Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation inCDG-Ia (congenital disorders of glycosylation type Ia)

The R141H mutation in the PMM2 gene is the most frequent mutation in type l a of the congenital disorders of glycosylation (formerly carbohydrate-defic ient glycoprotein syndromes)(CDC-la). However, it has never been observed i n the homozygous state. Homozygosity for this mutation is probably incompat ible with life. In this study, we determined the frequency of R141H in two normal populations: in neonates of Dutch origin 1/79 were carriers, whilst in the Danish population, a carrier frequency of 1/60 was found. These figu res are clearly in disequilibrium with the frequency of CDG-Ia that has bee n estimated at 1/80 000 to 1/40 000 in these populations. Haplotype analysi s of 43 patients with the R141H mutation of different geographic origins in dicated that the R141H is an old mutation in the Caucasian population. Base d on the new data, the disease frequency has been calculated at 1/20 000 in these populations. It is concluded that the disease is probably underdiagn osed.