HMGB1

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0700354

Submitter: ClinGen

*HMGB1* (High Mobility Group Box 1) is located at chromosome 13 at 13q12.3 and encodes a high mobility group box protein that functions as a DNA chaperone and prototypical damage-associated molecular pattern (DAMP). *HMGB1* was first reported in relation to autosomal dominant *HMGB1*-related brachyphalangy, polydactyly and tibial aplasia syndrome in 2023 (Mensah et al., PMID: 36755093). The disorder is characterized by a distinct skeletal phenotype which includes brachydactyly, brachyphalangy of fingers, tibia aplasia or hypoplasia, polydactyly, and contractures of large joints. Additionally, most affected individuals present with developmental delay, hearing impairment and genitourinary abnormalities, and more variably, microcephaly, malformed ears, and blepharophimosis. *HMGB1* has also been associated with autosomal dominant *HMGB1*-related neurodevelopmental disorder. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanism and phenotypic variability. Therefore, the following disease entities have been split into two disease entities, autosomal dominant *HMGB1*-related brachyphalangy, polydactyly and tibial aplasia syndrome (MONDO: 0700354), and *HMGB1*-related neurodevelopmental disorder (PMID: 34164801). The split curation for autosomal dominant *HMGB1*-related neurodevelopmental disorder will be curated separately. Two frameshift variants, both located in intrinsically disordered acidic C-terminal tail region of *HMGB1* that have been reported in at least six probands from two publications and a ClinVar entry (PMIDs: 36755093, 20661588; ClinVar ID 1810206) are included in this curation. Both frameshift variants lead to protein extension and the addition of arginine residues which cause the acidic C-terminal to become basic. In vitro studies using recombinant protein and overexpression in continuous cell lines demonstrate mutant protein is associated with altered nuclear localization and a suspected gain of function mechanism of pathogenicity (PMID: 36755093). This gene-disease relationship is supported by experimental data, namely expression. Expression data showing differential spatial and temporal expression of Hgmb1 protein in the developing mouse limb (PMID: 17548469). A *Hmgb1* homozygous targeted knock out mouse model also supports a role for *Hmgb1* protein in bone development during embryogenesis but the model was not scored because of difference in zygosity and variant type (PMID: 17548469). In summary, there is moderate evidence supporting the relationship between HMBG1 and autosomal dominant brachyphalangy, polydactyly and tibial aplasia syndrome. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic disease GCEP on the meeting date February 24, 2026 (SOP Version 12).