PMC9149378_01
PMC9149378_02
PMC9149378_03
DNA electrophoregram with the (C)2141G > T [p.G714 V] in CDK13 gene of (A) proband (B) father, and (C) mother.
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F1
American College of Medical Genetics and Genomics (ACMG) Standard guidelines for the interpretation of sequence variants were followed in this study. A heterozygous missense variant in CDK13 gene located on 7p14.1, NM_003,718, exon 4, c.2141G > T (p.G714V) was identified (full report of the variant found by WES in the trio was summarized in Supplementary Table S1), and Sanger sequencing showed the variant was de novo since his unaffected parents did not have the variant (Figure 1).
Overview of CDK13 variants (A) Location of pathogenic variants in the CDK13 protein of all presently reported individuals. Missense variants are annotated in black (presently reported variant in red), and others in grey. Numbers in brackets refer to the corresponding variants presented in more than one individual. Up to half (21/46) of the variants perturb the wild-type asparagine residue at amino acid position 842. (B) Crystal structure of one heterodimer (chains A-B) of CDK13-cyclin K (PDB id: 5efq); CDK13 and cyclin K are shown in new-cartoon format, colored cyan and pink, respectively, with sidechains of selected residues (red) and ligands (orange) shown in licorice format. (C) The exact positions of CDK13 residue 714 in wild-type (WT) CDK13, Gly714Val (G714 V) variant, Gly714Asp (G714D) variant, and Gly714Arg (G714R) variant, showing in red licorice format.
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F2
Residue Gly714, lying within the nucleotide binding domain of CDK13 (Figure 2), is highly conserved, and this variant is predicted to be pathogenic by SIFT, PolyPhen-2, MutationTaster, GERP++ and REVEL. This variant is not found in all population databases, and has not been described in variant databases and therefore is novel (Figure 2A), and moreover, alternative variants in the same position are classified as pathogenic by ClinVar. This novel sidechain is putative to cause changes in the CDK13 structure (Figures 2B,C).
PMC9149378_04
Facial features of the patient with CDK13-related disorder and bone marrow smears. (A) Anterior and profile facial photographs show his facial anomalies with mild exophthalmos, blepharoptosis, broad nasal bridge, big front teeth with wide space, low set and posteriorly rotated ears. He presented with drowsiness, emotional apathy after HLH onset (Left). (B) Bone marrow smears showing morphologic blasts cells with a proportion of 48% at diagnosis of acute lymphoblastic leukemia (ALL).
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F3
Upon hospital admission, the boy was noted to have atypical facial anomalies (Figure 3A). After two chemotherapy cycles of corticosteroid, cyclosporin A and etoposide (VP16), his condition returned back to stable at the middle of November 2019, and bone marrow morphology was revaluated, showing acute lymphoblastic leukemia (ALL) with a proportion of leukemic blasts of 48% (reference intervals (RI): <5%) (Figure 3B).