NCKAP1 – intellectual disability

NCKAP1 has emerged as a compelling gene associated with intellectual disability, with multiple independent studies underscoring its clinical relevance. Disruptive variants in NCKAP1, including truncating and missense changes, have been identified in individuals presenting with neurodevelopmental abnormalities, providing strong evidence for its role in disease. In a recent multi‐patient study, 21 affected individuals from 20 unrelated families were reported carrying predicted deleterious variants, thereby establishing an autosomal dominant inheritance pattern (PMID:33157009) and supporting its involvement in the disorder (PMID:28940097).

Genetic evidence is robust, with variants such as c.2111del (p.Pro704fs) serving as clear examples of disruptive alleles. These variants have been observed to segregate with disease in extended families and are supported by detailed case reports, reinforcing the pathogenic role of NCKAP1. The aggregation of diverse variant types – including truncating mutations and missense changes – favors a loss-of-function mechanism that disrupts normal neuronal development. Segregation data from families further substantiate these findings, with multiple affected relatives harboring the same deleterious variant.

Functional studies complement the genetic data by demonstrating that loss of NCKAP1 function impacts neuronal cytoskeletal dynamics and alters neuronal migration during cortical development. In vivo assays, particularly mouse in utero electroporation experiments, have provided mechanistic insight into how reduced NCKAP1 activity leads to aberrant neuronal positioning, which is consistent with the neurodevelopmental phenotypes observed. These experimental results lend moderate support to the association by linking the molecular mechanism directly to the pathology of intellectual disability.

Evaluated collectively, the genetic and functional evidence categorizes the NCKAP1–intellectual disability association as strong. The evidence includes a significant burden of deleterious variants across multiple unrelated families along with segregation in a large pedigree, and the functional experiments robustly demonstrate the downstream impact on neuronal migration. The replication of findings across different studies, along with convergent mechanistic data, provides a reliable basis for diagnostic decision‑making.

Additional reports have also demonstrated that even though some variants may be associated with autism spectrum disorder, a significant proportion of affected individuals present predominantly with intellectual disability. This highlights the gene’s pleiotropic effects, necessitating careful phenotypic stratification in clinical practice and supporting its clinical utility in the diagnostic workflow.

Key take‑home sentence: The strong association between disruptive NCKAP1 variants and intellectual disability, reinforced by comprehensive segregation and functional evidence, establishes its utility as a critical biomarker for neurodevelopmental disorders.

References

• American journal of human genetics • 2020 • NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism PMID:33157009
• Human genetics • 2017 • Expanding the genetic heterogeneity of intellectual disability PMID:28940097

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