CHAMP1 – Intellectual Disability

CHAMP1 has been repeatedly implicated in intellectual disability through multiple independent studies reporting de novo loss‑of‑function mutations. The collective clinical evidence includes several case reports and multi‐patient series demonstrating a consistent phenotype comprising intellectual disability, developmental delay, and dysmorphic features. These studies uniformly identify de novo truncating, frameshift, and nonsense variants that disrupt CHAMP1 function, reinforcing its critical role in neurodevelopment (PMID:28944241).

Clinical case reports have documented more than 40 unrelated probands carrying de novo mutations in CHAMP1, often identified by trio whole‑exome sequencing. In these cases, the identified variants, including the recurrent c.1192C>T (p.Arg398Ter), segregate with the disease in sporadic presentations and are supported by comprehensive phenotypic analyses. The observed genetic spectrum encompasses diverse loss‑of‑function events, with similar clinical manifestations across independent cohorts (PMID:26751395).

Genetic evidence is further consolidated by detailed mutation analyses where the de novo variant c.1192C>T (p.Arg398Ter) is repeatedly reported across studies. This variant fulfills established HGVS criteria with a complete coding alteration that reliably predicts haploinsufficiency. The recurrence of this specific variant in multiple unrelated individuals provides robust support for its pathogenicity and a strong genetic association between CHAMP1 and intellectual disability (PMID:37628598).

Functional studies have complemented clinical findings by demonstrating that CHAMP1 deficiency disrupts kinetochore–microtubule attachment, leading to defects in chromosome segregation and cytokinesis. In vitro and in vivo assays, including knock‐down and knockout models, reveal that the resultant cellular dysfunction correlates with the neurodevelopmental phenotype observed in patients. These experimental data solidify the proposed mechanism of haploinsufficiency as a key driver of the disorder (PMID:26340335).

No significant conflicting evidence has emerged to dispute the association between CHAMP1 mutations and intellectual disability. Although additional neurodevelopmental phenotypes such as autism spectrum disorder have been reported in some cases, the recurring theme of intellectual disability remains the dominant clinical presentation, supporting a unified disease mechanism.

In summary, the integration of comprehensive genetic analyses, robust functional studies, and consistent clinical observations establishes a strong association between CHAMP1 and intellectual disability. This evidence is critical for diagnostic decision‑making and informs future clinical management as well as commercial testing strategies.

References

• Molecular genetics & genomic medicine • 2017 • Disturbed chromosome segregation and multipolar spindle formation in a patient with CHAMP1 mutation PMID:28944241
• Human mutation • 2016 • De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability PMID:26751395
• American journal of human genetics • 2015 • De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment PMID:26340335

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