A draft human pangenome reference

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample

Clinical and molecular delineation of the 17q21.31 microdeletion syndrome.

The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high-resolution genome analyses in patients with unexplained mental retardation. Here we report the molecular and/or clinical characterization of 22 individuals with the 17q21.31 microdeletion syndrome. We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination, reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behavior are the most characteristic features. Other clinically important features include epilepsy, heart defects (ASD, VSD), and kidney/ urologic anomalies. Using high-resolution oligonucleotide arrays, we narrow the 17q21.31 critical region to a 424-kb genomic segment (chr17: 41046729-41470954, hg17), encompassing at least six genes, among which the gene encoding microtubule-associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease-associated variants. In five deletion carriers, we identify a <500-bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined, the parent originating the deletion carries a common 900-kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10-5). Our data establishes the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognizable genomic disorder