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Case Reports
. 2010 Apr;18(4):429-35.
doi: 10.1038/ejhg.2009.192. Epub 2009 Nov 18.

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

Marjolein H Willemsen  1 , Bridget A Fernandez, Carlos A Bacino, Erica Gerkes, Arjan P M de Brouwer, Rolph Pfundt, Birgit Sikkema-Raddatz, Stephen W Scherer, Christian R Marshall, Lorraine Potocki, Hans van Bokhoven, Tjitske Kleefstra
Affiliations
Case Reports

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

Marjolein H Willemsen et al. Eur J Hum Genet. 2010 Apr.

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.

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Figures

Figure 1
Figure 1
Facial profiles of patients 1–4. (a–c) Patient 1 at several ages, from 6 years (a) to 22 years (b and c). (d–f) Patient 2 at the age of 3 years (d) and at the age of 8 years (e and f). (g and h) Patient 3 at the age of 7 years. (i and j) Patient 4 at the age of 8 years and 10 months. Facial features comprise high forehead/frontal bossing and large ears (all patients), broad mouth, long smooth philtrum and pointed chin (patient 1–3). Note the change in facial phenotype in patient 1 at adult age, showing a long and oval face with a full upturned nose, retrognathia and a pronounced groove in the chin.
Figure 2
Figure 2
Schematic overview of deleted regions on chromosome 16q24.3 in the presented patients. All deletions were mapped according to the USCS genome browser build May 2004. The relative positions of the genes of interest are indicated. The region of 90 kb overlap is demarcated with a gray zone. The deletions in patient 3 and 4 extend beyond the figure (Mb positions of proximal delineations: 86.06 and 86.79, respectively). Arrows indicate the direction in which the genes are transcribed. SRO: shortest region of overlap.
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