Variable skeletal phenotypes associated with biallelic variants in PRKG2
| Autor: | Homa Tajsharghi, Kathryn Bailey, Katarina Ejeskär, Mehran Beiraghi Toosi, Mohammad Doosti, Ehsan Ghayoor Karimiani, A. Wainwright, Matteo P. Ferla, Benito Banos-Pinero, Alistair T. Pagnamenta, Jenny C. Taylor, Francisca Díaz-González, Reza Maroofian, Alistair Calder, Karen E. Heath, Deborah J. Shears, Paul Wordsworth, Tracy Lester |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Journal of Medical Genetics. 59:947-950 |
| ISSN: | 1468-6244 0022-2593 |
| DOI: | 10.1136/jmedgenet-2021-108027 |
| Popis: | 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 >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 … |
| Databáze: | OpenAIRE |
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