Akademik Veri Yönetim Sistemi
GENOMICS OF RARE DISEASE 2025, Cambridge, İngiltere, 9 - 11 Nisan 2025, (Yayınlanmadı)
Background: Chromosomal inversions are a type of
structural variation (SV) characterized by DNA segments in reverse orientation compared
to a reference genome. Inversion detection is challenging due to their balanced
nature and the tendency for breakpoints to map to repetitive regions. These
detection challenges complicate establishing genotype-phenotype correlations for
inversions in the pathogenesis of genetic diseases. Advancements in sequencing
technologies and the availability of publicly accessible SV datasets have
significantly improved our ability to study the populational and molecular
features of inversions, although the cross-comparison of inversions in these datasets
remains unexplored. Method: Here, we report a proband with a clinical diagnosis
of hemophagocytic lymphohistiocytosis (HLH) by HLH-2004 criteria (PMID:
16937360). Initial clinical genome sequencing identified a pathogenic splicing
variant (c.1389+1G>A) and an inversion NC_000017.11:75576992_75829587inv
disrupting UNC13D. We further performed optical genome mapping and Oxford nanopore (ONT)
sequencing. Since a similar inversion is present in 0.006345% of individuals in
gnomAD (v4.0), we comprehensively compared inversions in multiple datasets, including
gnomAD (v4.0), DGV (release date: 2020-02-25), 1KGP (release date: 2021-10-05),
inversions released by Ebert et al. (PMID: 33632895) and Porubsky et
al. (PMID: 35525246) to investigate their molecular features,
frequency and potential impact on protein-coding genes in the human genome. Results:
OGM and ONT confirmed the variants in UNC13D, and phasing indicated the
pathogenic SNV, and inversion are in trans consistent with the recessive
inheritance model of familial HLH type-3 (OMIM #608898). We then investigated
the genetic features of inversions in the datasets disrupting the
protein-coding genes by classifying them into three categories: gene-spanning,
gene-disrupting, and intragenic. Remarkably, 98.9% of gnomAD inversions are
rare (MAF <5%), and disrupt 5% of
protein-coding genes associated with a phenotype in OMIM. Moreover, 106
autosomal recessive (AR) disease genes are potentially disrupted by inversions
only presented in a heterozygous state. Next, comparative analysis of all datasets
revealed common and dataset-specific inversion characteristics that suggest
methodology detection biases. The majority of
inversions in all datasets, except 1KGP, that overlap with protein-coding genes
are in the gene-spanning category. We also found that most of the protein-coding
genes in OMIM disrupted by inversions are associated with AR phenotypes,
supporting the hypothesis that inversions in trans with other variants
are hidden causes of genetic diseases. Conclusion: This study aims to
address the knowledge gap regarding the molecular characteristics of inversions
with low frequency in the population and emphasize the importance of
identifying them in rare disease research.