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The prevalence and phenotypic range associated with biallelic PKDCC variants |
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| Authors: | Alistair T. Pagnamenta Rebecca S. Belles Bonnie Anne Salbert Ingrid M. Wentzensen Maria J. Guillen Sacoto Francis Jeshira Reynoso Santos Alesky Caffo Matteo Ferla Benito Banos-Pinero Karolina Pawliczak Mina Makvand Hossein Najmabadi Genomics England Research Consortium Reza Maroofian Tracy Lester Ana Lucia Yanez-Felix Camilo E. Villarroel-Cortes Fan Xia Khowla Al Fayez Amal Al Hashem Deborah Shears Melita Irving Amaka C. Offiah Ariana Kariminejad Jenny C. Taylor |
| Affiliation: | 1. NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK;2. Geisinger Health System, Danville, Pennsylvania, USA;3. GeneDx, Gaithersburg, Maryland, USA;4. Joe DiMaggio Children's Hospital, Hollywood, Florida, USA Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA;5. Joe DiMaggio Children's Hospital, Hollywood, Florida, USA;6. Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK;7. South East Genomic Laboratory Hub, Guy's Hospital, London, UK;8. Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran;9. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK;10. Human Genetics Department, National Pediatrics Institute, Mexico City, Mexico;11. Baylor Genetics, Houston, Texas, USA;12. Department of Pediatrics, Division of Clinical Genetic and Metabolic Medicine, Prince Sultan Medical Military City, Riyadh, Saudi Arabia;13. Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK;14. Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK;15. Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK |
| 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. |
| Keywords: | bone diseases medical genetics skeletal dysplasia whole genome sequencing |