CHAMP1

Inheritance Pattern: AD

Disease ID:MONDO:0014699

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*CHAMP1* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2015 (Deciphering Developmental Disorders Study, PMID: 25533962). *De novo* nonsense and frameshift variants in *CHAMP1* have consistently been shown to result in a distinct phenotype characterized by developmental delay / intellectual disability (ID), hypotonia, impaired language, and dysmorphic features. In contrast, the clinical profile of patients with large deletions encompassing *CHAMP1* is milder, characterized by borderline intellectual disability or very mild neurodevelopmental issues, and nonspecific and mild facial dysmorphisms. Thus, it is unlikely that heterozygous loss-of-function (LOF) is the mechanism behind the complex neurodevelopmental disorders reported in relation to *de novo* nonsense/frameshift variants in *CHAMP1*. Given that the gene is only a single exon, it is likely that truncating variants result in NMD escape. Two reported cases with *de novo* missense variants in *CHAMP1* displayed more severe neurodevelopmental impairment, coupled with refractory infantile myoclonic epilepsy. However, due to the limited number of patients with missense variants and the absence of functional evidence, these variants were not included in this curation. Fifteen *de novo* variants (nonsense and frameshift) that have been reported in eighteen probands in four publications (PMIDs: 25533962, 26340335, 26751395, 27148580) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. A mechanism of gain-of-function or dominant negative has been proposed. The gene-disease relationship is also supported by *in vitro* functional assays (PMIDs: 26751395, 36044844). Two studies have demonstrated the interaction between CHAMP1 and POGZ; *POGZ* has been definitively related to similar neurodevelopmental disorders sharing a comparable phenotype. In addition, CHAMP1 mutants all lack the C-terminal region that is required for interaction with POGZ, suggesting that the inability to form complexes with POGZ may affect CHAMP1 function. Furthermore, heterozygous, *de novo POGZ* variants found in patients with ID lead to truncations of the POGZ C-terminal region, which is also required for interaction with CHAMP1. Altogether, the C-terminals of POGZ and CHAMP1 are reportedly important functional domains, the loss of which is believed to eliminate interactions between the two proteins leading to ID. In summary, there is definitive evidence supporting the relationship between *CHAMP1* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on the meeting date January 11th, 2024 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0014699

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0014699

Submitter: Ambry Genetics