CFAP410 – Axial Spondylometaphyseal Dysplasia

Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive ciliopathy marked by dysplasia of the axial skeleton (flared ribs, metaphyseal abnormalities of proximal femora and lacy ilia) and early‐onset retinal dystrophy. CFAP410 (formerly C21orf2) encodes a basal‐body ciliary protein critical for skeletal development and photoreceptor function. Biallelic variants in CFAP410 have been linked to both skeletal and retinal phenotypes, underscoring its role in cartilage differentiation and photoreceptor cilium integrity.

Initial multi‐patient analysis identified CFAP410 as the causative gene in axial SMD by whole exome sequencing in six unrelated families out of nine studied, revealing five distinct biallelic mutations (three missense and two splice‐site) with RNA‐level confirmation of aberrant splicing ([PMID:26974433]). This cohort included a total of six probands with autosomal recessive inheritance and no additional affected relatives reported ([PMID:26974433]).

A subsequent case report described a seventh patient with overlapping axial SMD and Jeune asphyxiating thoracic dystrophy phenotypes carrying the recurrent homozygous variant c.218G>C (p.Arg73Pro) ([PMID:28422394]). This variant has been observed in both syndromic and non‐syndromic presentations, highlighting a spectrum of severity linked to CFAP410 dysfunction ([PMID:28422394]).

The variant spectrum in axial SMD includes three missense changes (p.Arg73His, p.Pro116Leu, p.Tyr107His) and two canonical splice‐site mutations (c.545+1G>C, c.545+1G>A). The p.Arg73Pro allele recurs in multiple ethnic backgrounds and appears to represent a founder or hotspot mutation, suggesting allelic heterogeneity and population‐specific recurrence ([PMID:26974433]; [PMID:28422394]).

Functional assays in chondrocytes demonstrated that CFAP410 deficiency impairs cartilage differentiation, consistent with skeletal dysplasia ([PMID:26974433]). In photoreceptor models, missense variants such as c.331G>A (p.Val111Met) and c.320A>G (p.Tyr107Cys) reduced protein stability and disrupted ciliary localization ([PMID:27548899]). Further cell‐based studies of c.319T>C (p.Tyr107His) and c.347C>T (p.Pro116Leu) showed impaired protein stability, altered ubiquitination and cell‐cycle dysregulation, confirming pathogenic mechanisms via proteasomal degradation pathways ([PMID:37901396]).

Structural biology work revealed that the C‐terminal domain of CFAP410 forms a tetrameric helical bundle crucial for basal body targeting; the SMD‐associated L224Pro mutation disassembles this bundle and abrogates ciliary localization ([PMID:39255848]).

Collectively, autosomal recessive biallelic CFAP410 variants cause axial SMD through loss of ciliary function in skeletal and retinal tissues. Genetic and functional concordance across multiple studies supports a strong gene–disease association. Key take‐home: CFAP410 testing should be integrated into diagnostic panels for skeletal ciliopathies with retinal dystrophy to guide clinical management and genetic counseling.

References

• PloS One • 2016 • Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations. PMID:26974433
• American journal of medical genetics. Part A • 2017 • Homozygous variant in C21orf2 in a case of Jeune syndrome with severe thoracic involvement: Extending the phenotypic spectrum. PMID:28422394
• Investigative ophthalmology & visual science • 2016 • Identification of Novel Mutations in the LRR-Cap Domain of C21orf2 in Japanese Patients With Retinitis Pigmentosa and Cone-Rod Dystrophy. PMID:27548899
• Frontiers in medicine • 2023 • Pathogenicity and functional analysis of CFAP410 mutations causing cone-rod dystrophy with macular staphyloma. PMID:37901396
• Open Biology • 2024 • The C-terminus of CFAP410 forms a tetrameric helical bundle that is essential for its localization to the basal body. PMID:39255848

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