Relevance to Autism

ANKRD11 is in an ASD-associated multi-genic CNV on chromosome 16q24.3 (Willemsen et al., 2010; Marshall et al., 2008). Two de novo LoF variants in the ANKRD11 gene (both frameshift) have been identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768). Mutations in ANKRD11 are also responsible for KBG syndrome (OMIM 148050), which is characterized by developmental delay/intellectual disability and, in some cases, autism (PMID 21782149, 19597979). A comprehensive clinical and genetic evaluation of 20 patients with KBG syndrome from 13 families published in 2014 found that many patients displayed behavioral abnormalities such as ASD (PMID 25424714). In this report, de novo LoF variants in ANKRD11 were observed in three KBG patients that also presented with ASD (two frameshift, one nonsense), while another frameshift variant in ANKRD11 segregated with disease in a multi-generational pedigree in which a mother with intellectual disability and autistic features transmitted this variant to four affected children, all of whom presented with ASD and intellectual disability. Clinical evaluation of 32 patients with KBG syndrome in Low et al., 2016 found that 8 out of 32 cases (25%) had a formal diagnosis of ASD, with an additional case presenting with some autistic features. De novo variants in the ANKRD11 gene have been reported in individuals with a non-classic Cornelia de Lange phenotype (Ansari et al., 2014; Parenti et al., 2016). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with ANKRD11 mutations presented with autism spectrum disorder. Two additional de novo likely gene-disruptive variants in ANKRD11 were observed in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified ANKRD11 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified ANKRD11 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This locus encodes an ankryin repeat domain-containing protein. The encoded protein inhibits ligand-dependent activation of transcription. Mutations in this gene have been associated with KBG syndrome, which is characterized by macrodontia, distinctive craniofacial features, short stature, skeletal anomalies, global developmental delay, seizures and intellectual disability.

External Links

References

Model Summary

Identification of a novel genetic regulator of bone homeostasis.

References