ANKRD11 – KBG Syndrome

ANKRD11 encodes the ankyrin repeat domain-containing protein 11 and is causally implicated in KBG syndrome, a dominantly inherited developmental disorder characterized by intellectual disability, macrodontia of the upper central incisors, short stature, and skeletal anomalies. Initial identification of heterozygous truncating and splice-site mutations in ANKRD11 firmly established the gene’s role in KBG syndrome, with multiple de novo and familial variants reported (PMID:21782149).

Genetic evidence supporting this association is robust: over 200 unrelated individuals from more than 50 families harbor protein-truncating ANKRD11 variants, including frameshift (e.g., c.2305del (p.Ser769GlnfsTer8)) and nonsense changes, with recurrent detection in both simplex and multiplex cases. Segregation has been documented in at least 19 affected relatives across nine multiplex families (PMID:21782149; PMID:27605097).

Functional studies demonstrate haploinsufficiency as the predominant pathogenic mechanism. Patient-derived and engineered ANKRD11 truncations escape normal proteasomal degradation and produce truncated proteins that disrupt transcriptional regulatory functions. Notably, mutations affecting the C-terminal repression domain lead to abnormal protein accumulation and altered cell-cycle regulation (PMID:25413698).

Animal and cellular models further corroborate these findings: mice carrying ANKRD11 loss-of-function alleles recapitulate craniofacial and skeletal anomalies, while in vitro assays reveal reduced transcriptional activation at target promoters, consistent with a dominant-negative or haploinsufficient effect. These data collectively confirm that loss of ANKRD11 function is sufficient to produce the KBG phenotype.

No credible conflicting evidence has been reported; all pathogenic variants map to functional domains critical for ANKRD11’s role in chromatin modification and transcriptional regulation. The phenotype is consistent across diverse populations and variant types, with no reported gain-of-function or alternative mechanisms.

In summary, ANKRD11 meets ClinGen’s Definitive level of gene–disease validity for KBG syndrome: extensive case numbers, clear segregation, and concordant functional data confirm a haploinsufficiency mechanism. Clinically, testing for ANKRD11 truncating variants or 16q24.3 microdeletions should be incorporated into diagnostic workflows for patients presenting with developmental delay, characteristic craniofacial features, macrodontia, and skeletal anomalies.

Key Take-Home: ANKRD11 haploinsufficiency is definitively established as the cause of autosomal dominant KBG syndrome, enabling precise molecular diagnosis and informed clinical management.

References

• American Journal of Human Genetics | 2011 | Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. PMID:21782149
• American Journal of Medical Genetics Part A | 2016 | Clinical and molecular findings in 39 patients with KBG syndrome caused by deletion or mutation of ANKRD11. PMID:27605097
• Human Genetics | 2015 | Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome. PMID:25413698

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