Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome

Abstract

The clinical use of array comparative genomic hybridization in the evaluation of patients with multiple congenital anomalies and/or mental retardation has recently led to the discovery of a number of novel microdeletion and microduplication syndromes. We present four male patients with overlapping molecularly defined de novo microdeletions of 16q24.3. The clinical features observed in these patients include facial dysmorphisms comprising prominent forehead, large ears, smooth philtrum, pointed chin and wide mouth, variable cognitive impairment, autism spectrum disorder, structural anomalies of the brain, seizures and neonatal thrombocytopenia. Although deletions vary in size, the common region of overlap is only 90 kb and comprises two known genes, Ankyrin Repeat Domain 11 (ANKRD11) (MIM 611192) and Zinc Finger 778 (ZNF778), and is located approximately 10 kb distally to Cadherin 15 (CDH15) (MIM 114019). This region is not found as a copy number variation in controls. We propose that these patients represent a novel and distinctive microdeletion syndrome, characterized by autism spectrum disorder, variable cognitive impairment, facial dysmorphisms and brain abnormalities. We suggest that haploinsufficiency of ANKRD11 and/or ZNF778 contribute to this phenotype and speculate that further investigation of non-deletion patients who have features suggestive of this 16q24.3 microdeletion syndrome might uncover other mutations in one or both of these genes.

Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities

“…The individuals in our study also have ECAs with neurocognitive deficits and facial dysmorphisms (Table 2), as described in other studies. 42,47 CES caused by dup 22q11 is frequently associated with heart defects, particularly total anomalous pulmonary venous return or tetralogy of Fallot. 48 Although the critical region responsible for CVM has been ill-defined in children affected with CES, Riazi et al 49 have shown that overexpression of CECR1 causes heart defects in mice, including ASD.…”

Haploinsufficiency of ANKRD11 causes mild cognitive impairment, short stature and minor dysmorphisms

“…1,2 When comparing the facial features of our patients with the previously described patients, some resemblance is noted: high forehead, a broad mouth and prominent chin. 1 Both patients also had a relatively small nasal bridge with mild synophrys and a bulbous nose tip, resembling patient 1 of the study of Willemsen et al at adult age. As in our patients, the stature of the reported patients is also relatively short compared with the other growth parameters.…”

“…Last year, in this journal, Willemsen et al 1,2 presented four patients with an interstitial deletion of chromosome band 16q24.3. The overlapping phenotypical features provided evidence for a novel microdeletion syndrome characterized by variable levels of intellectual disability, autistic features (ASD) and facial dysmorphisms.…”

Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome

“…Heterozygous deletions at 16q24.3 that contain the ANKRD11 gene were also described in patients with ID, autistic spectrum disorder, and in some cases with brain anomalies, a clinical phenotype overlapping with KBG syndrome (Marshall et al 2008;Willemsen et al 2010;Handrigan et al 2013;Isrie et al 2012;Sacharow et al 2012;Khalifa et al 2013;Miyatake et al 2013).…”

“…ANKRD11 localizes mainly to the nuclei of neurons and accumulates in discrete inclusions when neurons are depolarized (Sirmaci et al 2011). Thus, it is not surprising that ANKRD11 mutations lead to a neurobehavioral phenotype (Willemsen et al 2010;Handrigan et al 2013;Sacharow et al 2012;Spengler et al 2013). However, how ANKRD11 mutations act at the molecular level remains unknown.…”