Loss of function in causes DNA methylation signature similar to that in Wolf-Hirschhorn syndrome.

PURPOSE

Wolf-Hirschhorn syndrome (WHS), a contiguous gene syndrome caused by heterozygous deletions of the distal short arm of chromosome 4 that includes , reportedly causes specific DNA methylation signatures in peripheral blood cells. However, the genomic loci responsible for these signatures have not been elucidated. The present study aims to define the loci underlying WHS-related DNA methylation signatures and explore the role of in these signatures.

METHODS

We conducted genome-wide methylation analysis of individuals with WHS or variants using an array method. We studied genome-edited knockin mice and induced pluripotent stem cells to explore the function of variants.

RESULTS

Three undiagnosed cases with variants showed WHS-related DNA methylation signatures. In patient-derived induced pluripotent stem cells and genome-edited knockin mice, these variants cause loss of function, respectively. The p.Pro905Leu variant caused decreased Nsd2 protein levels and altered histone H3-lysine 36 dimethylation levels similarly to what was observed in knockout mice. knockout and p.Pro905Leu knockin mice exhibited common DNA methylation changes.

CONCLUSION

These results revealed that WHS-related DNA methylation signatures are dependent on dysfunction and could be useful in identifying variants of uncertain significance.