BPNT2 was first reported in relation to autosomal recessive Chondrodysplasia with joint dislocations GPAPP type (MONDO:0013561) in 2011 (Vissers LE et al., 2011; PMID:21549340). GPAPP deficiency is a genetic, primary bone dysplasia characterized by prenatal onset of disproportionate short stature, shortening of the limbs, congenital joint dislocations, micrognathia, posterior cleft palate, brachydactyly, short metacarpals and irregular size of the metacarpal epiphyses, supernumerary carpal ossification centers and dysmorphic facial features. In addition, hearing impairment and mild psychomotor delay have also been reported. The disease can be caused by homozygous mutation in the BPNT2 gene (614078) on chromosome 8q12.1. This gene encodes a member of the inositol monophosphatase family. The encoded protein is localized to the Golgi apparatus and catalyzes the hydrolysis of phosphoadebbnosine phosphate (PAP) to adenosine monophosphate (AMP). Mutations in this gene are a cause of GRAPP type chondrodysplasia with joint dislocations, and a pseudogene of this gene is on the long arm of chromosome 1 and has 3 transcripts.
More than 300 unique variants (e.g., synonymous, missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. 4 variants (2 nonsense, and 2 missense) that have been reported in approximately 4 probands in 2 publications (Venkatapuram VS et al., 2022; PMID: 34989141; Vissers LE et al., 2011; PMID:21549340). There is also a non-scorable publication that describes similar phenotypes of gPAPP deficiency but was not included in this curation (Nizon M et al., 2012; PMID:22887726). This gene-disease relationship is also supported by an animal models study (Frederick JP et al., 2008; PMID:18695242). In summary, there is moderate evidence to support the relationship between BPNT2 and Chondrodysplasia with joint dislocations GPAPP type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date XXX X, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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