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SPAG6 is a critical axonemal protein that plays an essential role in the formation and function of cilia and flagella. Variants in SPAG6 have been associated with primary ciliary dyskinesia (PCD), a disorder that manifests clinically with severe asthenoteratozoospermia and multiple morphological abnormalities of the sperm flagella (MMAF) (PMID:35232447). This association is supported by recent genetic studies, which utilized whole‐exome sequencing and Sanger validation to identify homozygous and compound heterozygous variants in affected individuals.
In one study, two unrelated Han Chinese patients with MMAF were found to harbor homozygous SPAG6 variants, one of which is the recurrent frameshift mutation c.587del (p.Lys196SerfsTer6) (PMID:35232447). In a separate patient series, a compound heterozygous state involving SPAG6 variants, including a similar mutation, was reported in a sporadic case of PCD, further consolidating the genetic evidence for this gene‑disease association (PMID:32124190).
Segregation analysis in these familial cases demonstrated that the identified variants co‐segregate with the MMAF phenotype, as confirmed by pedigree analysis and Sanger sequencing. Although the detailed count of affected relatives with segregating variants is limited in the available studies, the presence of pathogenic variants in unrelated probands contributes substantially to the diagnostic confidence.
From a genetic perspective, the variant spectrum in SPAG6 includes loss‑of‑function mutations such as frameshift deletions. The recurrent variant, c.587del (p.Lys196SerfsTer6), exemplifies the type of mutation observed and supports a pathogenic mechanism involving haploinsufficiency or complete loss of function (PMID:35232447). This genetic evidence meets ClinGen guidelines for a strong association in the context of an autosomal recessive inheritance pattern.
Functional studies further reinforce the clinical relevance of SPAG6 in ciliogenesis. Investigations using Spag6‑deficient mouse embryonic fibroblasts revealed markedly reduced cell proliferation, altered morphology, and disrupted ciliogenesis (PMID:26585507). Moreover, Spag6 knockout mouse models exhibited ultrastructural defects in cilia and flagella, mirroring the clinical phenotype observed in patients (PMID:28819108). These experiments provide mechanistic insights that are concordant with the genetic data and the disruption of normal ciliary structure and function.
Taken together, the genetic and functional evidence strongly supports the association between SPAG6 variants and primary ciliary dyskinesia. The data underscore that SPAG6 pathogenic variants, particularly those leading to loss of function, are clinically actionable markers for a subset of PCD patients presenting with severe sperm flagellar abnormalities. This integrated evidence thus enhances both diagnostic decision‑making and therapeutic management, with implications for patient care and reproductive counseling.
Key Take‑home sentence: SPAG6 variants represent a robust genetic marker for primary ciliary dyskinesia, with converging genetic and functional evidence that informs clinical diagnosis and patient management.
Gene–Disease AssociationStrongMultiple unrelated probands identified with homozygous and compound heterozygous SPAG6 variants, including the recurrent c.587del (p.Lys196SerfsTer6) (PMID:35232447) and supportive segregation data (PMID:32124190). Genetic EvidenceStrongGenetic findings from independent studies revealed loss‑of‑function variants in SPAG6 in at least two unrelated families, with recurrence of the c.587del variant affirming its pathogenic role. Functional EvidenceModerateFunctional assays in Spag6‑deficient cell and mouse models demonstrate impaired ciliogenesis and axonemal defects, which align with the PCD phenotype (PMID:26585507, PMID:28819108). |