SPAG1 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder characterized by defective motile cilia leading to chronic oto-sino-pulmonary disease, laterality defects and fertility issues. SPAG1 encodes a dynein axonemal assembly factor essential for outer and inner dynein arm formation and trafficking.

In 2013, exome sequencing of three unrelated PCD probands identified biallelic loss-of-function variants in SPAG1 in one family with three affected siblings, and screening of 98 additional PCD cases revealed 11 more individuals with LoF mutations ([PMID:24055112]). Segregation analysis confirmed co-segregation in sibships. In a Czech cohort of 33 families, SPAG1 was the causative gene in 8 probands, all confirmed by Sanger segregation ([PMID:26228299]). Chinese pediatric studies reported SPAG1 variants in 1/50 and 1/75 cases ([PMID:32502479], [PMID:33577779]), and an Indian cohort found SPAG1 mutations in 1/29 definite PCD patients ([PMID:39004944]).

A case with unexplained PCD carried one coding SPAG1 variant and a second-allele 3 kb promoter deletion detected by RNA-seq and targeted long-read sequencing, demonstrating allele-specific expression and confirming autosomal recessive inheritance ([PMID:39364610]).

Functional assays show that SPAG1 interacts with multiple dynein heavy and intermediate chains and DNAAF components; SPAG1 mutants exhibit reduced DHC–DIC binding and dynein arm loss in human airway epithelia. Zebrafish morpholino knockdown recapitulates PCD phenotypes, and a 60 kDa isoform partially rescues axonemal assembly ([PMID:35178554], [PMID:24055112]).

Together, >20 unrelated probands across ≥14 families, robust segregation and concordant cellular and animal models support a strong SPAG1–PCD association. Functional data confirm SPAG1’s role in dynein arm assembly via R2TP-like scaffolding.

Key Take-home: SPAG1 fulfills ClinGen criteria for a strong autosomal recessive PCD gene, with diagnostic utility spanning coding and non-coding variant detection.

References

• American Journal of Human Genetics • 2013 • Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms. PMID:24055112
• Pediatric Pulmonology • 2016 • An effective combination of sanger and next generation sequencing in diagnostics of primary ciliary dyskinesia. PMID:26228299
• The Journal of Pediatrics • 2020 • Clinical and Genetic Spectrum of Children with Primary Ciliary Dyskinesia in China. PMID:32502479
• Chest • 2021 • Clinical and Genetic Spectrum of Children With Primary Ciliary Dyskinesia in China. PMID:33577779
• Clinical Genetics • 2024 • Genetics of 67 patients of suspected primary ciliary dyskinesia from India. PMID:39004944
• American journal of medical genetics. Part A • 2025 • Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia. PMID:39364610
• Journal of Cell Science • 2022 • The role of SPAG1 in the assembly of axonemal dyneins in human airway epithelia. PMID:35178554

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