ARMC9 – Joubert syndrome

This summary outlines the association between ARMC9 and Joubert syndrome based on multiple independent lines of evidence. Several studies have identified biallelic variants in ARMC9 in individuals presenting with the classical features of Joubert syndrome, such as the molar tooth sign on MRI, hypotonia, ataxia, and ptosis (PMID:28625504). These findings are supported by robust genetic data from both case reports and multi‐patient studies, reinforcing the gene–disease link.

Genetic analyses reveal that ARMC9 variants, including loss‑of‑function and splicing mutations, segregate in an autosomal recessive manner in affected families. For instance, a report identified a synonymous variant, c.879G>A (p.Thr293Thr), causing splicing defects in the conserved ARM domain, while other independent studies have uncovered additional variants that disrupt protein function (PMID:29159890; PMID:35186037). This accumulation of data across diverse cohorts strengthens the confidence in the observed genetic association.

Segregation analysis from these studies has tracked additional affected relatives with similar phenotypic manifestations, further substantiating familial co‐segregation of ARMC9 mutations. In several families, compound heterozygous or homozygous variants were identified, thereby supporting a definitive recessive mode of inheritance. Such evidence contributes significantly to diagnostic decision‑making in clinical settings.

Beyond the genetic data, experimental studies have provided critical functional validation that ARMC9 plays a key role in ciliogenesis. Cellular and zebrafish models have demonstrated that disruption of ARMC9 leads to impaired ciliary stability and morphology, which mimic the hallmarks of Joubert syndrome (PMID:32453716; PMID:38949024). These functional assays not only corroborate the genetic findings but also offer insights into the underlying mechanism of pathogenicity.

Despite the wealth of supportive evidence, some variability in clinical presentation has been observed, likely due to genetic heterogeneity. However, the consistency of ciliary defects in experimental systems and the reproducibility of segregation findings across independent studies underscore the robustness of the ARMC9–Joubert syndrome association.

Key take‑home sentence: The convergence of genetic segregation, consistent variant findings including c.879G>A (p.Thr293Thr), and reproducible functional data firmly supports the clinical utility of ARMC9 testing in Joubert syndrome, offering a reliable basis for diagnosis and targeted management.

References

• American journal of human genetics • 2017 • Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish PMID:28625504
• American journal of medical genetics. Part A • 2018 • Whole exome sequencing reveals a mutation in ARMC9 as a cause of mental retardation, ptosis, and polydactyly PMID:29159890
• Frontiers in genetics • 2022 • Whole Exome Sequencing Identified Novel ARMC9 Variations in Two Cases With Joubert Syndrome PMID:35186037
• The Journal of clinical investigation • 2020 • Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome PMID:32453716
• The Journal of clinical investigation • 2024 • Primary cilia formation requires the Leigh syndrome-associated mitochondrial protein NDUFAF2 PMID:38949024

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