ZDHHC9 – X-linked Intellectual Disability

ZDHHC9 has been robustly associated with X-linked intellectual disability (MONDO:0100284) through multiple lines of genetic and functional evidence. Several independent studies have identified a spectrum of pathogenic variants in ZDHHC9 – including nonsense, missense, splice, and frameshift mutations – that segregate with the disorder in affected families. For example, a novel pathogenic mutation, c.892C>T (p.Arg298Ter), was reported to cosegregate with disease in a large family, supporting a clear genetic link (PMID:24357419).

Genetic investigations across different cohorts have uncovered over 11 rare variants in ZDHHC9 in unrelated probands. Studies have documented both familial and de novo occurrences – with recurrent mutations such as c.892C>T (p.Arg298Ter) and c.286C>T (p.Arg96Trp) observed in separate investigations – thereby reinforcing the gene’s role in the pathogenic mechanism of X-linked intellectual disability (PMID:28687527, PMID:25649377). In addition, segregation analyses have revealed that multiple affected relatives in individual families carry the pathogenic variants, further strengthening the gene‐disease relationship.

Functional studies have provided complementary evidence supporting a loss‑of‑function mechanism. Animal models, including murine systems with disrupted Zdhhc9, exhibit neuroanatomical alterations such as a reduction in corpus callosum volume and behavioral abnormalities that mirror the cognitive deficits seen in patients. These experimental findings underscore the biological plausibility of ZDHHC9’s involvement in cognitive development and its contribution to the disease phenotype (PMID:29944857, PMID:36416207).

Clinical reports not only describe intellectual disability but also document additional features including mild intellectual impairment, acrocyanosis, global developmental delay, and occasionally subtle dysmorphic features. These variable phenotypic presentations necessitate comprehensive clinical evaluation and support the utility of targeted genetic testing for patients with suspected X‑linked intellectual disability.

In summary, the convergence of multiple case reports, segregation analyses, and functional validation studies solidifies the association between pathogenic variants in ZDHHC9 and X‑linked intellectual disability. While additional genetic factors may contribute to phenotype variability, the current evidence offers strong support for the clinical validity and diagnostic utility of ZDHHC9 testing in affected patients.

Key Take‑home Sentence: Robust genetic and functional evidence establish that pathogenic variants in ZDHHC9 are strongly associated with X‑linked intellectual disability, underscoring the clinical importance of testing this gene in relevant cases.

References

• American journal of medical genetics. Part A • 2014 • Expanding the clinical phenotype of patients with a ZDHHC9 mutation PMID:24357419
• American journal of human genetics • 2007 • Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X‑linked mental retardation associated with a Marfanoid habitus PMID:17436253
• European journal of medical genetics • 2017 • The first patient with sporadic X‑linked intellectual disability with de novo ZDHHC9 mutation identified by targeted next‑generation sequencing PMID:28687527
• European journal of human genetics • 2015 • Next‑generation sequencing in X‑linked intellectual disability PMID:25649377
• Experimental neurology • 2018 • Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model PMID:29944857
• American journal of medical genetics. Part A • 2023 • ZDHHC9 X‑linked intellectual disability: Clinical and molecular characterization PMID:36416207

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