Skeletal dysplasia

Gene: H2AFY

I don't know

Comment on list classification: There are at least 5 unrelated families reported in literature with individuals affected by Liebenberg syndrome (brachydactyly-elbow wrist dysplasia syndrome), harbouring heterozygous CNVs which affect the H2AFY promoter region. Both deletions and translocations have been reported. In addition, PMID: 30711920 Kragesteen et al., 2021 describe a mouse model supporting Pitx1 upregulation through H2afy promoter loss as the likely mechanism of disease. However, these structural variants would not be detected in the current NGS analysis pipeline and H2AFY should remain Amber for Skeletal dysplasia.

Created: 29 Dec 2025, 3:38 p.m. | Last Modified: 29 Dec 2025, 3:38 p.m.

Panel Version: 8.26

PMID: 30711920 Kragesteen et al., 2021
Used WGS in a non-consanguineous Italian family with 3 mildly affected individuals (mother and her two sons) with Liebenberg syndrome and identified a 8.5 kb deletion (chr5:134 729 406–134 737 909 (hg19)) including the first non-coding exon of H2AFY. This deletion overlaps with previous mutations reported in Liebenberg syndrome and greatly reduces the minimal critical region.
Patient presentation: mild arm-to-leg transformation affecting the lower arms - brachydactyly, camptodactyly of the fifth finger, fusion of proximal scaphoid and lunate, enlarged triquetrum, enlarged and dysplastic distal humerus.
Also created a CRISPR/Cas9 mouse model, showing that specifically the deletion of H2afy promoter causes ectopic Pitx1 expression. Deletion of H2afy while leaving the promoter intact does not have the same effect. Similarly, deletion of both H2afy and Pen (Pitx1 enhancer element leads to a WT phenotype). Hence, the mechanism of disease is likely to be Pitx1 upregulation through H2afy promoter loss.

PMID: 23587911 Al-Qattan et al., 2013
Report of Saudi Arabian family with Liebenberg syndrome (father and 3 of his children were affected). CGH revealed a deletion upstream of PITX1 (H2AFYgene and 190, 428 bp of downstream region; including a gene of unknown function LOC 340073).

PMID: 23022097 Spielmann et al., 2012
Investigated three unrelated families affected by Liebenberg syndrome. Families 1 & 2 habroured heterozygous deletions encompassing H2AFY, upstream of PITX1. WGS + Sanger showed a translocation t(5;18)(q31.1;q12.3) in Family 3.

H2AFY (HGNC approved symbol: MACROH2A2) is not yet linked to any phenotype in OMIM (accessed 29th Dec 2025).

Created: 29 Dec 2025, 3:15 p.m. | Last Modified: 29 Dec 2025, 3:15 p.m.

Panel Version: 8.26

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
brachydactyly-elbow wrist dysplasia syndrome, MONDO:0008520

Publications

• 23022097
• 23587911
• 30711920

Green List (high evidence)

H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome
Sources: Literature

Created: 9 Dec 2025, 2:33 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Liebenberg syndrome

Publications

• PMID: 30711920, PMID: 23587911