Deletion of first noncoding exon in ANKRD11 leads to KBG syndrome

Abstract

Phenotypic features of KBG syndrome include craniofacial anomalies, short stature, cognitive disability and behavioral findings. The syndrome is caused by heterozygous pathogenic single nucleotide variants and indels in ANKRD11, or a heterozygous deletion of 16q24.3 that includes ANKRD11. We performed genome sequencing on a patient with clinical manifestations of KBG syndrome including distinct craniofacial features as well as a history of mild intellectual disability and attention‐deficit hyperactivity disorder. This led to the identification of a 43 kb intragenic deletion of ANKRD11 affecting the first noncoding exon while leaving the coding regions intact. Review of the literature shows that this is the smallest 5′ deletion affecting only the noncoding exons of ANKRD11. Real‐time polymerase chain reaction demonstrated that the copy number variant was not present in either of the proband's parents, suggesting it occurred de novo. RNA expression analysis demonstrated significantly decreased transcript abundance compared to controls. This provides new evidence for haploinsufficiency as a mechanism of disease in KBG syndrome.

Functional investigation of a novel ANKRD11 frameshift variant identified in a Chinese family with KBG syndrome

“…Previous studies have demonstrated that pathogenic ANKRD11 missense variants or three-base pair deletions resulting in a single-amino-acid deletion did not significantly impact the expression levels of mRNA and protein, as well as nuclear localization, but impair the stability or transcriptional activity of encoded protein, particularly missense variants clustered in the C-terminal repression domain 2 (RD2) [ 28 , 30 ]. In contrast, deletion of first noncoding exon obviously decreased the mRNA level of ANKRD11 [ 32 ]. Taken together, ANKRD11 frameshift variant (c.2280_2281delGT) appeared to trigger more substantial damage to the gene/protein compared to other variant types.…”