Submission Details

The ANTXR2 gene is located on chromosome 4q21.21 and encodes a 55 kDa type I transmembrane protein. ANTXR2 was first reported in relation to autosomal recessive hyaline fibromatosis syndrome in 2003 (Hanks et al., PMID: 14508707; Dowling et al., PMID: 12973667). Hyaline fibromatosis syndrome (HFS) is characterized by accumulation of amorphous, unidentified hyaline material in the skin and other organs. Clinical features of HFS include progressive contractures, hyperpigmented skin over bony prominences, subcutaneous nodules, gingival thickening, and failure to thrive secondary to protein-losing enteropathy. HFS is a progressive disease and its manifestations tend to be additive over time. At least 50 variants (including missense, nonsense, frameshift, deletions, and splice variants) have been reported in the literature. Nine variants, including 5 missense variants and 4 frameshift variants that have been reported in 7 probands in four publications are included in this curation (PMID: 12973667; Deuquet et al., 2011, PMID: 21328543; Denadai et al., 2012, PMID: 22383261; Mohamed et al., 2017, PMID: 25458638). The gene-disease relationship is supported by markedly reduced protein expression in patient cells (Burgi et al., 2017, PMID: 28604699), homozygous knockout mice (PMID: 28604699), and rescue of protein expression in patient cells (PMID: 21328543; Burgi et al., 2020, PMID: 32428455). In summary, there is definitive evidence to support the relationship between ANTXR2 and autosomal recessive hyaline fibromatosis syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 11.22.2022 (SOP Version 9.0).