Parental sex effect in spina bifida: A role for genomic imprinting?

Fifty families (491 individuals in 137 sibships) with more than one living case of isolated, nonsyndromic spina bifida (SB) were analyzed genetically. There were twice as many gene‐carrier females (56) as gene‐carrier males (28) (P < 0.005). This was not an artifact of ascertainment bias because the sex ratio of gene‐carriers was the same whether the pedigree was obtained through the proband's father or mother. Also, this effect was not observed in other disorders analyzed by the same method. Neither was the effect due to differential fertility because the number and sex of affected and unaffected children per gene‐carrier parent were not different for male or female gene‐carrier parents. There was no evidence that the missing male gene‐carriers were lost by selective spontaneous abortion. There was no deficit of male‐to‐male or male‐to‐female transmission, excluding simple X‐linked or simple mitochondrial inheritance. If genomic imprinting plays a role in the unequal female and male carrier frequencies in SB, penetrance should differ with parental sex. Penetrance was higher for off‐spring of female parents than of male parents, but the difference was not statistically significant. In addition, both male and female gene‐carriers were frequently found in the same pedigree. Thus, the present data suggest a possible role for imprinting in SB. © Wiley‐Liss, Inc.