CFAP53 – Situs Inversus

CFAP53 (HGNC:26530) encodes a coiled-coil domain protein essential for motile cilia function and left–right axis determination. Pathogenic variants in CFAP53 have been reported in multiple consanguineous families presenting with autosomal recessive laterality defects, most notably situs inversus totalis. The association between CFAP53 and situs inversus (MONDO:0010029) is supported by both genetic segregation in affected kindreds and functional studies in patient cells and animal models.

Autosomal recessive inheritance has been demonstrated in three independent families encompassing five probands with complete or partial laterality inversion. A splice-donor variant, c.1213+1G>A, was identified homozygously in two siblings with situs inversus totalis in Family 1 (PMID:22577226). A second consanguineous pedigree harbored a truncating CCDC11 mutation in two affected sibs, one with heterotaxy and one with non-primary ciliary dyskinesia situs inversus (PMID:28621423). A third case involved a fetus with compound heterozygous loss-of-function alleles including c.777G>T (p.Val259=) presenting as fetal situs inversus totalis (PMID:39969775).

Segregation analysis across these families revealed segregation of deleterious CFAP53 alleles in four affected relatives; all unaffected parents and siblings were heterozygous carriers or wild type (PMID:22577226, PMID:28621423). No variants were observed in ethnically matched controls (n = 112) in Family 1, supporting rarity and pathogenicity of the splice-site change.

Variant spectrum is dominated by loss-of-function alleles including canonical splice-site and truncating mutations. To date, no recurrent or founder variants beyond these consanguineous cohorts have been described, and carrier frequency remains unknown. Reported symptomatic presentation is principally situs inversus totalis (HP:0001696), with occasional visceral heterotaxy requiring clinical management.

Functional assays in patient-derived fibroblasts demonstrated abnormally elongated motile cilia and mislocalized truncated CFAP53 protein at centrioles and actin cytoskeleton (PMID:28621423). In Xenopus laevis embryos, Ccdc11 knockdown or overexpression of truncated human protein disrupted left–right axis determination, phenocopying human laterality defects and confirming a loss-of-function mechanism (PMID:28621423).

Collectively, moderate genetic evidence from five probands and four segregations, coupled with concordant cellular and animal model data, supports a moderate clinical validity classification for CFAP53 in autosomal recessive situs inversus. Additional studies in larger cohorts and functional rescue experiments would strengthen this gene–disease association. Key take-home: CFAP53 should be included in diagnostic gene panels for autosomal recessive laterality disorders.

References

• Journal of medical genetics • 2012 • A human laterality disorder associated with recessive CCDC11 mutation. PMID:22577226
• The International journal of developmental biology • 2017 • Roles of the cilium-associated gene CCDC11 in left-right patterning and in laterality disorders in humans. PMID:28621423
• Journal of applied genetics • 2025 • Identification of novel biallelic mutations in CFAP53 associated with fetal situs inversus totalis and literature review. PMID:39969775

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