Mutations in ANKRD11 Cause KBG Syndrome, Characterized by Intellectual Disability, Skeletal Malformations, and Macrodontia

Abstract

KBG syndrome is characterized by intellectual disability associated with macrodontia of the upper central incisors as well as distinct craniofacial findings, short stature, and skeletal anomalies. Although believed to be genetic in origin, the specific underlying defect is unknown. Through whole-exome sequencing, we identified deleterious heterozygous mutations in ANKRD11 encoding ankyrin repeat domain 11, also known as ankyrin repeat-containing cofactor 1. A splice-site mutation, c.7570-1G>C (p.Glu2524_Lys2525del), cosegregated with the disease in a family with three affected members, whereas in a simplex case a de novo truncating mutation, c.2305delT (p.Ser769GlnfsX8), was detected. Sanger sequencing revealed additional de novo truncating ANKRD11 mutations in three other simplex cases. ANKRD11 is known to interact with nuclear receptor complexes to modify transcriptional activation. We demonstrated that ANKRD11 localizes mainly to the nuclei of neurons and accumulates in discrete inclusions when neurons are depolarized, suggesting that it plays a role in neural plasticity. Our results demonstrate that mutations in ANKRD11 cause KBG syndrome and outline a fundamental role of ANKRD11 in craniofacial, dental, skeletal, and central nervous system development and function.

Regions of variable DNA methylation in human placenta associated with newborn neurobehavior

“…Genetic polymorphisms of these genes have been associated with attention related phenotypes, [32][33][34] and this study suggests that epigenetic variability of these genes may also contribute to an infant's ability to track visual and auditory stimuli. We observed increased DNA methylation in genes involved in biological pathways related to neurobehavior and cellular transport, which may be reflective of the influence of placental function on neurological outcomes.…”

Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities

“…Mutations in the ANKRD11 gene within this 16q24.3 interval have been described in patients with KBG syndrome, characterized by intellectual disability, skeletal malformations and macrodontia. 43 Congenital heart defects including VSD, partial atrioventricular canal defect and stenosis of the left pulmonary artery have also been reported in some patients with KBG syndrome. [44][45][46] Rare microdeletions involving ANKRD11 and the flanking genes ZNF778 and CDH15 were observed most frequently in our CVM cohort.…”

Disease gene identification strategies for exome sequencing

“…Ng et al 71 Hoischen et al 33 Ng et al 30 Simpson et al 72 Isidor et al 73 Vissers et al 74 Albers et al 75 Dickinson et al 76 Sirmaci et al 77 Agrawal et al 78 De novo (Figure 3e Byun et al 79 Haack et al 80 Worthey et al 44 Götz et al 69c Erlich et al 45 Ozgul et al 81 a,b,c Indicate studies that use a combination of two strategies.…”