Why use it

Stratifies recurrence risk precisely based on parental H1/H2 genotype rather than using a blunt population average. The mathematical model from Koolen et al. demonstrates that although differences between genotype combinations are small in absolute terms, the principle of personalized risk is important.

About

Koolen-de Vries Syndrome (KdVS) is mostly caused by a ~500-600kb microdeletion at 17q21.31 encompassing the KANSL1 gene. This deletion occurs almost exclusively on the H2 inversion haplotype background via Non-Allelic Homologous Recombination (NAHR). The H2 haplotype is a ~900kb inversion polymorphism common in Europeans (~20% allele frequency). This tool implements the exact Koolen et al. (2012) Bayesian model to calculate offspring risk based on parental genotypes, using Hardy-Weinberg proportions and weighted risk calculations.

When to use

Counseling couples where one or both parents have known H1/H2 inversion status.
After the birth of a child with KdVS, estimating recurrence risk.
Estimating population-specific risks for 17q21.31 deletions in different ethnic backgrounds.

Formula

f(NN)=p²=0.64, f(NV)=2pq=0.32, f(VV)=q²=0.04 Relative risk r: NN×NN=0, NN×NV=a, NN×VV=2a, NV×NV=2a, NV×VV=3a, VV×VV=4a Solving: Σ(f×r) = 1/16000 → a ≈ 1/12,093 Recurrence per couple = r value for their genotype combination

Pearls & pitfalls

The H2 haplotype frequency is ~20% in Europeans, but rare (<5%) in Africans and East Asians. Adjust the population frequency accordingly.
Population frequency of KdVS deletion is approximately 1 in 16,000 live births.
Using Koolen et al. (2012) math: with p(H1)=0.8, q(H2)=0.2, the six couple combinations are NN×NN (41%), NN×NV (41%), NN×VV (5%), NV×NV (10%), NV×VV (2.5%), VV×VV (0.5%).
The calculated "a" (risk per H2 allele from one heterozygous parent) works out to approximately 1/12,093, and 2a for homozygous = 1/6,047.
Without the H2 allele (H1/H1 × H1/H1), the risk of the classical NAHR-mediated deletion is virtually zero.
About 5% of KdVS is due to KANSL1 intragenic mutations, not captured by this deletion model.

Next steps

Discuss the relatively low absolute risk. Consider that ~5% of KdVS cases are caused by point mutations in KANSL1 rather than deletion (not covered by this calculator).

Evidence

Koolen DA et al. Nat Genet. 2006;38(9):999-1001. Koolen DA et al. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J Med Genet. 2008;45:710-720. Koolen DA et al. The Koolen-de Vries syndrome. In: GeneReviews, 2012.

References

Koolen DA et al. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet. 2012;44:639-641.
Koolen DA et al. A new chromosome 17q21.31 microdeletion syndrome. Nat Genet. 2006;38(9):999-1001.
Gardner RJM, Sutherland GR, Shaffer LG. Chromosome Abnormalities and Genetic Counseling. Chapter 4, pp. 120-122.

17q21.31 Microdeletion Risk (Koolen-de Vries)

Calculator