Extending the phenotype associated with the CSNK2A1‐related Okur–Chung syndrome—A clinical study of 11 individuals

Abstract

Variants in the Protein Kinase CK2 alpha subunit, encoding the CSNK2A1 gene, have previously been reported in children with an intellectual disability and dysmorphic facial features syndrome: now termed the Okur-Chung neurodevelopmental syndrome. More recently, through trio-based exome sequencing undertaken by the Deciphering Developmental Disorders Study (DDD study), a further 11 children with de novo CSNK2A1 variants have been identified. We have undertaken detailed phenotyping of these patients. Consistent with previously reported patients, patients in this series had apparent intellectual disability, swallowing difficulties, and hypotonia. While there are some shared facial characteristics, the gestalt is neither consistent nor readily recognized. Congenital heart abnormalities were identified in nearly 30% of the patients, representing a newly recognized CSNK2A1 clinical association. Based upon the clinical findings from this study and the previously reported patients, we suggest an initial approach to the management of patients with this recently described intellectual disability syndrome.

CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual

“…To date, many researchers have worked to reveal interactions between genetic variants and disease phenotypes. Recently, COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-020-0755-1 ARTICLE COMMUNICATIONS BIOLOGY | (2020) 3:33 | https://doi.org/10.1038/s42003-020-0755-1 | www.nature.com/commsbio genome-wide quantification analyses have shown that rare mutations are found in normal tissue, whereas risk variants from neurodevelopmental disorder patients are common genetic variants, implying that non-rare genetic variants may cause genetic disease in some patients [50][51][52][53][54][55] . In this study, we showed that correction of the ATP7A M1311V mutation can rescue the function of MNs derived from cells of one ALS patient of Ashkenazi Jewish descent.…”

Common genetic variants contribute to risk of rare severe neurodevelopmental disorders

“…There are thousands of rare human disorders caused by a single deleterious, proteincoding genetic variant 1 . However, patients with the same genetic defect can have different clinical presentation [2][3][4] , and some individuals carrying known disease-causing variants can appear unaffected 5 . What explains these differences?…”

A complex of distal appendage-associated kinases linked to human disease regulates ciliary trafficking and stability

“…These results indicate that the OCNDS-associated mutations may alter the morphology and structure of primary cilia. OCNDS exhibits overlapping clinical features with ciliopathies (20,43,46,47). Our work, therefore, establishes a new link between Csnk2a1 and cilia regulation and raises the possibility that OCNDS might be linked, at least partially, to disrupted cilia structure or function.…”

“…Dominant mutations in Csnk2a1 were recently associated with a human syndrome known as Okur-Chung neurodevelopmental syndrome (OCNDS) (20,(40)(41)(42)(43)(44). This disorder is characterized by dysmorphic facial features as well as neurological phenotypes, bearing some similarities to human ciliopathies.…”

“…This disorder is characterized by dysmorphic facial features as well as neurological phenotypes, bearing some similarities to human ciliopathies. To test whether the OCNDS-associated mutations are associated with defects in primary cilia, we stably expressed the wild-type version of CSNK2A1 as well as three different OCNDSassociated variants R80H, D156H, and R191Q ( Fig 6A) (41,43,45) in WT MEFs. We previously showed that the GFP tagged-CSNK2A1 WT localized to the centrosome, similar to the endogenous protein ( Fig 2B).…”