SET

Molecular characteristics

Pathogenic mutations in the SET gene in affected patients mostly occur de novo. In one family autosomal dominant inheritance from an affected parent was observed. Mutations are assumed to cause loss-of-function (LoF) and typically concern frameshift variants leading to a premature termination codon, nonsense variants and splice site variants. These LoF variants affect all four isoforms of the SET transcript. LoF variants have been described in control individuals, but these variants only affect one of these isoforms. A recurrent de novo frameshift variant (c.167_170del in NM_001122821.1) has been observed. De novo missense variants affecting highly conserved amino acid residues in the Nucleosome Assembly Protein (NAP) domain have also been observed.

Haploinsufficiency is the plausible pathogenetic mechanism given the type of mutations observed and the gene’s constraint metrics.