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The prevalence and phenotypic range associated with biallelic PKDCC variants

Pagnamenta, AT; Belles, RS; Salbert, BA; Wentzensen, IM; Guillen Sacoto, MJ; Santos, FJR; Caffo, A; ... Taylor, JC; + view all (2023) The prevalence and phenotypic range associated with biallelic PKDCC variants. Clinical Genetics 10.1111/cge.14324. (In press). Green open access

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Abstract

PKDCC encodes a component of Hedgehog signalling required for normal chondrogenesis and skeletal development. Although biallelic PKDCC variants have been implicated in rhizomelic shortening of limbs with variable dysmorphic features, this association was based on just two patients. In this study, data from the 100 000 Genomes Project was used in conjunction with exome sequencing and panel-testing results accessed via international collaboration to assemble a cohort of eight individuals from seven independent families with biallelic PKDCC variants. The allelic series included six frameshifts, a previously described splice-donor site variant and a likely pathogenic missense variant observed in two families that was supported by in silico structural modelling. Database queries suggested that the prevalence of this condition is between 1 of 127 and 1 of 721 in clinical cohorts with skeletal dysplasia of unknown aetiology. Clinical assessments, combined with data from previously published cases, indicate a predominantly upper limb involvement. Micrognathia, hypertelorism and hearing loss appear to be commonly co-occurring features. In conclusion, this study strengthens the link between biallelic inactivation of PKDCC and rhizomelic limb-shortening and will enable clinical testing laboratories to better interpret variants in this gene.

Type: Article
Title: The prevalence and phenotypic range associated with biallelic PKDCC variants
Location: Denmark
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/cge.14324
Publisher version: https://doi.org/10.1111/cge.14324
Language: English
Additional information: © 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: bone diseases, medical genetics, skeletal dysplasia, whole genome sequencing
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10168391
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