B9D1 – Joubert Syndrome

Joubert syndrome is an autosomal recessive ciliopathy characterized by the molar tooth sign on brain MRI, hypotonia, developmental delay, and variable multiorgan involvement. Biallelic pathogenic variants in B9D1, a component of the ciliary B9 protein complex, have been reported in five unrelated JS probands (PMID:24886560; PMID:32622957). In a 2014 series, four patients with mild JS phenotypes harbored compound heterozygous or homozygous B9D1 mutations, confirming AR inheritance and segregation in nuclear families (PMID:24886560). A recent case report identified a novel missense B9D1 variant, c.341G>A (p.Arg114Gln), demonstrating aberrant splicing via mRNA analysis (PMID:32622957).

Functional studies in model organisms support a disease mechanism of defective ciliogenesis. Mice lacking B9d1 display polydactyly, kidney cysts, neural tube patterning defects, and impaired Hedgehog signaling (PMID:21763481). In Caenorhabditis elegans, B9 proteins including the B9D1 ortholog function redundantly with nephrocystins to regulate ciliary formation and maintenance (PMID:18337471). These data concordantly link B9D1 dysfunction to JS-relevant ciliary phenotypes.

No conflicting evidence has been reported to date. Additional studies may further define variant spectrum and long-term outcomes. Key Take-home: B9D1 should be included in diagnostic gene panels for Joubert syndrome to enable accurate AR carrier detection and early clinical management.

References

• European journal of medical genetics • 2020 • Two novel B9D1 variants causing Joubert syndrome: Utility of mRNA and splicing studies. PMID:32622957
• Orphanet journal of rare diseases • 2014 • Mutations in B9D1 and MKS1 cause mild Joubert syndrome: expanding the genetic overlap with the lethal ciliopathy Meckel syndrome. PMID:24886560
• American journal of human genetics • 2011 • Disruption of a ciliary B9 protein complex causes Meckel syndrome. PMID:21763481
• Molecular biology of the cell • 2008 • Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis elegans ciliogenesis. PMID:18337471
• European journal of human genetics • 2016 • Joubert syndrome: genotyping a Northern European patient cohort. PMID:25920555

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