KIAA0586 – Joubert syndrome

KIAA0586 encodes TALPID3, a basal body protein essential for primary cilia formation and Hedgehog signaling. Biallelic truncating and splice variants in KIAA0586 disrupt ciliogenesis, leading to the characteristic cerebellar vermis hypoplasia and molar tooth sign of Joubert syndrome (PMID:26096313).

Autosomal recessive inheritance is supported by compound heterozygous or homozygous LoF variants in >40 probands from >20 unrelated families, with segregation in affected sibships and unaffected parents (PMID:26026149; PMID:26386247; PMID:36635699). A recurrent founder frameshift, c.392del (p.Arg131fs), exemplifies the truncating variant spectrum (PMID:26026149).

Functional genomic screens identified KIAA0586 as a JS gene, and Talpid3 knockout or conditional deletion in mice disrupts primary cilia, neurogenesis, and glial scaffolds, recapitulating aspects of JS neuropathology (PMID:26026149; PMID:35470378). In patient‐derived fibroblasts, biallelic deleterious alleles impair ciliogenesis and can be rescued by wild-type TALPID3 (PMID:26386247).

A hypomorphic allele, c.428delG, is common (gnomAD AF 0.0031) and found homozygous in healthy individuals, indicating it causes JS only in compound heterozygosity with a more severe variant (PMID:30120217). This variable expressivity underscores the need for comprehensive variant interpretation in diagnostic testing.

Collectively, the genetic and experimental data fulfill ClinGen criteria for a Strong gene–disease association. KIAA0586 sequencing and CNV/splice‐site analysis are clinically indicated in patients with JS features to guide diagnosis, prognosis, and reproductive counseling.

Key Take-home: Biallelic LoF mutations in KIAA0586 cause autosomal recessive Joubert syndrome; functional assays and animal models confirm pathogenicity, while hypomorphic variants like c.428delG require a second severe allele.

References

• eLife | 2015 | Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome. PMID:26026149
• Human Mutation | 2015 | KIAA0586 is Mutated in Joubert Syndrome. PMID:26096313
• eLife | 2015 | TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23). PMID:26386247
• Journal of Medical Genetics | 2019 | Homozygosity for the c.428delG variant in KIAA0586 in a healthy individual: implications for molecular testing in patients with Joubert syndrome. PMID:30120217
• Human Molecular Genetics | 2022 | Hippocampal neurogenesis is impaired in mice with a deletion in the coiled coil domain of Talpid3-implications for Joubert syndrome. PMID:35470378
• BMC Medical Genomics | 2023 | A novel 1.38-kb deletion combined with a single nucleotide variant in KIAA0586 as a cause of Joubert syndrome. PMID:36635699

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