Congenital disorders of glycosylation type Ia or CDG-Ia (MIM 212065) is the most common type of a group of recessive disorders characterised by deficient glycosylation.¹ The disease is caused by mutations in the PMM2 gene, coding for a phosphomannomutase (PMM). PMM converts mannose-6-phosphate to mannose-1-phosphate, a precursor of the mannosyl donor in N-and O-glycosylation and the synthesis of GPI anchors. PMM deficiency leads to underglycosylation and altered processing of the N-glycans in serum proteins of CDG-Ia patients.^2,3

A plethora of different mutations, mostly missense mutations, results in a clinical spectrum ranging from mild to very severe with neonatal death.^4,5 A founder effect for the mutation F119L (c.357C→A) in the Scandinavian population results in a more homogenous group of patients in these countries.⁶

Around 37% of CDG-Ia patients are heterozygous for the missense mutation R141H (c.422G→A), which has never been observed in the homozygous state.^7,8 The very low residual (<1%) activity of the mutant R141H protein is probably not sufficient for viability.⁹ In spite of this genetic lethality, the carrier frequency for R141H is rather high, being 1/72 in the Dutch and Danish populations.⁸

Without a mechanism counteracting the constant loss of recessive disease alleles, this R141H mutation would have vanished. The most obvious explanations for its persistence are a high mutation rate, genetic drift, a heterozygous advantage, or a transmission distortion.

The first possibility has been discounted by the observation that, in most patients and carriers, the mutation is associated with a specific haplotype, and thus represents a single, ancestral event.^6,8 Based on linkage disequilibrium with marker D16S3020 the most recent common ancestor was calculated to have lived at least 250 generations ago (R Colombo and E Schollen, unpublished data). Genetic drift could be an important factor in …