The Smallest Reported Distal 11q25 Deletion in Jacobsen Syndrome (JBS): Two Patients with Variable Phenotype

Abstract

all non-coding RNA (ncRNA) genes and regulatory elements. NGS-based proximity mapping has revealed a nuclear organization of the genome, with about 2,000 to 3,000 topologically associating domains (TAD), which can be further organized into loops. To facilitate the functional characterization of TADs, TAD-boundaries and loops, we have initiated a systematic mapping of constitutional “balanced” chromosomal rearrangements (BCR) that must affect this nuclear organization. Our first unbiased re-examination of prenatally diagnosed de novo BCRs (pBCRdn) showed breakpoints affect genomic compartments according to their size, e.g., protein coding/noncoding genes; regulatory domains associated with long-range position effects (LRPE); unannotated gaps; and TAD and TADboundaries. We also showed that the unbiased morbidity risk of pBCRdn are 2to 3-fold higher than previously estimated (approximately 20%), due to later onset neurodevelopmental disorders. This morbidity can in some cases be linked to truncation of known disease genes and LRPE-regions, but we also highlight the existing gap in genotype-phenotype knowledge. To address this gap, we have established IBMC, presently involving >150 partners from >50 countries and 6 continents, with the aim to mate-pair map w10,000 chromosomal breakpoints. This will target an estimated w2,700 protein coding genes, w1,500 ncRNA genes, most of the LRPEregions that specify the vertebrate body plan, link phenotypes with disruption/rearrangement of nuclear domains, and identify human models for their functional characterization. The project will include participants from undeveloped, developing and developed countries, and hence facilitate global mobility and technology transfer.