Reanalysis of Whole-Exome Sequencing Data of an Infant with Suspected Diagnosis of Jeune Syndrome Revealed a Likely Pathogenic Variant in <i>GRK2:</i> A Newly Associated Gene for Jeune Syndrome Phenotype

Abstract

<b><i>Introduction:</i></b> Ciliopathies with major skeletal involvement embrace a group of heterogeneous disorders caused by pathogenic variants in a group of diverse genes. A narrow thorax with shortening of long bones inspires a clinical entity underlined by dysfunction of primary cilia. Currently, more than 23 genes are listed in the OMIM database corresponding to this clinical entity: WDR19/34/35/60, IFT43/52/80/81/140/172, DYNC2LI1, TTC21B, DYNLT2B, EVC2, EVC, INTU, NEK1, CEP120, DYNC2H1, KIAA0586, SRTD1, KIAA0753, and SRTD12. Recently, individuals with biallelic loss-of-function variants in <i>GRK2</i> are shown to demonstrate a phenotype compatible with Jeune syndrome. Experimental evidence has shown that impaired function of <i>GRK2</i> compromises cilia-based signaling of Hedgehog pathway as well as Wnt signaling, while cilia morphology remains intact. Hence, <i>GRK2</i> is now considered an essential protein in regulation of the skeletogenesis. <b><i>Case Presentation:</i></b> We presented a female infant born to a consanguineous marriage who was found to have a biallelic p.R474* alteration in <i>GRK2</i> in reanalysis of the whole-exome sequencing (WES) data. The patient was exhibiting major clinical features of Jeune syndrome, such as shortened long bones, ribs, and narrow thorax. <b><i>Discussion:</i></b> Our reanalysis of WES data revealed a likely pathogenic biallelic variant in the <i>GRK2</i> which is probably responsible for the Jeune syndrome phenotype in the patient. Hence, our report supports the recently discovered association of <i>GRK2</i> loss-of-function variants with Jeune syndrome phenotype and emphasizes the significance of reanalysis of WES data, notably in patients with phenotypes suggestive of a such discernible Mendelian disorder.