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).