TIGS 1255 No. of Pages 8

Forum Table 1 summarizes the characteristics of unclear whether this is related to its signal- and Cancer risk for ASD that are also risk genes ing function or a consequence of a second for cancers, extending the original finding independent PTEN activity, but this dual Share Risk Genes, that the PI3K-Akt-mTOR signaling axis function may provide the rationale for the (involving PTEN, FMR1, NF1, TSC1, and dominant role of PTEN in cancer and Pathways, and Drug TSC2) was associated with inherited risk autism. Other genes encoding common Targets for both cancer and ASD [6–9]. Recent tumor signaling pathways include MET8[1_TD$IF],[2_TD$IF] genome-wide exome-sequencing studies PTK7, and HRAS, while , AKT, mTOR, Jacqueline N. Crawley,1,2,* of de novo variants in ASD and cancer WNT, NOTCH, and MAPK are compo- Wolf-Dietrich Heyer,3,4 and have begun to uncover considerable addi- nents of signaling pathways regulating Janine M. LaSalle1,4,5 tional overlap. What is surprising about the the nuclear factors described above. genes in Table 1 is not necessarily the Autism is a neurodevelopmental number of risk genes found in both autism Autism is comorbid with several mono- and cancer, but the shared functions of genic neurodevelopmental disorders, disorder, diagnosed behaviorally genes in remodeling and including Fragile X (FMR1), Rett syndrome by social and communication genome maintenance, transcription fac- (MECP2), Phelan-McDermid (SHANK3), fi de cits, repetitive behaviors, tors, and pathways 15q duplication syndrome (UBE3A), and restricted interests. Recent leading to nuclear changes [7,8]. Chroma- neurofibromatosis (NF1), tuberous sclero- genome-wide tin remodeling factors important in altering sis (TSC1 and TSC2), and Cornelia de has revealed extensive overlap in nucleosome accessibility for transcription Lange syndrome (NIPBL and SMC1A) risk genes for autism and for can- and genome maintenance mechanisms (Table 1). Neurofibromatosis and tuberous cer. Understanding the genetic include CHD8, CHD7, CHD2, ARID1B, sclerosis are directly associated with commonalities of autism(s) and and ATRX. ATRX may exert a more spe- tumors, but such tumors are benign and cancer(s), with a focus on mecha- cific function in telomere maintenance, rarely associated, if at all, with malignan- nistic pathways, could lead to analogous to other Swi2/Snf2 family fac- cies. However, mutations in NF1, TSC1, repurposed therapeutics. tors, such as ERCC6, RAD54, HTLF, or TSC2 enhance the risk for developing SHPRH,orRAD16, which function in ded- cancer [6]. Notably, NF1, TSC1, and icated DNA repair pathways. TSC2 function like PTEN in the AKT path- Autism is a neurodevelopmental disor- involved in histone methyltransferase way of mTOR control. Mutations in tran- der, diagnosed by behavioral symptoms reactions important in setting the histone scriptional factor genes also mediate including impaired social interactions and code include ASHL1, EHMT1, EHMT2, downstream signaling pathways that communication, repetitive behaviors, and KMT2C, KMT2D, and SUV420H1. include key proteins implicated in cell pro- restricted interests [1]. Extraordinarily PHF2, KDM5B, and KDM6B are histone liferation or differentiation pathways impli- high heritability for autism spectrum dis- demethylases, and MACROD2 encodes a cated in cancer and autism, such as order (ASD) has been detected in twin nuclear factor regulated by a metabolite of mTOR, RAS GTPases, MAP kinases, studies, with a range of 50–90% concor- histone deacetylation. modifica- AKT, EIF4E, WNT, ERK, PI3K, and dance between monozygotic twins, tions to histones and other proteins are CHD8. A risk originally identified in compared with 0–30% between dizy- implicated by the risk genes CUL3, individuals with cancer may present as a gotic twins and siblings, and approxi- HERC2, MIB1, TBL1XR1, TRIP12, de novo mutation in a small number of mately 1% prevalence in the general UBE3A, and WAC. Transcription factors individuals with ASD, or may be implicated population, along with a high male:female genetically implicated in both autism and in ASD through interactome analysis of ratio [2]. International consortia searching cancer include ADNP, PAX5, FOXP1, interrelated genes and interacting pro- for the genetic causes of ASD quickly TCF7L2, and TBLXR1. Interestingly, these teins, such as within a signaling pathway recognized that autism is not a mono- nuclear factors are downstream of several (Table 1). genic disorder. Hundreds of de novo key signal transduction pathways also and familial risk genes, copy number var- genetically implicated in ASD and cancer, What does tumor cell proliferation have in iants, and epigenetic modifiers have been including PTEN [7].PTENfunctions in the common with brain development and identified through linkage analysis, AKT signaling pathway, where its phospha- neuronal synapse formation? Similar to genome wide-association studies, and tase activity is needed for AKT downregu- cancers, ‘autisms’ are best conceptual- exon and whole-genome sequencing of lation. Nuclear PTEN also regulates ized in the plural. ASD encompasses a individuals with ASD over the past 2 years recombinational DNA repair, a key genome broad range of putative causes, symptom [2–5]. maintenance pathway (see below). It is presentations, and outcomes, including

Trends in Genetics, Month Year, Vol. xx, No. yy 1 TIGS 1255 No. of Pages 8 25363768 Refs (PMID) 25891009 24779060 24768552 25891009 chromatin regulation Cancer Susceptibility or Pathway p53, WNTProteoglycans 25891009 25863124 cancer Breast cancer, telomeres Chromatin regulation 25891009 chromatin regulation chromatin regulation [ 6 _ T D $ I F ] Van der Siris syndrome ESR1, WNT; prostate [ 7 _ T D $ I F ] – n fi Autism, susceptibility WNT signaling, Autism-Related Neu- rodevelopmental Syndrome Autism, susceptibility Chromatin regulation 26402605 Helsmoortel- Aa syndrome Long (Electrocardiographic) QT Syndrome 4 Cof Autism, susceptibility Lysine degradation 26402605 Alpha-thalassemia/ mental retardation syndrome encephalopathy, childhood-onset CHARGE syndrome WNT signaling, Autism, susceptibility WNT signaling, KLHL3, NEDD8, KEAP1, RBX1, CASP8 Proteins DNMT3L, DNMT3B, UHRF1 SMARCA4, SMARCC2, ARID1A DMD, DCTN4, ACTF1 ARID1A, SMARCA2, RELB, SMAD9, ASF1A SMAD7, HIST1H3A CBX5, DAXX, HDAC1, SMC1A, SMC3 SUMO1, PARK7 Epileptic CHD8, PBRM1, SMARCC1, SMARCC2, SMARCE1 RBBP5, WDR5, CTNNB1, USF1, CTCF de [ 8 _ T D $ I F ] at telomeres ligase – a [ 3 _ T D $ I F ] Cancer cally methylating Lys-36 of methylation; essential for fi Protein Function Interacting novo establishment of DNA methylation patterns during development mediate some neuroprotective peptide VIP-associated effects proteins to cytoskeletal elements and regulates cell motility, activation, proliferation, and contact remodeling complex speci histone H3 (H3K36me) motor protein that acts in heterochromatin and motor protein that acts aschromatin a remodeling factor and transcriptional regulator, and also in DNA repair motor protein that acts aschromatin a remodeling factor and transcriptional regulator motor protein that acts aschromatin a remodeling factor and transcriptional regulator RING-based BCR (BTB-CUL3- RBX1) E3 ubiquitin complex Location 2p23.3 Required for genome-wide 20q13.13 Potential . May 6q25.3 Subunit1q22 of SWI/SNF chromatin Histone methyltransferase Xq21.1 SWI/SNF ATP-dependent DNA 15q26.1 SWI/SNF ATP-dependent DNA 8q12.2 SWI/SNF ATP-dependent DNA 14q11.2 SWI/SNF ATP-dependent DNA [ 5 _ T D $ I F ] Name Human DNA (5-cytosine)- methyltransferase 3A Activity-dependent neuroprotector Ankyrin 2, Neuronal 4q25AT Rich Interacting Domain 1B (SWI1- like), BRG1-Binding Attaches integral membrane protein Lysine N-Methyltransferase 2H RAD54, Alpha Thalassemia/Mental Retardation Syndrome X-linked Chromodomain DNA Binding Protein 2, ATP-dependent helicase Chromodomain Helicase DNA Binding Protein 7, ATP-dependent helicase Chromodomain Helicase DNA Binding Protein 8, HELSNF1, AUTS18 Cullin 3 2q36.2 Core component of multiple cullin- Gene Symbol Gene DNMT3A ADNP ANK2 ARID1B ASH1L ATRX CHD2 CHD7 CHD8 CUL3 Table 1. Characteristics of Risk Genes Implicated in Both Autism and

2 Trends in Genetics, Month Year, Vol. xx, No. yy TIGS 1255 No. of Pages 8 25363768 Refs (PMID) 17583556 24779060 26402605 24768552 24779060 24768552 signaling, cervical b chromatin regulation Cancer Susceptibility or Pathway NOTCH signaling, translation regulation NOTCH, lysine degradation and colon cancer Transcription-coupled DNA repair Class I MHC Ag presentation and processing pathway dence ASD fi Autism, susceptibility Lung cancerAutism, susceptibility Retinoblastoma, 26402605 Autism-Related Neu- rodevelopmental Syndrome Down syndrome, mental retardation, autosomal dominant 7 Kleefstra syndrome Cellular senescence, Autism, susceptibility TGF High con candidate gene Autism, susceptibility WNT, Notch signaling 25363768 Mental retardation, autosomal recessive 38 (MRT38) Costello syndrome Oncogene, MAPK UPF1, UPF2, INTS1, INTS3, INTS8 ARID1B, RB1, HDAC1, PAX9 Proteins HIPK2, SFN, YWHAB, YWHAE, DCAF MDM2, p53, SUV39H1, HIST1H3A, CTBP1, SUV39H1 ERBB2, SMAD2, SMAD3, NRG2, PKP4 Cockayne's Syndrome-A/ ERCC8 TFIIH, SMARCA5/ SNF2H, BAZ1B/ WSTF, SF3B1, DEK, MYO1C, MYBBP1A, DDX21, KIAA1530/ UVSSA. CTBP1, FOXP2, FOXP4, , NCOR2 UBE3A, SUMO1, RNF8, BRCA1 RAF1, SOS1, RIN1, ABL2, CAV1 -B signaling and k ammatory cytokine fl involved in small nuclear RNA transcription and processing, tumor suppressor demethylates K4 of histone H3 Protein Function Interacting in cell survival, proliferation,differentiation and H3K9me and H3K9me2 in euchromatin , inhibits NOD2- dependent NF- proin secretion motor protein that acts in transcription-coupled DNA repair and putative tumor suppressor regulates repair proteins on damaged , regulates replication fork progression that bind GTP and GDP,intrinsic with GTPase activity 1q32.1 Histone demethylase that 13q14.3 Component of Integrator complex, Chromosome Location 21q22.13 Serine/threonine kinase implicated 9q34.3 Histone methyltransferase of 5q12.3 Acts as adapter for ERBB2 10q11.23 SWI/SNF ATP-dependent DNA 15q13 E3 ubiquitin-protein ligase that 11p15.5 RAS oncogene family members city fi [ 5 _ T D $ I F ] Name Human Dual-speci tyrosine phosphorylation- regulated kinase 1A Euchromatic Histone-Lysine N- Methyltransferase, KMT1D, CLP ERBB2 Interacting protein Cockayne's Syndrome B Forkhead box P1HECT 3p13 And RLD Domain Containing E3 Ubiquitin Protein Ligase 2 Forkhead box transcription factor Harvey Rat Sarcoma Viral Oncogene Homolog, p21RAS Integrator complex subunit 6, DICE1 Gene Symbol Gene KDM5B DYRK1A EHMT1 ERBB2IP ERCC6 FOXP1 HERC2 HRAS INTS6 Table 1. (continued)

Trends in Genetics, Month Year, Vol. xx, No. yy 3 TIGS 1255 No. of Pages 8 24768552 Refs (PMID) 25418537 19548256 24768552 Colorectal and gastric cancer Cancer Susceptibility or Pathway lymphoblastic, susceptibility (ALL3), WNT pathway renal carcinoma (RCCP), glioma, Leukemia, juvenile myelomonocytic (JMML), Ras, MAPK pathways bromatosis, fi Cornelia de Lange syndrome 1 Autism-Related Neu- rodevelopmental Syndrome Autism, susceptibility Leukemia, acute Autism, susceptibility Chromatin regulation 25363768 Autism, susceptibility Chromatin regulation 26402605 Autism, susceptibility Lysine degradationKabuki syndrome 26402605 Lysine degradation 25891009 Rett syndrome Chromatin regulation 24779060 Autism, association Hereditary papillary type 1 Autism, susceptibility Notch signalingNeuro 26402605 Proteins EP300, CEBBP, ETS1, TBP, EBF1 ESR1, CSNK2B, HIST1H3D TP53, RBBP7, SUZ12, EZH2 NCOA6, ASCL2, ASH2L, AK1, TSC22D1 ESR1, PAXIPI, RBBP5, SMAD1, SMAD9 SIN3A, SMARCA2, ATRX HGF, CBL, GRB2, UBC, PTPN1 NOTCH1, UBC, UBE2N, DAPK1 GADD45A, SMARCC1, SMARCD1, GTF2A1 SMC3, HDAC1, HDAC2, ATAD5 promoter interactions in – cally demethylates K27 of fi Protein Function Interacting involved in B cell development, neural development, spermatogenesis; recurrent translocations in lymphoma speci histone H3 recruited to trimethylated Lys-4 of histone H3 (H3K4me3) at rDNA promoters and promotes expression of rDNA methylates K4 of histone H3 K4me transcriptional regulator that binds to methylated DNA transduces signals from extracellular matrix by binding HGF, activates RAS-ERK, AKT, or PLC pathways mediates ubiquitination of Delta receptors, which act as ligandsNotch of proteins pathway enhancer Drosophila Chromosome Location 9p13.2 Paired box transcription factor 17p13.1 Histone demethylase that 9q22.31 Lysine histone demethylase [ 9 _ T D $ I F ] 7q36.1 Histone methyltransferase that Xq28 Chromosomal protein and 7q31 Receptor tyrosine kinase that 18q11.2 E3 ubiquitin-protein ligase that 5p13.2 Cohesion protein that facilitates 17q11.2 Negative regulator of RAS signal c c c fi fi fi bromin 1, [ 5 _ T D $ I F ] Name Human fi Paired Box 5, ALL3, BSAP Lysine (K)-Speci Demethylase 5B, JARID1B Lysine (K)-Speci Demethylase 6B, JMJD3 PHD Finger Protein 2 Lysine (K)-Speci Methyltransferase 2C, MLL3 MLL2Methyl CpG binding protein 2, AUTSX3 12q13.12 Histone methyltransferase of AUTS9, HGFR, c-Met Mindbomb E3 Ubiquitin Protein Ligase 1 Nipped-B Homolog (Drosophila), CDLS1 NFNS Neuro Gene Symbol Gene PAX5 KDM6B PHF2 KMT2C KMT2D MECP2 MET MIB1 NIPBL NF1 Table 1. (continued)

4 Trends in Genetics, Month Year, Vol. xx, No. yy TIGS 1255 No. of Pages 8 Refs (PMID) 24768552 25418537 24768552 26069883 / Cancer Susceptibility or Pathway Cowden syndrome, glioblastoma, mTOR pathway, recombinational DNA repair presentation and processing Genome maintenance, colorectal cancer Genome maintenance 24768552 metabolism dence ASD fi Autism, susceptibility NOTCH, Rho GTPase 26402605 Autism-Related Neu- rodevelopmental Syndrome Macrocephaly/autism syndrome Autism, susceptibility Class I MHC Ag Autism, susceptibility WNT and AKT signaling 26402605 Cornelia de Lange syndrome 2 High con candidate gene Autism, susceptibility Lysine degradation 26402605 Autism, susceptibility NOTCH1, PPAR Autism, susceptibility WNT signaling 25363768 Autism, susceptibility PI-3K 25363768 RAC1, RAC3, HCRTR2, DISC1, CDC5L Proteins NEDD4, AKT1, PTK2, UBC, SLC9A3R1 MYC, TRADD, SMARCC1, CDKN2A, DVL1, DVL2, DVL3, CTNNB1, WNT9B SMC3, RAD21, STAG2, SMC2, SSU72 SMC1A, SMC4, NCAPH, NCAPH2, NCAPD2 TP53BP1, NCOA2, YWHAQ TBL1X, HDAC3, NCOR1, THRB, CACNA1C, CACNA1E TCF7, CTNNB1, RUVBL2 TP53, AGO1, CDK4, EIF2C1 city protein phosphatase cally trimethylates K20 of fi fi GTP, coordinates cell matrix and cytoskeletal rearrangements necessary for cell migration and cell growth Protein Function Interacting speci in ubiquitin fusion degradation pathway, suppresses spreading of canonical and noncanonical Wnt signaling pathways, functions in cell adhesion, cell migration, cell polarity, proliferation, actin cytoskeleton reorganization, and apoptosis cycle and DNA repair condensation and DNA repair speci histone H4 ubiquitin/19S complex to nuclear hormone receptors, degradation of N-Cor for transcriptional activation containing transcription factor that has key role in Wntpathway signaling silencing by both miRNAs and short interfering RNAs (siRNAs) Chromosome Location 2q36.3 E3 ubiquitin-protein ligase involved [ 1 0 _ T D $ I F ] 6p21.1 Inactive tyrosine kinase involved in Xp11.22 Chromosome cohesion during cell 9q31.1 Critical for mitotic chromosome 11q13.2 Histone methyltransferase that 3q26.32 F-box-like protein recruits 10q25.2 High mobility group (HMG) box- 22q13.1 Has role in RNA-mediated gene 5p15.2 Promotes exchange of GDP by c fi [ 5 _ T D $ I F ] Name Human Thyroid interacting protein, E3 MMAC1Protein Tyrosine 10q23.3Kinase 7 (Inactive) Tumor suppressor, dual- Structural Maintenance Of Chromosomes 1A Structural Maintenance Of Chromosomes 2 Lysine N- Methyltransferase 5B, KMT5B Transducin (Beta)- Like 1 X-linked Receptor 1, TBLR1, IRA1 T-Cell-Speci Transcription Factor 4 Trinucleotide Repeat Containing 6B Trio Rho Guanine Nucleotide Exchange Factor Gene Symbol Gene TRIP12 PTEN PTK7 SMC1A SMC2 SUV420H1 TBL1XR1 TCF7L2 TNRC6B TRIO Table 1. (continued)

Trends in Genetics, Month Year, Vol. xx, No. yy 5 TIGS 1255 No. of Pages 8 Refs (PMID) 24779060 Cancer Susceptibility or Pathway Class I MHC Ag presentation and processing, PEDF, estrogen Autism-Related Neu- rodevelopmental Syndrome Tuberous sclerosis MTOR, AKT pathway 24768552 Tuberous sclerosis MTOR, AKT pathway 24768552 Angelman syndrome (del), Dup15q syndrome (dup) Autism, susceptibility Chromatin regulation 26402605 Proteins SMARCE1, THRB, PSMC5, TMEFF2 TSC2, MAPK1, RHEB, AKT1, IKBKB TSC1, RHEB, YWHAZ, YWAB RAD23A, HERC2, RING1B, ESR1, RARA UBC, UBQLN4, POL2R2A ed by PIMD numbers in the far right column. Information describing each gene was assembled from fi Protein Function Interacting Ub-chromatin at damaged chromosomes signaling signaling cofactor for nuclear hormone receptors, maternal mutations cause Angelman syndrome, imprinted in brain; in cervical cancer degrades p53 in presence of E6 transcription and histone H2B monoubiquitination at K120 Chromosome Location 9q34.13 Negative regulation of mTORC1 16p13.3 Negative regulation of mTORC1 15q11.2 E3 ubiquitin-protein ligase, 10p12.1 Acts as linker between gene ed as autism risk genes from publications in the cited references identi fi [ 5 _ T D $ I F ] Name Human Ubiquitin-Protein Ligase For Arf Tuberous Sclerosis 1, LAM Tuberous Sclerosis 2, TSC4, LAM E6AP Ubiquitin- Protein Ligase, ANCR WW Domain Containing Adaptor With Coiled-Coil Gene Symbol Gene TSC1 TSC2 UBE3A WAC Genes summarized here were identi sources compiled within GeneCards and OMIM databases. Table 1. (continued) a

6 Trends in Genetics, Month Year, Vol. xx, No. yy TIGS 1255 No. of Pages 8

both macrocephaly and microcephaly, DNA replication, differentiation, and cell similarities can be leveraged into thera- suggesting deficits in the cellular commit- cycle phasing will greatly increase the risk peutic strategies. It may be possible to ment to proliferation versus differentiation, of mutations targeted to these genes repurpose available cancer drugs with similar to cancer. This difference may be in encoding critical brain functions. Tran- reasonable safety profiles as targeted the life stage of cellular proliferation. Errors scription-coupled repair, the pathway treatments for ASD. For example, evalua- associated with genome maintenance defined by ERCC6, is of particular impor- tion of a rapamycin analog in patients with during fetal life may occur at critical time tance for terminally differentiated cells and tuberous sclerosis included outcome periods for proliferation of neuronal pre- long transcription units. Overall, too little is measures for ASD features, along with cursors that affect prenatal brain develop- known about DNA repair in terminally dif- seizures, sleep disturbances, and aca- ment, resulting in neurodevelopmental ferentiated cells and more studies are demic skills (NCT01289912, Clinical- disorders, whereas errors more com- needed to evaluate other pathways, such Trials.gov). Stratifying individuals with monly occur during adult life in cell types as recombinational DNA repair in differen- ASD who harbor a risk gene for autism susceptible to tumors. Biological mecha- tiated cells and somatic genomic instabil- that is also a risk gene for cancer may nisms with potential commonalities ity in neurons. Thus, similar to cancer, the enable therapeutic development of per- between genes implicated in both cancers inherited risk for autism may be com- sonalized medicines based on the specific and autisms may be revealed from closer pounded by further somatic mutations causal mutation. investigation of the specific actions of associated with mutations in known risk genes and converging pathways identified genes that may be biased for genes with Acknowledgements in both [8]. For example, UBE3A, which is neuronal functions. Supported by Autism Speaks Targeted Award #8703 duplicated in approximately 1–2% of ASD, (J.N.C.), NINDS 1R01NS085709-01 (J.N.C.), NICHD encodes the ubiquitin E3 ligase protein The functional overlap of genes and path- U54 HD079125 (J.N.C.), NCI CA92276 (W.D.H.), NCI E6-AP, first named as an E6 interacting ways between autism and cancer would CA154920 (W.D.H.), NIHGMS GM58015 (W.D.H.), DOD W81XWH-14-1-0435 (W.D.H.), NINDS protein that degrades p53 in human cer- suggest that individuals with autism carry R01NS081913 and R01NS076263 (J.M.L.), NIEHS vical cancer [10]. a higher cancer risk. While there is some R01ES021707 and 2P01ES011269 (J.M.L.). epidemiological evidence of higher cancer The intersection between autism and can- risk in children, adolescents, and young 1MIND Institute, School of Medicine, University of cer in genome maintenance pathways is adults with ASD [9,12], the absolute num- California Davis, Sacramento, CA 95817, USA 2Department of Psychiatry and[1_TD$IF] Behavioral Sciences, novel and particularly compelling. A large ber of cases is low and more studies need School of Medicine, University of California Davis, cohort of autism and cancer genes affect to be conducted, particularly in adults, Sacramento, CA 95817, USA 3 [1_TD$IF] genome maintenance, including signaling because cancer incidence is significantly Department of Microbiology and Molecular Genetics, University of California Davis, Davis, CA 95616, USA molecules (PTEN), DNA repair factors correlated with age. 4Comprehensive Cancer Center, University of California (ERCC6 and SMARCA2), structural chro- Davis, Sacramento, CA, 95817, USA 5 [1_TD$IF] mosome components, such as cohesins Mouse models with mutations in many of Department of Medical Microbiology and Immunology and Genome Center, University of California Davis, Davis, (NIPBL, SMC1A, and SMC2), factors these genes have been widely used in CA 95616, USA needed for Alternative Lengthening of both cancer and autism research. Some Telomeres (ATRX), and post-translational of these mutant mouse models recapitu- *Correspondence: [email protected] (J.N. Crawley). http://dx.doi.org/10.1016/j.tig.2016.01.001 modifiers (TRIP12, UBE3A, and HERC2). late behavioral and biological features of

The functional overlap goes beyond this autism [13]. These model systems are References common gene set, because genomes proving useful in understanding the con- 1. Lord, C. and Bishop, S.L. (2015) Recent advances in fi autism research as reflected in DSM-5 criteria for autism from individuals with ASD show muta- sequences of speci c mutations on over- spectrum disorder. Annu. Rev. Clin. Psychol. 11, 53–70 tional hotspots and a high incidence of growth of brain regions, unusual patterns 2. Bourgeron, T. (2015) From the genetic architecture to copy number variations. These genetic of white matter connectivity, aberrant synaptic plasticity in autism spectrum disorder. Nat. Rev. 16, 551–563 events signal pathological outcomes of numbers of synapses, and altered mor- 3. Iossifov, I. et al. (2014) The contribution of de novo DNA replication stress. Many neuron-spe- phology of dendritic spines, in parallel to coding mutations to autism spectrum disorder. Nature 515, 216–221 cific genes are rather large, with primary understanding cell proliferation, , 4. De Rubeis, S. et al. (2014) Synaptic, transcriptional and transcripts in the Mbp range. Such genes DNA repair, and epigenetic causes in chromatin genes disrupted in autism. Nature 515, 209–215 are at particular risk for transcription–DNA malignancies. 5. Geschwind, D.H. and State, M.W. (2015) Gene hunting in fl fi autism spectrum disorder: on the path to precision medi- replication con icts that underpin a signi - cine. Lancet Neurol. 14, 1109–1120 cant amount of genome instability [11]. Considerable translational value can be 6. Martincorena, I. and Campbell, P.J. (2015) Somatic While these genes are typically transcribed gained from a new focus on understand- mutation in cancer and normal cells. Science 349, 1483–1489 only in terminally differentiated cells, any ing the genetic commonalities of autism(s) 7. Zhou, J. and Parada, L.F. (2012) PTEN signaling in autism miscoordination of transcriptional control, and cancer(s). Importantly, mechanistic spectrum disorders. Curr. Opin. Neurobiol. 22, 873–879

Trends in Genetics, Month Year, Vol. xx, No. yy 7 TIGS 1255 No. of Pages 8

8. Pinto, D. et al. (2014) Convergence of genes and cellular 10. LaSalle, J.M. et al. (2015) Epigenetic regulation of UBE3A 12. Chiang, H-L. et al. (2015) Risk of cancer in children, ado- pathways dysregulated in autism spectrum disorders. Am. and roles in human neurodevelopmental disorders. Epige- lescents, and young adults with autistic disorder. J. Pediatr. J. Hum. Genet. 94, 677–694 nomics 7, 1213–1218 166, 418–423 9. Crespi, B. (2011) Autism and cancer risk. Autism Res. 4, 11. Aguilera, A. and Garcia-Muse, T. (2013) Causes of genome 13. Kazdoba, T.M. et al. (2016) Behavioral phenotypes of genetic 302–310 instability. Annu. Rev. Genet. 47, 1–32 mouse models of autism. Genes Brain Behav. 15, 7–26

8 Trends in Genetics, Month Year, Vol. xx, No. yy