ANKRD11 variants: KBG syndrome and beyond

Abstract

Mutations affecting the transcriptional regulator Ankyrin Repeat Domain 11 (ANKRD11) are mainly associated with the multisystem developmental disorder known as KBG syndrome, but have also been identified in individuals with Cornelia de Lange syndrome (CdLS) and other developmental disorders caused by variants affecting different chromatin regulators. The extensive functional overlap of these proteins results in shared phenotypical features, which complicate the assessment of the clinical diagnosis. Additionally, re‐evaluation of individuals at a later age occasionally reveals that the initial phenotype has evolved toward clinical features more reminiscent of a developmental disorder different from the one that was initially diagnosed. For this reason, variants in ANKRD11 can be ascribed to a broader class of disorders that fall within the category of the so‐called chromatinopathies. In this work, we report on the clinical characterization of 23 individuals with variants in ANKRD11. The subjects present primarily with developmental delay, intellectual disability and dysmorphic features, and all but two received an initial clinical diagnosis of either KBG syndrome or CdLS. The number and the severity of the clinical signs are overlapping but variable and result in a broad spectrum of phenotypes, which could be partially accounted for by the presence of additional molecular diagnoses and distinct pathogenic mechanisms.

Things are not always what they seem: From Cornelia de Lange to KBG phenotype in a girl with genetic variants in NIPBL and ANKRD11

“…An incorrect genetic diagnosis can have severe consequences for prognostic and therapeutic management of the patient, and, as in this case, for the reproductive advice. Moreover, our findings seem to support recent evidences of age‐dependent phenotypic evolution in individuals harboring ANKRD11 variants (Parenti et al, 2021 ), and demonstrate the importance of including KBGS in the differential diagnosis of young children with CdLS features. Therefore, it is crucial to include ANKRD11 in gene panels used for molecular testing of individuals presenting with clinical characteristics of CdLS.…”

“…Nevertheless, several studies have stressed the importance of a critical reconsideration of genetic results and a further implementation of protocols for variant‐level reevaluation and case‐level reanalysis (Deignan et al, 2019 ). This is especially relevant in the context of syndromes, such as the chromatinopathies Cornelia de Lange syndrome (CdLS, OMIM#122470) and KBG syndrome (KBGS, OMIM #148050), with overlapping phenotypes that may evolve over time (Parenti et al, 2021 ). Here, we present a challenging familiar case reanalyzed in which phenotypic features of both KBGS and CdLS are observed, and where genetic variants in ANKRD11 and NIPBL were identified.…”

Deletion of first noncoding exon in ANKRD11 leads to KBG syndrome

“…Prior studies have noted that haploinsufficiency is the likely pathogenic mechanism in these cases based on the tightly regulated abundance of ANKRD11 during the cell cycle (Walz et al, 2015). Moreover, molecular analysis of cohorts of patients with KBG syndrome have found that the majority of ANKRD11 pathogenic variants are frameshift and nonsense variants leading to a loss‐of‐function, and presumably, haploinsufficiency as well (Gnazzo et al, 2020; Goldenberg et al, 2016; Loberti et al, 2022; Low et al, 2016; Parenti et al, 2021; Scarano et al, 2019). Recenty, functional studies performed on ANKRD11 missense variants found these decreased ANKRD11 stability and transcriptional activity, further supporting haploinsufficiency as a pathologic mechanism for KBG syndrome (de Boer et al, 2022).…”

“…Heterozygous single nucleotide variants and indels within ANKRD11 (OMIM #611192), which encodes ankyrin repeat domain 11, were found to cause KBG syndrome and heterozygous deletions at 16q24.3 that contain ANKRD11 have been shown to produce an overlapping clinical phenotype (Sacharow et al, 2012; Sirmaci et al, 2011). Larger case series have since established that KBG syndrome exhibits variable expressivity, and although no definitive genotype–phenotype correlations have been identified, individuals with microdeletions encompassing ANKRD11 and other surrounding genes appear to have an increased risk for neurologic involvement and a higher incidence of congenital heart defects, astigmatism, and thrombocytopenia (Goldenberg et al, 2016; Low et al, 2016; Novara et al, 2017; Parenti et al, 2021).…”

“…Initial molecular analysis of patients with KBG syndrome found consistent disruption of the ANKRD11 C‐terminus suggesting a potential dominant‐negative mechanism through mutant dimerization with wild‐type ANKRD11 (Walz et al, 2015). Subsequent reports have shown a relatively high prevalence of ANKRD11 nonsense, frameshift, and small indel variants as well as deletions of the entire gene leading to KBG syndrome, which suggests haploinsufficiency may also be a mechanism of disease (Goldenberg et al, 2016; Parenti et al, 2021; Scarano et al, 2019; Swols et al, 2017).…”