ZDHHC9 – X-linked intellectual disability with marfanoid habitus

Lujan-Fryns syndrome (X-linked intellectual disability with marfanoid habitus) is characterized by intellectual disability, marfanoid habitus with disproportionate tall stature, minor facial anomalies and hypernasal speech. Although ZDHHC9 has been included in broad definitions of LFS, targeted sequencing of 28 males with a tentative clinical diagnosis of LFS failed to identify causative ZDHHC9 variants (PMID:26358559). Functional studies in Zdhhc9-null mice reproduce mild-to-moderate intellectual disability, hypotonia and reduced corpus callosum volume but do not recapitulate marfanoid habitus or hypernasal speech (PMID:29944857). Additionally, pathogenic ZDHHC9 variants (e.g., c.777+1G>A) underlie X-linked intellectual disability without marfanoid features, consistent with a loss-of-function mechanism but lacking LFS-specific phenotypes (PMID:36416207). In the absence of segregation data, recurrent alleles or functional concordance with marfanoid habitus, evidence supporting ZDHHC9 as a primary cause of MONDO_0010655 remains limited.

Key Take-home: ZDHHC9 should not be included in diagnostic panels for Lujan-Fryns syndrome owing to lack of causative variants and phenotype specificity.

References

• American journal of medical genetics. Part A • 2016 • Tentative clinical diagnosis of Lujan-Fryns syndrome--A conglomeration of different genetic entities? PMID:26358559
• 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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