Familial severe skeletal Class II malocclusion with gingival hyperplasia caused by a complex structural rearrangement at the KCNJ2-KCNJ16 locus
Year: 2024
Type: article
Abstract: The aim of this work was to identify the underlying genetic cause in a four-generation family segregating an unusual phenotype comprising a severe form of skeletal Class II malocclusion with gingival hyperplasia. SNP array identified a copy number gain on chromosome 1 (chr1); however, this chromosomal region did not segregate correctly in the extended family. Exome sequencing also failed to identify a candidate causative variant but highlighted co-segregating genetic markers on chr17 and chr19. Short- and long-read genome sequencing allowed us to pinpoint and characterize at nucleotide-level resolution a chromothripsis-like complex rearrangement (CR) inserted into the chr17 co-segregating region at the KCNJ2-SOX9 locus. The CR involved the gain of five different regions from chr1 that are shuffled, chained, and inserted as a single block (∼828 kb) at chr17q24.3. The inserted sequences contain craniofacial enhancers that are predicted to interact with KCNJ2/KCNJ16 through neo-topologically associating domain (TAD) formation to induce ectopic activation. Our findings suggest that the CR inserted at chr17q24.3 is the cause of the severe skeletal Class II malocclusion with gingival hyperplasia in this family and expands the panoply of phenotypes linked to variation at the KCNJ2-SOX9 locus. In addition, we highlight a previously overlooked potential role for misregulation of the KCNJ2/KCNJ16 genes in the pathomechanism of gingival hyperplasia associated with deletions and other rearrangements of the 17q24.2-q24.3 region (MIM 135400).
Authors: Reza Maroofian, Alistair T. Pagnamenta, Alireza Navabazam, Ron Schwessinger, Hannah E. Roberts, Maria Lopopolo, Mohammadreza Dehghani, Mohammad Yahya Vahidi Mehrjardi, Alireza Haerian, Mojtaba Soltanianzadeh, Mohammad Hadi Noori Kooshki, Samantha J.L. Knight, Kerry A. Miller, Simon J. McGowan, Nicolas Chatron, Andrew T. Timberlake, Uirá Souto Melo, Stefan Mundlos, David Buck, Stephen R.F. Twigg, Jenny C. Taylor, Andrew O.M. Wilkie, Eduardo Calpena
Institutions: UCL Queen Square Institute of Neurology, University College London, Centre for Human Genetics, National Institute for Health and Care Research, University of Oxford, Shahid Sadoughi University of Medical Sciences and Health Services, MRC Weatherall Institute of Molecular Medicine, Hospices Civils de Lyon, NYU Langone Health, New York University, Max Planck Institute for Molecular Genetics, Instituto de Investigación Sanitaria La Fe
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,300
OpenAlex ID: W4402390568