CPLANE1 – Orofaciodigital Syndrome Type VI

Oral-facial-digital syndrome type VI (OFD6), also called Varadi-Papp syndrome, is a rare autosomal recessive ciliopathy characterized by the molar tooth sign, tongue hamartomas, mesoaxial polydactyly, additional frenula, and craniofacial anomalies. Pathogenic variants in CPLANE1 (HGNC:25801) have been implicated in OFD6 and overlapping Joubert syndrome phenotypes, establishing a link between gene dysfunction and ciliary transition zone defects (Gene Symbol – Disease Name).

A multi-patient exome study in three unrelated OFD6 cases identified three novel missense CPLANE1 alleles, c.3599C>A (p.Ala1200Glu) (PMID:27081551) and c.3599C>T (p.Ala1200Val) (PMID:27081551), plus one previously reported variant. All variants were found in trans, absent in population databases, and predicted deleterious, confirming autosomal recessive inheritance and loss-of-function mechanism.

A separate clinical report described a 19-year-old man with mild developmental delay and orofacial anomalies carrying a homozygous missense variant c.365T>G (p.Val122Gly) confirmed by Sanger sequencing, with heterozygous parents and an unaffected homozygous wild-type sibling, supporting complete segregation (PMID:39911166).

In aggregate, four unrelated OFD6 probands across two studies have been documented with biallelic CPLANE1 variants and consistent autosomal recessive transmission, with no additional affected relatives reported.

Reported alleles are predominantly missense, although frameshift and splice variants in Joubert syndrome expand the spectrum. Recurrent variants cluster in conserved exons, underscoring critical domains for CPLANE1 function in ciliogenesis.

Direct functional studies in OFD6 are lacking, but Jbts17 (C5orf42) mutant mice exhibit ciliary transition zone defects, cerebellar hypoplasia, polydactyly, and craniofacial anomalies, mirroring human OFD6 features and supporting haploinsufficiency as the pathogenic mechanism (PMID:25877302).

Overall, the current evidence yields a Moderate clinical validity classification for the CPLANE1–OFD6 association. Targeted functional assays in patient-derived cells will be key to confirming variant pathogenicity. Key take-home: CPLANE1 sequencing is recommended for diagnosis and genetic counseling in suspected autosomal recessive OFD6.

References

• Human genome variation • 2015 • Exome sequencing identifies novel mutations in C5orf42 in patients with Joubert syndrome with oral-facial-digital anomalies PMID:27081551
• Molecular syndromology • 2025 • A Novel Homozygous Variant in CPLANE1 Gene in a Patient with Developmental Deficits PMID:39911166
• Human molecular genetics • 2015 • Novel Jbts17 mutant mouse model of Joubert syndrome with cilia transition zone defects and cerebellar and other ciliopathy related anomalies PMID:25877302

Evidence Based Scoring (AI generated)