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A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP

Abstract

Despite the high heritability of autism spectrum disorders (ASD), characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities1, a genetic diagnosis can be established in only a minority of patients. Known genetic causes include chromosomal aberrations, such as the duplication of the 15q11-13 region, and monogenic causes, as in Rett and fragile-X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most. Even with the recent developments in next-generation sequencing, for the large majority of cases no molecular diagnosis can be established2,3,4,5,6,7. Here, we report ten patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex. We estimate this gene to be mutated in at least 0.17% of ASD cases, making it one of the most frequent ASD-associated genes known to date.

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Figure 1: Frontal facial photographs of patients.
Figure 2: Schematic overview of the ADNP gene structure and functional domains.

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Acknowledgements

This work was funded by the Belgian National Fund for Scientific Research-Flanders (FWO) to G.V. and R.F.K., the Special Research Fund of the University of Antwerp (Bijzonder Onderzoeksfonds (BOF-IWT)) to C.H., by grants from the Dutch Organization for Health Research and Development (917-86-319 and 40-00812-98-12109 to B.B.A.d.V. and 907-00-365 to T.K.), the EU-funded GENCODYS project (EU-7th-2010-241995 to A.T.V.-v.S., B.B.A.d.V. and T.K.), Simons Foundation Autism Research Initiative award (SFARI191889EE to E.E.E.) and NIH (MH101221 to E.E.E.). We acknowledge R. Pettinato and M. Elia for the first enrolling of patients 8 and 9, respectively, and J. Shendure and B. O'Roak for details regarding ADNP molecular inversion probe design. E.E.E. is an investigator of the Howard Hughes Medical Institute.

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Authors

Contributions

The study was designed and the results were interpreted by A.T.V.-v.S., B.B.A.d.V., T.K., B.P.C., E.E.E., C.H., G.V., N.V.d.A. and R.F.K. Subject ascertainment and recruitment were carried out by A.T.V.-v.S., J.H.M.S.-H., C.L.M., M.H.W., B.B.A.d.V., T.K., C.R., J.v.d.E., N.V.d.A., A.N., G.A., M.B. and M.W. Sequencing, validation and genotyping were carried out and interpreted by C.H., L.R., G.V., H.M., K.T.W., P.B., B.P.C., L.E.L.M.V., M.F., K.T.W. and H.G.Y. The manuscript was drafted by C.H., G.V., N.V.d.A. and R.F.K. All authors contributed to the final version of the paper.

Corresponding authors

Correspondence to R Frank Kooy or Nathalie Van der Aa.

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Competing interests

E.E.E. is on the scientific advisory boards for Pacific Biosciences, Inc., SynapDx Corp. and DNAnexus, Inc.

Integrated supplementary information

Supplementary Figure 1 De novo 4-bp ADNP frameshift deletion (chr20:49508752_49508755delTTTA) detected in patient 1.

(a) WES data: IGV overview of reads for the patient and both parents. The 4-bp deletion is indicated by thin black lines. (b) Sanger sequencing confirmation of the de novo 4-bp deletion (black rectangle) in the patient and both parents.

Supplementary Figure 2 Short hairpin formation by surrounding sequence for the identified ADNP mutations, as predicted by Mfold (Zuker 2003).

Mutated positions are indicated by red rectangles.

Supplementary Figure 3 Relative gene expression levels.

(a) ABCF3, (b) ADNP, (c) ADNP2, (d) CCNC, (e) PLAGL2, (f) TMPO and (g) TP53 in lymphoblastoid cell lines from patients 1, 2, 6 and 8 and eight independent control samples. Expression values of two cDNA syntheses originating from two different RNA isolations per patient were compared to the values obtained from eight control individuals. The experiment was replicated once. ADNPwt primers cannot amplify the 4-bp deletion of patients 1, 4 and 6. *P < 0.05, **P < 0.01, ***P < 0.001, according to Linear Mixed Models.

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Supplementary Figure 4 Graphical overview of the five deletions (partially) affecting ADNP (blue vertical box) (UCSC Genome Browser).

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–4 and Supplementary Table 1 (PDF 1385 kb)

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Helsmoortel, C., Vulto-van Silfhout, A., Coe, B. et al. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat Genet 46, 380–384 (2014). https://doi.org/10.1038/ng.2899

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