Molecular characteristics

CHD5 is intolerant to both missense substitutions (Z-score 5.32) and Loss-of-Function variants (pLi=1). In line with these predictions, all types of variants have been identified in association with CHD5, including missense substitutions, out-of-frame deletions/duplications, nonsense variants and splicing variants. Variants can be present in a germline or somatic state. Mosaicism does not necessarily lead to milder phenotypes.
Missense substitutions affect highly conserved amino acids and tend to cluster in functional domains. The truncating variants are predicted to result in transcripts that are subject to nonsense-mediated mRNA decay or to generate a truncated protein.
The precise mechanisms by which CHD5 mutations lead to disease is yet to be elucidated.

Identification of CHD5 mutations can be achieved by different methods: targeted analysis of the CHD5 gene by Sanger sequencing or next-generation sequencing; gene panel sequencing including CHD5, exome or genome sequencing. Intragenic deletions have to be searched for by appropriate methods like microarrays, multiplex ligation-dependent probe amplification (MLPA) analysis or any method allowing to assess the copy number of each exon.
Interpretation of a novel CHD5 variant should be performed according to the ACMG criteria, taking into account the inheritance of the mutation (de novo/inherited), the segregation of the mutation with the disorder in the family (for inherited variants ), the location of the mutation on the protein and conservation of the amino acid altered in orthologues and paralogues.