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Increased recurrence risk in congenital disorders of glycosylation type Ia (CDG-Ia) due to a transmission ratio distortion
  1. E Schollen1,
  2. S Kjaergaard2,
  3. T Martinsson3,
  4. S Vuillaumier-Barrot4,
  5. M Dunoe2,
  6. L Keldermans1,
  7. N Seta4,
  8. G Matthijs1
  1. 1Center for Human Genetics, University of Leuven, Leuven, Belgium
  2. 2Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark
  3. 3Department of Clinical Genetics, Göteborg University, Sahlgrenska University Hospital East, SE-41685 Göteborg, Sweden
  4. 4Hôpital Bichat Claude Bernard AP-HP, Paris Cedex 18, France
  1. Correspondence to:
 Gert Matthijs
 Center for Human Genetics, University of Leuven, Leuven, Belgium;

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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 …

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  • This research was supported by grants from the Fund for Scientific Research (FWO, Flanders; grant 9.0243.98), from the Interuniversity Poles of Attraction Federal Program (grant P5/25), from the French Research Network on CDG GIS-Institut des Maladies Rares (GIS-MR0308), and from the European Commission (Fifth Framework Programme, contract QLG1-2000-00047 to EUROGLYCAN;

  • Conflict of interest: none declared.