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

Introduction: 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 GRK2 are shown to demonstrate a phenotype compatible with Jeune syndrome. Experimental evidence has shown that impaired function of GRK2 compromises cilia-based signaling of Hedgehog pathway as well as Wnt signaling, while cilia morphology remains intact. Hence, GRK2 is now considered an essential protein in regulation of the skeletogenesis. Case Presentation: We presented a female infant born to a consanguineous marriage who was found to have a biallelic p.R474* alteration in GRK2 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. Discussion: Our reanalysis of WES data revealed a likely pathogenic biallelic variant in the GRK2 which is probably responsible for the Jeune syndrome phenotype in the patient. Hence, our report supports the recently discovered association of GRK2 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.

Coexistence of Megaconial Congenital Muscular Dystrophy and Cystinuria: Mimicking Hypotonia-Cystinuria Syndrome.

Introduction: Hypotonia-cystinuria syndrome is a contiguous gene deletion syndrome that is characterized by hypotonia, developmental delay, and cystinuria type A. We present a male patient who was admitted to our center with clinical findings of hypotonia-cystinuria syndrome and diagnosed with megaconial congenital muscular dystrophy and cystinuria. Case Presentation: A 16-month-old male patient was admitted with complaints of restlessness and body laxity. It was stated that the patient had hypotonia and growth retardation at the age of 2 months. Physical examination revealed mild hypotonia, growth retardation, and development delay, while laboratory examinations identified elevated serum creatine kinase and elevated dibasic amino acid in urine analysis. Because of the findings of hypotonia, growth retardation, developmental delay, and cystinuria, hypotonia-cystinuria syndrome was considered as a differential diagnosis. However, by chromosomal microarray no contiguous deletion in region 2p21 was found, while a novel homozygous c.225-2A>T pathogenic variant in the CHKB gene and a c.1266_1267delGT heterozygous variant in the SLC7A9 gene inherited from the mother were identified with whole-exome sequencing. The co-occurrence of megaconial congenital muscular dystrophy and cystinuria, mimicking hypotonia-cystinuria syndrome, was confirmed. Conclusion: This case suggests that in countries with a high frequency of consanguineous marriage, even if the molecular genetic analysis results are not compatible with the clinical findings, it should be kept in mind that different genetic diseases may coexist.