Skewed sex ratios in familial holoprosencephaly and in people with isolated single maxillary central incisor

Autosomal dominant holoprosencephaly is a rare but well documented entity a nd it can be the result of mutations in the Sonic Hedgehog gene (SHH). The transmitting parent may be normal or have a single maxillary central inciso r. We describe a skewed sex ratio among the transmitting parents with SHH muta tions, with more mothers than fathers having the mutation (p=0.002). The me chanism underlying this skewed sex ratio is not clear; the SHH mutations do not involve triplet repeats, imprinting is plausible but untested, and the re is no evidence that the risk of holoprosencephaly is greater among males carrying such a mutation (p=0.15). We considered the possibility that male s with such a mutation are at greater risk of other malformations outside t he central nervous system, which could reduce their reproductive fitness. To avoid ascertainment bias in identifying children with various malformati ons in kindreds with familial holoprosencephaly, we reviewed the reports of people with single maxillary central incisor and no other congenital malfo rmations. Of the 16 cases identified, 13 were female (p=0.0085). We suggest that boys with mutations associated with autosomal dominant holo prosencephaly may be at greater risk of major malformations outside the cen tral nervous system than girls.