SPEF2 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder characterized by impaired motility of respiratory cilia resulting in chronic sinopulmonary disease. SPEF2 encodes a central pair–associated protein critical for ciliary and flagellar function. Patients present with recurrent airway infections, bronchiectasis, and sinusitis without laterality defects.

Genetic evidence supports SPEF2 as a PCD gene. Biallelic SPEF2 variants have been identified in 6 probands (PMID:31942643), 1 proband (PMID:36615117), 1 proband (PMID:31545650), and 3 probands (PMID:38568462), totaling 11 unrelated individuals. All cases exhibit autosomal recessive inheritance with homozygous or compound heterozygous loss‐of‐function or deleterious missense variants.

The variant spectrum includes splice‐site, nonsense, frameshift, and missense changes. A representative pathogenic change is c.1645G>T (p.Glu549Ter), which abolishes the IFT20‐binding domain of SPEF2 and segregates with PCD in a Chinese family (PMID:38568462).

Functional studies demonstrate absence of SPEF2 protein in patient respiratory cilia by immunofluorescence and a moderate reduction in ciliary beat frequency. A Spef2 knockout mouse recapitulates PCD‐like respiratory defects and reduced fertility, confirming haploinsufficiency as the pathogenic mechanism (PMID:31942643). In vitro rescue of SPEF2 restores ciliary motility.

No studies have refuted the association, and there is no evidence of conflicting phenotypes. The combined genetic and functional concordance fulfills ClinGen criteria for a strong gene–disease association.

Key take-home: SPEF2 harbors biallelic loss‐of‐function or deleterious missense variants that underlie autosomal recessive primary ciliary dyskinesia, guiding molecular diagnosis and management.

References

• Journal of clinical medicine • 2022 • Novel SPEF2 Variant in a Japanese Patient with Primary Ciliary Dyskinesia: A Case Report and Literature Review. PMID:36615117
• Human genetics • 2020 • Novel mutations in SPEF2 causing different defects between flagella and cilia bridge: the phenotypic link between MMAF and PCD. PMID:31942643
• American journal of respiratory cell and molecular biology • 2020 • SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics. PMID:31545650
• Journal of assisted reproduction and genetics • 2024 • Novel SPEF2 variants cause male infertility and likely primary ciliary dyskinesia. PMID:38568462

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