OFD1 – Joubert syndrome 10

Orofaciodigital syndrome 1 gene (OFD1) is causally implicated in X-linked recessive Joubert syndrome type 10 (JBTS10) characterized by cerebellar vermis hypoplasia and the molar tooth sign. Pathogenic variants in OFD1 disrupt primary cilium function, leading to neurodevelopmental defects. The association between OFD1 and JBTS10 is supported by multiple unrelated probands, familial segregation, and concordant cellular rescue experiments.

JBTS10 follows an X-linked recessive inheritance mode with hemizygous males affected and carrier females typically asymptomatic. To date, at least 12 unrelated probands with OFD1 variants have been described (including three in the index study) ([PMID:28344780]). Segregation in a three-generation Malaysian pedigree confirmed co-segregation of hemizygous frameshift alleles in two affected males with obligate carrier females ([PMID:19800048]), and six additional affected relatives across pedigrees further support pathogenicity. The variant spectrum comprises predominantly loss-of-function alleles—frameshifts (e.g., c.2656del (p.Gln886LysfsTer2)), nonsense (c.2848A>T (p.Lys950Ter)), and splice-site mutations (c.2488+2T>C)—as well as a recurrent missense variant c.599T>C (p.Leu200Pro) in three affected males ([PMID:32944789]). Multiple truncating mutations cluster in exons 20–22 of OFD1, suggesting critical C-terminal domains for ciliary function.

Functional studies in patient-derived fibroblasts reveal abnormal N- and O-linked glycosylation profiles and impaired ciliogenesis in JBTS10 cells. Wild-type OFD1 expression rescues both ciliogenesis defects and glycosylation anomalies, indicating a loss-of-function mechanism ([PMID:28344780]). Additional cellular assays demonstrate reduced OFD1 protein levels from splice and nonsense alleles due to nonsense-mediated decay, leading to deficient Sonic hedgehog signaling in neural progenitors ([PMID:32944789]; [PMID:36704348]).

No studies have reported conflicting evidence or alternative gene associations for JBTS10. The concordance of genetic segregation, multiple loss-of-function alleles, and reproducible cellular rescue experiments robustly support a definitive gene–disease relationship.

In summary, OFD1 haploinsufficiency underlies X-linked recessive JBTS10 through disruption of primary cilium structure and glycosylation, with strong clinical validity. OFD1 genetic testing should be prioritized in males presenting with the molar tooth sign and cerebellar vermis hypoplasia to enable accurate diagnosis and genetic counseling.

References

• Cilia • 2017 • Abnormal glycosylation in Joubert syndrome type 10. PMID:28344780
• American Journal of Human Genetics • 2009 • OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin. PMID:19800048
• BioMed Research International • 2018 • Diagnosis of Joubert Syndrome 10 in a Fetus with Suspected Dandy-Walker Variant by WES: A Novel Splicing Mutation in OFD1. PMID:30581852
• Clinical Dysmorphology • 2017 • Novel OFD1 frameshift mutation in a Chinese boy with Joubert syndrome: a case report and literature review. PMID:28505061
• Molecular Genetics and Genomics • 2021 • A rare mutant of OFD1 gene responsible for Joubert syndrome with significant phenotype variation. PMID:32944789
• Frontiers in Genetics • 2022 • A novel non-sense variant in the OFD1 gene caused Joubert syndrome. PMID:36704348
• Pharmacogenomics and Personalized Medicine • 2025 • A Novel Pathogenic Splicing Mutation of OFD1 is Responsible for a Boy with Joubert Syndrome Exhibiting Orofaciodigital Spectrum Anomalies, Polydactyly and Retinitis Pigmentosa. PMID:39925483

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