Molecular characteristics

Seven individuals were reported by Schoch et al. (2017) with an identical, recurrent, de novo heterozygous variant c.892C>T (p.Arg298Trp). The authors are aware of five additional individuals with this recurring variant since the time of publication. One of the original seven individuals is mosaic for this variant and has a milder phenotype. All individuals were identified through whole exome sequencing.

The c.892C>T (p.Arg298Trp) variant is not observed in the ExAC or gnomAD databases, although a missense change from arginine to leucine of the same amino acid has been observed in one individual in the ExAC database and in four individuals in gnomAD. This suggests that the p.Arg298Trp change exerts a specific functional effect on the protein and may lead to the distinct disease phenotype.

NACC1 encodes the protein NAC1 which forms a homodimer or heterodimers with other binding partners through the BTB/POZ domain and functions as a transcriptional repressor. A dominant-negative function or gain-of-function mechanism is possible, but further studies are needed to elucidate the mechanism.