In addition, among these eight genes involved in the double damaging heterozygous mutations combinations (Table 1), damaging variants of the CELSR1 [7, 8], VANGL1 [10], LPR6 [13] and Dvl3 [5] are known to be associated with NTDs, indicating that compound heterozygote damaging variants, LRP6 p.Arg386Cys and CELSR1 p.Arg714His (case NTD_15), CELSR1 p.Thr1086Met and VANGL1 p.Arg207His (case NTD_19) may increase human NTD risk. Here, VANGL1 is linked to neural tube defect.