CDK13-Related Disorder: Novel Insights From A Series of 27 Cases and Recommendations for Clinical Management

Abstract

In 2016, Sifrim and colleagues described the first group of patients carrying heterozygous pathogenic variants in CDK13 and sharing major clinical features mainly consisting of congenital heart defects, intellectual disability and peculiar facial features (Congenital Heart Defects, Dysmorphic Facial Features, and Intellectual Developmental Disorder; CHDFIDD, OMIM # 617360). This condition is generally referred to as CDK13-related disorder, and since then other reports have provided further clinical and molecular information. Here we describe a group of 27 previously unreported patients to more accurately profile the clinical spectrum associated with CDK13 variants, disclosing novel associated findings, such as complex craniosynostosis and variable skeletal features (e.g., cranio-cervical anomalies). We also focused on the ocular phenotype that appears to include bilateral congenital glaucoma, posterior embriotoxon, buphthalmos and Duane anomaly. Finally, we observed two cases of mother-to-daughter transmission. Our work clarifies some novel features of CHDFIDD, defines the differential diagnosis of this disorder, and provides recommendations for its clinical management.

Keywords: CDK13; CDK13‐related disorder; CHDFIDD; cyclin‐dependent kinase; syndromic intellectual disability.

FIGURE 1

Schematic representation of the variants in CDK13 reported in the present cohort. The green area identifies the kinase domain (residues 705–998). The different variant classes are indicated by red dots (frameshift variants), orange dots (nonsense variants), blue dots (missense variants) and violet dots (splicing variants). Numbers inside the dot correspond to the number of participants carrying the same variant (single cases, if not specified). The cartoon was created using ProteinPaint. [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Selected radiological features. (A, B) Brain MRI from participant #11 performed at 5 years of age shows asymmetric cerebral and cerebellar hemispheres (A) and Arnold‐Chiari malformation (B). (C, D) Brain MRI from participant #4 shows partial agenesis of the corpus callosum associated with lipoma (performed at 5 years of age). (F, G) Computed tomography scan of the skull performed at 1 month and 6 days of age shows precocious fusion of the metopic (F) and right lambdoid (G) sutures in participant #11. (H, I) Brain MRI from participant #6 (10 days old) shows a wide area of polymicrogyria, mostly in the anterior region of the right side.

FIGURE 3

Main phenotypic features in our cohort. A–F, Facial phenotype: Wide nasal root associated with large nasal tip, epicanthal folds, arched eyebrows showing a marked median apex with a steep inclination (A, D, F), thin upper lip (A, F), everted lower lip (C, D, E). G–L, Ear anomalies: Hypoplastic and horizontal helix (G, I, K), overfolded helix (G, H, I, L), hypoplastic lobe (G, I, L), uplifted lobe (J), hypertrofic tragus (L). A, G: Subject #11; B, H: Subject #6; C, I: Subject #24; D, J: Subject #25; E, K: Subject #1; F, L: Subject #18. [Colour figure can be viewed at wileyonlinelibrary.com]