Variant Classification Challenges in Hereditary Hemochromatosis Diagnostics
As NGS expands beyond HFE p.Cys282Tyr testing to broader gene panels for iron overload disorders, laboratories increasingly encounter variants of unknown significance in iron-regulatory genes. This review evaluates in silico prediction tools, in vitro models including iPSCs and organoids, and in vivo zebrafish and mouse models for functional variant assessment. The authors highlight how CRISPR-based gene editing is transforming the ability to classify novel variants, which is essential for accurate diagnostics and genetic counselling.
The original study
Genetic Diagnosis in Hereditary Hemochromatosis: Discovering and Understanding the Biological Relevance of Variants.
- Authors
- Baas FS, Rishi G, Swinkels DW, Subramaniam VN
- Journal
- Clinical chemistry
- Type
- Journal Article, Research Support, Non-U.S. Gov't, Review
- PMID
- 34402502
Original abstract
BACKGROUND: Hereditary hemochromatosis (HH) is a genetic disease, leading to iron accumulation and possible organ damage. Patients are usually homozygous for p. Cys282Tyr in the homeostatic iron regulator gene but may have mutations in other genes involved in the regulation of iron. Next-generation sequencing is increasingly being utilized for the diagnosis of patients, leading to the discovery of novel genetic variants. The clinical significance of these variants is often unknown. CONTENT: Determining the pathogenicity of such variants of unknown significance is important for diagnostics and genetic counseling. Predictions can be made using in silico computational tools and population data, but additional evidence is required for a conclusive pathogenicity classification. Genetic disease models, such as in vitro models using cellular overexpression, induced pluripotent stem cells or organoids, and in vivo models using mice or zebrafish all have their own challenges and opportunities when used to model HH and other iron disorders. Recent developments in gene-editing technologies are transforming the field of genetic disease modeling. SUMMARY: In summary, this review addresses methods and developments regarding the discovery and classification of genetic variants, from in silico tools to in vitro and in vivo models, and presents them in the context of HH. It also explores recent gene-editing developments and how they can be applied to the discussed models of genetic disease.