KIAA0586 – Joubert syndrome 23

Joubert syndrome 23 (JBTS23) is an autosomal recessive ciliopathy characterized by the molar tooth sign, global developmental delay, hypotonia, ataxia and, in some cases, epilepsy with risk of SUDEP. Biallelic pathogenic variants in KIAA0586 disrupt primary cilia assembly and Hedgehog signaling, underpinning the neurodevelopmental phenotype (MONDO:0014664).

Multiple unrelated families (n = 3) and a total of four affected individuals have been reported with compound heterozygous or homozygous deleterious KIAA0586 variants under an autosomal recessive model. One male with SUDEP carried the common frameshift allele rs534542684 (c.392del (p.Arg131fs)) in trans with an 8.3 kb deletion (PMID:32381069). A 9-month-old girl harbored c.3303G>A combined with a 1.38-kb intragenic deletion (PMID:36635699). Two siblings were compound heterozygotes for c.428delG (p.Ser143AlafsTer) and c.1413-1G>C (PMID:30120217).

The variant spectrum in JBTS23 includes: 2 small frameshift alleles (c.392del (p.Arg131fs), c.428delG (p.Ser143AlafsTer)), 2 splice-site variants (c.1413-1G>C, c.3940+1G>A), 1 coding SNV (c.3303G>A), and 2 structural deletions (8.3 kb, 1.38 kb). The c.428delG frameshift is frequent (gnomAD AF 0.003117) but only pathogenic when in compound heterozygosity with a more severe allele.

Functional evidence supports a loss-of-function mechanism. RNA studies show transcripts with c.428delG escape nonsense-mediated decay in healthy homozygotes, explaining incomplete penetrance of this allele. A conditional Talpid3 (KIAA0586) knockout mouse displays disrupted hippocampal neurogenesis, reduced dentate gyrus proliferation, absence of primary cilia, cytoskeletal disorganization and defective migration, recapitulating key features of JBTS (PMID:35470378).

Conflicting data include the observation that homozygous c.428delG carriers can be asymptomatic, indicating that this frameshift allele alone is insufficient for disease. This finding refines pathogenicity assignments and underscores the need for a second, more severe variant in JBTS23.

Overall, the clinical validity of KIAA0586 in JBTS23 is moderate based on four probands across three families, segregation in affected siblings, and concordant experimental models. Genetic and functional data integrate to confirm an autosomal recessive haploinsufficiency mechanism. Key Take-home: KIAA0586 sequencing and deletion analysis are essential for diagnosing JBTS23 and informing genetic counseling due to variable penetrance of common alleles.

References

• BMC medical genetics • 2020 • Sudden death in epilepsy and ectopic neurohypophysis in Joubert syndrome 23 diagnosed using SNVs/indels and structural variants pipelines on WGS data: a case report. PMID:32381069
• 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 • Hippocampals 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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