ZNF41 – Intellectual Disability

This summary evaluates the association between ZNF41 (HGNC:13107) and intellectual disability (MONDO_0001071). The evidence comprises both genetic and functional studies. Notably, individuals with intellectual disability, characterized by cognitive deficits (HP:0001249), have been found to harbor mutations in ZNF41. Such findings have been examined in detailed functional studies and family-based segregation analyses, supporting a moderate level of clinical validity (PMID:14628291).

Genetic evidence indicates an X-linked mode of inheritance. In the functional study, three unrelated probands were identified with ZNF41 mutations, including the complete coding variant c.332C>T (p.Pro111Leu) that was found in affected individuals (PMID:14628291). Additionally, segregation analysis within at least one family demonstrated that the mutation co-segregates with intellectual disability, where additional affected relatives were observed.

The study details a heterogeneous variant spectrum that includes missense mutations. Of note, the variant c.332C>T (p.Pro111Leu) was captured as a representative genetic alteration. Although the genetic evidence supports pathogenicity, large-scale exome sequencing studies have prompted a re-evaluation of several X-linked genes, and some data have raised caution regarding the specificity of reported mutations (PMID:23871722).

Functional evidence strongly supports a mechanism of haploinsufficiency. In the examined case, ZNF41 transcript expression was absent in patient cells, and further in vitro studies demonstrated that disruption of the conserved transcriptional repressor domain is consistent with the pathogenesis of intellectual disability (PMID:14628291).

While conflicting data exist due to challenges raised by large-scale sequencing studies, the combined genetic and functional findings provide a coherent narrative that supports a moderate association of ZNF41 with intellectual disability. The genetic findings, including the observed variant with segregation evidence, along with supportive functional studies, underscore the relevance of ZNF41 in diagnostic settings.

Key take‑home: The integration of genetic and experimental data indicates that ZNF41 plays a role in intellectual disability, offering a moderate level of clinical evidence that can inform diagnostic decision‑making and genetic counseling.

References

• American journal of human genetics • 2003 • Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X‑linked mental retardation PMID:14628291
• American journal of human genetics • 2013 • XLID‑causing mutations and associated genes challenged in light of data from large‑scale human exome sequencing PMID:23871722

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