Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders

Ober, C., Loisel, D.A., and Gilad, Y. (2008). Sex-specific genetic architecture of human disease. Nat. Rev. Genet. 9, 911-922. American Psychiatric Association and Kennedy, P.J. (2015). Understanding Mental Disorders: Your Guide to DSM-5. (Washington, DC: American Psychiatric Publishing). Fombonne, E. (2003). Epidemiological surveys of autism and other pervasive developmental disorders: an update. J. Autism Dev. Disord. 33, 365-382. Piton, A., Redin, C., and Mandel, J.L. (2013). XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. Am. J. Hum. Genet. 93, 368-383. Werling, D.M., and Geschwind, D.H. (2013). Sex differences in autism spectrum disorders. Curr. Opin. Neurol. 26, 146-153. Lehnhardt, F.G., Falter, C.M., Gawronski, A., Pfeiffer, K., Tepest, R., Franklin, J., and Vogeley, K. (2016). Sex-related cognitive profile in autism spectrum disorders diagnosed late in life: implications for the female autistic phenotype. J. Autism Dev. Disord. 46, 139-154. Piton, A., Gauthier, J., Hamdan, F.F., Lafreniere, R.G., Yang, Y., Henrion, E., Laurent, S., Noreau, A., Thibodeau, P., Karemera, L., et al. (2011). Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Mol. Psychiatry 16, 867-880. Sarachana, T., Xu, M., Wu, R.C., and Hu, V.W. (2011). Sex hormones in autism: androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism. PLoS ONE 6, e17116. Falconer, D.S. (1965). The inheritance of liability to certain diseases, estimated from incidence among relatives. Ann. Hum. Genet. 29, 51-76. Jacquemont, S., Coe, B.P., Hersch, M., Duyzend, M.H., Krumm, N., Bergmann, S., Beckmann, J.S., Rosenfeld, J.A., and Eichler, E.E. (2014). A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am. J. Hum. Genet. 94, 415-425. Turner, T.N., Sharma, K., Oh, E.C., Liu, Y.P., Collins, R.L., Sosa, M.X., Auer, D.R., Brand, H., Sanders, S.J., Moreno-De-Luca, D., et al. (2015). Loss of δ-catenin function in severe autism. Nature 520, 51-56. Chakravarti, A., and Turner, T.N. (2016). Revealing rate-limiting steps in complex disease biology: The crucial importance of studying rare, extreme-phenotype families. BioEssays 38, 578-586. Polyak, A., Rosenfeld, J.A., and Girirajan, S. (2015). An assessment of sex bias in neurodevelopmental disorders. Genome Med. 7, 94. Robinson, E.B., Lichtenstein, P., Anckarsater, H., Happe, F., and Ronald, A. (2013). Examining and interpreting the female protective effect against autistic behavior. Proc. Natl. Acad. Sci. USA 110, 5258-5262. Iossifov, I., O’Roak, B.J., Sanders, S.J., Ronemus, M., Krumm, N., Levy, D., Stessman, H.A., Witherspoon, K.T., Vives, L., Patterson, K.E., et al. (2014). The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216-221. De Rubeis, S., He, X., Goldberg, A.P., Poultney, C.S., Samocha, K., Cicek, A.E., Kou, Y., Liu, L., Fromer, M., Walker, S., et al.; DDD Study; Homozygosity Mapping Collaborative for Autism; UK10K Consortium (2014). Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209-215. Deciphering Developmental Disorders Study (2017). Prevalence and architecture of de novo mutations in developmental disorders. Nature 542, 433-438. Amir, R.E., Van den Veyver, I.B., Wan, M., Tran, C.Q., Francke, U., and Zoghbi, H.Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185-188. Migeon, B. (2014). Females Are Mosaics: X Inactivation and Sex Differences in Disease. Gend. Med. 4, 97-105. O’Roak, B.J., Vives, L., Fu, W., Egertson, J.D., Stanaway, I.B., Phelps, I.G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., et al. (2012). Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619-1622. O’Roak, B.J., Stessman, H.A., Boyle, E.A., Witherspoon, K.T., Martin, B., Lee, C., Vives, L., Baker, C., Hiatt, J.B., Nickerson, D.A., et al. (2014). Recurrent de novo mutations implicate novel genes underlying simplex autism risk. Nat. Commun. 5, 5595. Krumm, N., Turner, T.N., Baker, C., Vives, L., Mohajeri, K., Witherspoon, K., Raja, A., Coe, B.P., Stessman, H.A., He, Z.X., et al. (2015). Excess of rare, inherited truncating mutations in autism. Nat. Genet. 47, 582-588. Hashimoto, R., Nakazawa, T., Tsurusaki, Y., Yasuda, Y., Nagayasu, K., Matsumura, K., Kawashima, H., Yamamori, H., Fujimoto, M., Ohi, K., et al. (2016). Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder. J. Hum. Genet. 61, 199-206. Turner, T.N., Hormozdiari, F., Duyzend, M.H., McClymont, S.A., Hook, P.W., Iossifov, I., Raja, A., Baker, C., Hoekzema, K., Stessman, H.A., et al. (2016). Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. Am. J. Hum. Genet. 98, 58-74. C Yuen, R.K., Merico, D., Bookman, M., L Howe, J., Thiruvahindrapuram, B., Patel, R.V., Whitney, J., Deflaux, N., Bingham, J., Wang, Z., et al. (2017). Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat. Neurosci. 20, 602-611. Turner, T.N., Yi, Q., Krumm, N., Huddleston, J., Hoekzema, K.F., Stessman, H.A., Doebley, A.-L., Bernier, R.A., Nickerson, D.A., and Eichler, E.E. (2016). denovo-db: a compendium of human de novo variants. Nucleic Acids Res. 45, D804-D811. Retterer, K., Juusola, J., Cho, M.T., Vitazka, P., Millan, F., Gibellini, F., Vertino-Bell, A., Smaoui, N., Neidich, J., Monaghan, K.G., et al. (2016). Clinical application of whole-exome sequencing across clinical indications. Genet. Med. 18, 696-704. Li, H. (2013). Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv 1303.3997. Li, H. (2011). A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics 27, 2987-2993. Van der Auwera, G.A., Carneiro, M.O., Hartl, C., Poplin, R., Del Angel, G., Levy-Moonshine, A., Jordan, T., Shakir, K., Roazen, D., Thibault, J., et al. (2013). From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protocol. Bioinform. 11, 11.10.11-11.10.33. O’Leary, N.A., Wright, M.W., Brister, J.R., Ciufo, S., Haddad, D., McVeigh, R., Rajput, B., Robbertse, B., Smith-White, B., Ako-Adjei, D., et al. (2016). Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res. 44 (D1), D733-D745. Auton, A., Brooks, L.D., Durbin, R.M., Garrison, E.P., Kang, H.M., Korbel, J.O., Marchini, J.L., McCarthy, S., McVean, G.A., and Abecasis, G.R.; 1000 Genomes Project Consortium (2015). A global reference for human genetic variation. Nature 526, 68-74. Mills, R.E., Luttig, C.T., Larkins, C.E., Beauchamp, A., Tsui, C., Pittard, W.S., and Devine, S.E. (2006). An initial map of insertion and deletion (INDEL) variation in the human genome. Genome Res. 16, 1182-1190. McLaren, W., Gil, L., Hunt, S.E., Riat, H.S., Ritchie, G.R., Thormann, A., Flicek, P., and Cunningham, F. (2016). The Ensembl variant effect predictor. Genome Biol. 17, 122. Lek, M., Karczewski, K.J., Minikel, E.V., Samocha, K.E., Banks, E., Fennell, T., O’Donnell-Luria, A.H., Ware, J.S., Hill, A.J., Cummings, B.B., et al.; Exome Aggregation Consortium (2016). Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285-291. Deciphering Developmental Disorders Study (2015). Large-scale discovery of novel genetic causes of developmental disorders. Nature 519, 223-228. Quinlan, A.R., and Hall, I.M. (2010). BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841-842. Coe, B.P., Stessman, H.A.F., Sulovari, A., Geisheker, M.R., Bakken, T.E., Lake, A.M., Dougherty, J.D., Lein, E.S., Hormozdiari, F., Bernier, R.A., and Eichler, E.E. (2019). Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nat. Genet. 51, 106-116. Guo, H., Wang, T., Wu, H., Long, M., Coe, B.P., Li, H., Xun, G., Ou, J., Chen, B., Duan, G., et al. (2018). Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Mol. Autism 9, 64. Ware, J.S., Samocha, K.E., Homsy, J., and Daly, M.J. (2015). Interpreting de novo variation in human disease using denovolyzeR. Curr. Protoc. Hum. Genet. 87, 7.25.21-15. Smyth, G.K. (1998). Numerical Integration (London: Wiley). Hodge, R.D., Bakken, T.E., Miller, J.A., Smith, K.A., Barkan, E.R., Graybuck, L.T., Close, J.L., Long, B., Johansen, N., Penn, O., et al. (2019). Conserved cell types with divergent features in human versus mouse cortex. Nature 573, 61-68. Szklarczyk, D., Gable, A.L., Lyon, D., Junge, A., Wyder, S., Huerta-Cepas, J., Simonovic, M., Doncheva, N.T., Morris, J.H., Bork, P., et al. (2019). STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47 (D1), D607-D613. Uhlen, M., Fagerberg, L., Hallstrom, B.M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, A., Kampf, C., Sjostedt, E., Asplund, A., et al. (2015). Proteomics. Tissue-based map of the human proteome. Science 347, 1260419. McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., and DePristo, M.A. (2010). The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297-1303. Kircher, M., Witten, D.M., Jain, P., O’Roak, B.J., Cooper, G.M., and Shendure, J. (2014). A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310-315. Tukiainen, T., Villani, A.C., Yen, A., Rivas, M.A., Marshall, J.L., Satija, R., Aguirre, M., Gauthier, L., Fleharty, M., Kirby, A., et al.; GTEx Consortium; Laboratory, Data Analysis &Coordinating Center (LDACC)-Analysis Working Group; Statistical Methods groups-Analysis Working Group; Enhancing GTEx (eGTEx) groups; NIH Common Fund; NIH/NCI; NIH/NHGRI; NIH/NIMH; NIH/NIDA; Biospecimen Collection Source Site-NDRI; Biospecimen Collection Source Site-RPCI; Biospecimen Core Resource-VARI; Brain Bank Repository-University of Miami Brain Endowment Bank; Leidos Biomedical-Project Management; ELSI Study; Genome Browser Data Integration &Visualization-EBI; Genome Browser Data Integration &Visualization-UCSC Genomics Institute, University of California Santa Cruz (2017). Landscape of X chromosome inactivation across human tissues. Nature 550, 244-248. Snijders Blok, L., Madsen, E., Juusola, J., Gilissen, C., Baralle, D., Reijnders, M.R., Venselaar, H., Helsmoortel, C., Cho, M.T., Hoischen, A., et al.; DDD Study (2015). Mutations in DDX3X are a common cause of unexplained intellectual disability with gender-specific effects on Wnt signaling. Am. J. Hum. Genet. 97, 343-352. Kaiser, F.J., Ansari, M., Braunholz, D., Concepcion Gil-Rodriguez, M., Decroos, C., Wilde, J.J., Fincher, C.T., Kaur, M., Bando, M., Amor, D.J., et al.; Care4Rare Canada Consortium; University of Washington Center for Mendelian Genomics (2014). Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance. Hum. Mol. Genet. 23, 2888-2900. Rope, A.F., Wang, K., Evjenth, R., Xing, J., Johnston, J.J., Swensen, J.J., Johnson, W.E., Moore, B., Huff, C.D., Bird, L.M., et al. (2011). Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency. Am. J. Hum. Genet. 89, 28-43. Reijnders, M.R., Zachariadis, V., Latour, B., Jolly, L., Mancini, G.M., Pfundt, R., Wu, K.M., van Ravenswaaij-Arts, C.M., Veenstra-Knol, H.E., Anderlid, B.M., et al.; DDD Study (2016). De novo loss-of-function mutations in USP9X cause a female-specific recognizable syndrome with developmental delay and congenital malformations. Am. J. Hum. Genet. 98, 373-381. Haack, T.B., Hogarth, P., Kruer, M.C., Gregory, A., Wieland, T., Schwarzmayr, T., Graf, E., Sanford, L., Meyer, E., Kara, E., et al. (2012). Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am. J. Hum. Genet. 91, 1144-1149. Hamilton, M.J., Caswell, R.C., Canham, N., Cole, T., Firth, H.V., Foulds, N., Heimdal, K., Hobson, E., Houge, G., Joss, S., et al. (2018). Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability. J. Med. Genet. 55, 28-38. Geisheker, M.R., Heymann, G., Wang, T., Coe, B.P., Turner, T.N., Stessman, H.A.F., Hoekzema, K., Kvarnung, M., Shaw, M., Friend, K., et al. (2017). Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Nat. Neurosci. 20, 1043-1051. Gerber, S., Alzayady, K.J., Burglen, L., Bremond-Gignac, D., Marchesin, V., Roche, O., Rio, M., Funalot, B., Calmon, R., Durr, A., et al. (2016). Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome. Am. J. Hum. Genet. 98, 971-980. van de Leemput, J., Chandran, J., Knight, M.A., Holtzclaw, L.A., Scholz, S., Cookson, M.R., Houlden, H., Gwinn-Hardy, K., Fung, H.C., Lin, X., et al. (2007). Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet. 3, e108. Berridge, M.J. (1993). Inositol trisphosphate and calcium signalling. Nature 361, 315-325. O’Roak, B.J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B.P., Levy, R., Ko, A., Lee, C., Smith, J.D., et al. (2012). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246-250. Bernier, R., Golzio, C., Xiong, B., Stessman, H.A., Coe, B.P., Penn, O., Witherspoon, K., Gerdts, J., Baker, C., Vulto-van Silfhout, A.T., et al. (2014). Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158, 263-276. Talkowski, M.E., Mullegama, S.V., Rosenfeld, J.A., van Bon, B.W., Shen, Y., Repnikova, E.A., Gastier-Foster, J., Thrush, D.L., Kathiresan, S., Ruderfer, D.M., et al. (2011). Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder. Am. J. Hum. Genet. 89, 551-563. Berryer, M.H., Hamdan, F.F., Klitten, L.L., Moeller, R.S., Carmant, L., Schwartzentruber, J., Patry, L., Dobrzeniecka, S., Rochefort, D., Neugnot-Cerioli, M., et al. (2013). Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum. Mutat. 34, 385-394. SPARK Consortium. Electronic address: [email protected]; SPARK Consortium (2018). SPARK: A US cohort of 50,000 families to accelerate autism research. Neuron 97, 488-493. Hughes, J.F., and Page, D.C. (2015). The biology and evolution of mammalian Y chromosomes. Annu. Rev. Genet. 49, 507-527. Vollger, M.R., Dishuck, P.C., Sorensen, M., Welch, A.E., Dang, V., Dougherty, M.L., Graves-Lindsay, T.A., Wilson, R.K., Chaisson, M.J.P., and Eichler, E.E. (2019). Long-read sequence and assembly of segmental duplications. Nat. Methods 16, 88-94. Vollger, M.R., Logsdon, G.A., Audano, P.A., Sulovari, A., Porubsky, D., Peluso, P., Wenger, A.M., Concepcion, G.T., Kronenberg, Z.N., Munson, K.M., et al. (2019). Improved assembly and variant detection of a haploid human genome using single-molecule, high-fidelity long reads. Ann. Hum. Genet. 10.1111/ahg.12364.