CHAMP1-related disorders: pathomechanisms triggered by different genomic alterations define distinct nosological categories.

Scientists studied different changes to the CHAMP1 gene and found they cause different conditions. Some changes cause severe intellectual disability, autism, and distinctive facial features. Other changes cause milder learning difficulties. A rare type of change can cause severe seizures. This helps doctors better understand and diagnose these genetic conditions.

This review study examined different genetic changes in the CHAMP1 gene and their associated clinical presentations. Researchers analyzed 40 patients with loss-of-function variants, 7 patients with chromosome deletions, and 1 patient with a missense variant. The study found that different types of genetic alterations in CHAMP1 cause distinct clinical phenotypes through different pathological mechanisms. Loss-of-function variants cause severe intellectual disability, autism spectrum disorders, and distinctive facial features through a dominant negative effect.

Chromosome deletions result in milder borderline intellectual disability. Missense variants appear to cause severe epileptic encephalopathy through a gain-of-function mechanism.

Findings suggest CHAMP1-related disorders should be categorized by genetic mechanism rather than treated as a single condition. This may inform prognosis, treatment approaches, and genetic counseling. Different variants may require distinct clinical management strategies.

Study is based on case series and literature review rather than controlled trials. Small sample sizes, particularly for missense variants (n=1). Pathomechanisms are inferred rather than definitively proven.

Loss-of-function variants in CHAMP1 were recently described as cause of a neurodevelopmental disorder characterized by intellectual disability (ID), autism, and distinctive facial characteristics. By exome sequencing (ES), we identified a truncating variant in CHAMP1, c.1858A > T (p.Lys620*), in a patient who exhibited a similar phenotype of severe ID and dysmorphisms. Whether haploinsufficiency or a dominant negative effect is the underlying pathomechanism in these cases is a question that still needs to be addressed. By array-CGH, we detected a 194 kb deletion in 13q34 encompassing CHAMP1, CDC16 and UPF3, in another patient who presented with borderline neurodevelopmental impairment and with no dysmorphisms.

In a further patient suffering from early onset refractory seizures, we detected by ES a missense variant in CHAMP1, c.67 G > A (p.Gly23Ser). Genomic abnormalities were all de novo in our patients. We reviewed the clinical and the genetic data of patients reported in the literature with: loss-of-function variants in CHAMP1 (total 40); chromosome 13q34 deletions ranging from 1.1 to 4 Mb (total 7) and of the unique patient with a missense variant. We could infer that loss-of-function variants in CHAMP1 cause a homogeneous phenotype with severe ID, autism spectrum disorders (ASD) and highly distinctive facial characteristics through a dominant negative effect.

CHAMP1 haploinsufficiency results in borderline ID with negligible consequences on the quality of life. Missense variants give rise to a severe epileptic encephalopathy through gain-of-function mechanism, most likely. We tentatively define for the first time distinct categories among the CHAMP1-related disorder on the basis of pathomechanisms.