FHLdb

FHLdb catalogs genetic variants associated with familial hemophagocytic lymphohistiocytosis to consolidate variant-level evidence for clinical interpretation and research.

Key Features:

• Comprehensive Variant Collection: Curates variants from over 120 peer‑reviewed articles covering PRF1, UNC13D, STXBP2, and STX11 and enumerates variant types including missense (240), frameshift (69), nonsense (51), splicing (51), in‑frame indel (10), deep intronic (7), and large rearrangements (5).
• Variant Classification: Assigns each variant to ACMG categories: pathogenic, likely pathogenic, uncertain significance, likely benign, or benign.
• Functional and Clinical Data Integration: Records allelic status, carrier information, functional assay results, ClinVar and UniProt evidence, population frequencies from ExAC and gnomAD, and in silico pathogenicity predictions from PolyPhen-2 and SIFT.
• Visual Representation: Provides diagrams mapping each variant to gene exons and protein domain structures.

Scientific Applications:

• Variant interpretation: Supports interpretation of molecular results in FHL patients by consolidating curated genetic and functional evidence.
• Clinical decision support: Supplies categorized variant evidence to inform diagnosis and management of familial hemophagocytic lymphohistiocytosis.
• Genetic heterogeneity research: Enables study of mutation spectra across PRF1, UNC13D, STXBP2, and STX11.
• Therapeutic development and personalization: Informs development of personalized treatment strategies by linking variants to functional and clinical data.
• Resource model for other disorders: Serves as an example of a disease‑specific mutation database for primary immunodeficiencies.

Methodology:

Variants curated from over 120 peer‑reviewed articles; annotations incorporate ClinVar, UniProt, ExAC, and gnomAD; pathogenicity predictions from PolyPhen-2 and SIFT were recorded; variants were classified according to ACMG guidelines and mapped to exons and protein domains for diagram generation.