TY - JOUR T1 - Variable skeletal phenotypes associated with biallelic variants in <em>PRKG2</em> JF - Journal of Medical Genetics JO - J Med Genet SP - 947 LP - 950 DO - 10.1136/jmedgenet-2021-108027 VL - 59 IS - 10 AU - Alistair T Pagnamenta AU - Francisca Diaz-Gonzalez AU - Benito Banos-Pinero AU - Matteo P Ferla AU - Mehran B Toosi AU - Alistair D Calder AU - Ehsan G Karimiani AU - Mohammad Doosti AU - Andrew Wainwright AU - Paul Wordsworth AU - Kathryn Bailey AU - Katarina Ejeskär AU - Tracy Lester AU - Reza Maroofian AU - Karen E Heath AU - Homa Tajsharghi AU - Deborah Shears AU - Jenny C Taylor A2 - , Y1 - 2022/10/01 UR - http://jmg.bmj.com/content/59/10/947.abstract N2 - The 100 000 Genomes Project (100KGP) is a UK-wide initiative that has a goal of using whole genome sequencing (WGS) to identify genetic causes of rare inherited diseases and embed the use of this technology within the NHS.1 Using data from this resource alongside international gene-matching efforts, four individuals from two independent families were identified harbouring homozygous frameshift or stop-gain variants in PRKG2, a recently described skeletal dysplasia gene.2 Detailed clinical and radiological assessments helped extend the phenotypic range associated with this autosomal recessive condition while functional studies indicated that both variants had a similar impact on FGF-induced MAPK signalling. PRKG2 encodes the cyclic guanosine monophosphate dependent protein kinase II (cGKII), which acts downstream of the natriuretic peptide receptor-B/C- natriuretic peptide (NPR-B/CNP). NPR-B is encoded by NPR2, biallelic variants in which are responsible for acromesomelic dysplasia, Maroteaux type (AMDM; MIM 602875). Rodent models further implicate PRKG2 in skeletal development3 4 and cGKII deficiency was shown to be the cause of the dwarfism phenotype observed in Angus cattle.5 Building on support from pathway analysis and model organisms, a recent study showed that biallelic PRKG2 variants can result in acromesomelic dysplasia, PRKG2-type (AMDP) in humans,2 adding PRKG2 to a list of &gt;400 genes associated with genetic skeletal disorders.6 As only two affected individuals were reported, it is important that the full clinical range of this condition is described.In this study, we searched for rare biallelic PRKG2 variants using data from the 100KGP via the LabKey application available within Genomic England’s research environment. Researchers can apply for access online (www.genomicsengland.co.uk/join-a-gecip-domain). Initial filtering employed a 1% population allele frequency threshold based on data from the 1000 Genomes Project as well as in-house frequency information. An additional family was identified via a network of collaborators and variants were … ER -