Submission Details

APC Membrane Recruitment Protein 1 (AMER1; MIM#300647) is an inhibitor of the canonical WNT signaling pathway and is involved in ubiquitination and degradation of beta-catenin. AMER1, also called WTX, is a X-linked gene associated with Osteopathia striata with cranial sclerosis (OSCS, XL; MIM#300373). The molecular etiology of OSCS was first described by Jenkins, et.al in 2008 [PMID:19079258] and has been described in many affected male and female individuals since [PMID:20209645, 20950377, 25296999, 28425981, 34622833, 34414661, others]. Variants are nonsense, frameshift, and small inter- or intragenic deletions, and LOF is the proposed mechanism of disease. Phenotypes in females are variable though often include cranial sclerosis and metaphyseal striations of the long bones. Phenotypes in males are also variable and can be associated with mild phenotypes similar to those seen in females or in more severe cases, with multiple congenital anomalies resulting in demise in utero or in the neonatal or early infantile period. Genetic evidence for AMER1 and Osteopathia striata with cranial sclerosis was scored at the maximum of 12 points and includes both male and female probands with some variants segregating in affected families. Functional evidence including expression studies [PMID:19079258] and mouse models recapitulating the observed human phenotype [PMID:29329488, 21571217] were scored for an additional 2.5 points. Given this and its replication in the literature over time, the association with the AMER1 gene and Osteopathia striata with cranial sclerosis is curated as Definitive by the Prenatal Gene Curation Expert Panel.