunofluorescence shows loss of HYDIN and SPEF2 in the axoneme ([PMID:23022101], [PMID:31545650]). Hydin knockdown in model organisms and rescue experiments further corroborate a loss-of-function mechanism.

No studies have refuted biallelic HYDIN involvement in PCD, although HYDIN2 complicates short-read NGS analysis. Integration of long-read sequencing and immunofluorescence for SPEF2 enhances diagnostic yield and variant interpretation in central pair defect cases.

Taken together, genetic and experimental data provide strong evidence that HYDIN is a PCD‐causing gene. Inclusion of HYDIN in diagnostic gene panels with appropriate sequencing strategies is clinically actionable and supports genetic counseling and prenatal testing.

Key Take-home: Biallelic HYDIN variants cause autosomal recessive PCD with central pair apparatus defects, chronic respiratory disease, and infertility, warranting targeted sequencing and functional assays in suspected cases.

References

• American Journal of Human Genetics • 2012 • Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry. PMID:23022101
• Med (New York, N.Y.) • 2024 • Heterozygous cis HYDIN mutations cause primary ciliary dyskinesia. PMID:39317196
• Pediatric Pulmonology • 2024 • HYDIN variants cause primary ciliary dyskinesia in the Finnish population. PMID:39291810
• American Journal of Respiratory Cell and Molecular Biology • 2020 • SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics. PMID:31545650

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