OFD1 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a motile ciliopathy marked by recurrent respiratory infections, laterality defects, and infertility. OFD1 (HGNC:2567) encodes a centrosomal and basal body protein essential for cilia biogenesis. Although OFD1 was historically linked to X-linked dysmorphology syndromes, recent studies establish its role in isolated PCD without syndromic features.

Genetic evidence supports an X-linked recessive inheritance of OFD1-related PCD. To date, at least 11 hemizygous male probands across four unrelated cohorts have been reported with OFD1 loss-of-function variants presenting classic PCD manifestations ([PMID:35847568], [PMID:31373179], [PMID:31366608], [PMID:39156004]). No multi-generation segregation beyond maternal carrier status has been documented, consistent with X-linked recessive transmission.

Case reports describe novel truncating variants in the C-terminal region of OFD1. A 31-year-old man carried c.2795delA (p.Lys932ArgfsTer3) leading to recurrent oto-sino-pulmonary infections, situs inversus totalis, obesity, gastroesophageal reflux, and hearing impairment ([PMID:35847568]). Four additional patients harbored truncations in exons 20–21 with isolated respiratory phenotypes and no neurological or renal involvement ([PMID:31366608]), and two pediatric cases exhibited frameshifts c.2789_2793del (p.Ile930LysfsTer8) and c.2632_2635del (p.Glu878LysfsTer9) with typical PCD features ([PMID:39156004]).

Functional assays reveal abnormal motile cilia dynamics concordant with PCD. High-speed video microscopy consistently shows a stiff, hyperfrequent beat pattern, while transmission electron microscopy and immunofluorescence often appear normal ([PMID:35847568], [PMID:31366608]). These findings support a haploinsufficiency mechanism whereby C-terminal truncations selectively impair motile cilia without abolishing primary cilia function.

Despite limited ultrastructural defects, the consistent ciliary beat abnormalities across multiple studies strengthen causality. No conflicting evidence has refuted OFD1’s role in PCD; variability in TEM findings likely reflects technical limitations. The OFD1-PCD association remains robust and clinically actionable.

Integration of genetic and experimental data yields a strong gene-disease relationship. OFD1 should be included in X-linked PCD diagnostic panels, facilitating timely molecular diagnosis, carrier testing, and management. Key take-home: Loss-of-function variants in OFD1 cause X-linked PCD through haploinsufficiency of motile cilia components, with high diagnostic utility.

References

• Pharmacogenomics and personalized medicine • 2022 • Identification of a Novel OFD1 Variant in a Patient with Primary Ciliary Dyskinesia. PMID:35847568
• Molecular genetics & genomic medicine • 2019 • The expanding phenotype of OFD1-related disorders: Hemizygous loss-of-function variants in three patients with primary ciliary dyskinesia. PMID:31373179
• Journal of medical genetics • 2019 • Truncating mutations in exons 20 and 21 of OFD1 can cause primary ciliary dyskinesia without associated syndromic symptoms. PMID:31366608
• Case reports in genetics • 2024 • Two Pediatric Cases of Primary Ciliary Dyskinesia Caused by Loss-of-Function Variants in Oral-Facial-Digital Syndrome Gene, OFD1. PMID:39156004

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