Rare missense variants in CIC are associated with human NTD risks
WGS was performed on DNA samples from 140 spina bifida cases. Eight rare missense variants (allele frequency < 0.001 in gnomAD) in CIC gene were identified in 140 individuals (Table 1). Seven of the eight missense variants were predicted to be damaging using Polyphen or SIFT software, indicating they are likely pathogenic mutations. Lollipop plots showed that none of the eight missense mutations locates in the HMG box region (Fig. 1A). All eight variants were evolutionarily conserved across multiple mammalian species (Fig. 1B). Among these missense variants, p. E1452D and p. M671V were absent in the gnomAD database, indicating that they are novel variants. Notably p. M671V is also predicted-to-be-damaging by both prediction software and locates in a highly conserved region. All eight variants were heterozygous in the seven different infants with isolated spina bifida (myelomeningocele). Three CIC variants carriers were collected from California before folic acid fortification. One case carried biallelic CIC variants (p.R666H and p.R1205Q).