The majority of individuals with SIHIWES have de novo missense variants in ATPase and C terminal helicase domains or in between (78%). We know of 6 cases with missense variants in other conserved domains including the N terminal CHDNT domain, the second PHD zinc finger, the second chromodomain and in a conserved region in the C terminal part (DUF1087). Overall, the participants with variants in domains outside of the SNF2 like region had a phenotype similar to other participants and had similar dysmorphologies. To date we know of 3 cases with de novo loss of function variants (10%). For these individuals the phenotype was not highly specific for SIHIWES. At this time the mechanism in SIHIWES is thought to be dominant negative and loss of function variants are of uncertain significance.
CHD4