CFAP74 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder characterized by recurrent respiratory infections, nasosinusitis, tympanitis and male infertility. Multiple morphological abnormalities of the sperm flagella (MMAF) represent a severe form of teratozoospermia associated with PCD. Whole-exome sequencing in two unrelated probands revealed biallelic CFAP74 variants: c.983G>A (p.Gly328Asp) and c.3532G>A (p.Asp1178Asn) in patient 1, and c.652C>T (p.Arg218Trp) and c.4331G>C (p.Ser1444Thr) in patient 2, all predicted deleterious and confirmed absent CFAP74 signal on sperm immunofluorescence (PMID:32555313).

No additional affected relatives were reported, supporting autosomal recessive inheritance with limited segregation data. Functional studies in zebrafish morphants of cfap74 LOF alleles (c.163G>T; p.Glu55Ter, c.1072del; p.Arg358GlufsTer10, c.1714_1715del; p.Leu572ValfsTer7) demonstrated abnormal cardiac looping, defective Kupffer’s vesicle organogenesis and impaired ciliogenesis, concordant with human laterality and ciliary phenotypes (PMID:36459505).

These data provide limited genetic evidence (2 probands, no segregation) but moderate experimental support for a loss-of-function mechanism in CFAP74 causing PCD with MMAF. Inclusion of CFAP74 in diagnostic gene panels may improve molecular diagnosis and guide assisted reproductive strategies.

Key Take-home: Biallelic CFAP74 variants underlie autosomal recessive PCD and MMAF, with functional models confirming ciliary dysfunction and supporting clinical testing.

References

• Journal of human genetics • 2020 • Biallelic mutations of CFAP74 may cause human primary ciliary dyskinesia and MMAF phenotype. PMID:32555313
• PLoS genetics • 2022 • LOF variants identifying candidate genes of laterality defects patients with congenital heart disease. PMID:36459505

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