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However, many of the genes contributing to ASD\u2010DM have yet to be delineated. In this study, we identified additional ASD\u2010DM candidate genes with the aim to better define the genetic etiology of this subphenotype of autism. We expanded the previously studied sample size of ASD\u2010DM individuals ten fold by including probands from the Autism Phenome Project and Simons Simplex Collection, totaling 766 autistic individuals meeting the criteria for megalencephaly or macrocephaly and revealing 154 candidate ASD\u2010DM genes harboring\n                    <jats:italic>de novo<\/jats:italic>\n                    protein\u2010impacting variants. Our findings include 14 high confidence autism genes and seven genes previously associated with DM. Five impacted genes have previously been associated with both autism and DM, including\n                    <jats:italic>CHD8<\/jats:italic>\n                    and\n                    <jats:italic>PTEN<\/jats:italic>\n                    . By performing functional network analysis, we expanded to additional candidate genes, including one previously implicated in ASD\u2010DM (\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    ) as well as 184 additional genes connected with\u00a0ASD or DM alone. Using zebrafish, we modeled a\n                    <jats:italic>de novo<\/jats:italic>\n                    tandem duplication impacting\n                    <jats:italic>YTHDF2<\/jats:italic>\n                    , encoding an N6\u2010methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A)\u2010mRNA reader, in an ASD\u2010DM proband. Testing zebrafish CRISPR knockdown led to reduced head\/brain size, while overexpressing\n                    <jats:italic>YTHDF2<\/jats:italic>\n                    resulted in increased head\/brain size matching that of the proband. Single\u2010cell transcriptomes of\n                    <jats:italic>YTHDF2<\/jats:italic>\n                    gain\u2010of\u2010function larvae point to reduced expression of Fragile\u2010X\u2010syndrome\u2010associated FMRP\u2010target genes globally and in the developing brain, providing insight into the mechanism underlying autistic phenotypes. We additionally discovered a variant impacting a different gene encoding an m\n                    <jats:sup>6<\/jats:sup>\n                    A reader,\n                    <jats:italic>YTHDC1<\/jats:italic>\n                    , in our ASD\u2010DM cohort. Though we highlight only two cases to date, our study provides support for the m\n                    <jats:sup>6<\/jats:sup>\n                    A\u2010RNA modification pathway as potentially contributing to this severe form of autism.\n                  <\/jats:p>","DOI":"10.1002\/aur.3314","type":"journal-article","created":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T01:59:56Z","timestamp":1738288796000},"page":"966-982","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>\n                      m\n                      <sup>6<\/sup>\n                      A\n                    <\/scp>\n                    \u2010\n                    <scp>mRNA<\/scp>\n                    Reader\n                    <scp>\n                      <i>YTHDF2<\/i>\n                    <\/scp>\n                    Identified as a Potential Risk Gene in Autism With Disproportionate Megalencephaly"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4288-4567","authenticated-orcid":false,"given":"Sierra S.","family":"Nishizaki","sequence":"first","affiliation":[{"name":"Genome Center University of California  Davis CA USA"},{"name":"Autism Research Training Program University of California  Davis CA USA"},{"name":"Department of Psychiatry and Behavioral Sciences University of California  Davis CA USA"},{"name":"MIND Institute University of California  Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0489-9776","authenticated-orcid":false,"given":"Nicholas K.","family":"Haghani","sequence":"additional","affiliation":[{"name":"Genome Center University of California  Davis CA USA"},{"name":"MIND Institute University of California  Davis CA USA"},{"name":"Department of Biochemistry &amp; Molecular Medicine University of California  Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9007-3355","authenticated-orcid":false,"given":"Gabriana N.","family":"La","sequence":"additional","affiliation":[{"name":"Genome Center University of California  Davis CA USA"},{"name":"MIND Institute University of California  Davis CA USA"},{"name":"Department of Biochemistry &amp; Molecular Medicine University of California  Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6665-4512","authenticated-orcid":false,"given":"Natasha Ann F.","family":"Mariano","sequence":"additional","affiliation":[{"name":"Genome Center University of California  Davis CA USA"},{"name":"MIND Institute University of California  Davis CA USA"},{"name":"Department of Biochemistry &amp; Molecular Medicine University of California  Davis CA USA"},{"name":"Postbaccalaureate Research Education Program University of California  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4875-818X","authenticated-orcid":false,"given":"Jos\u00e9 M.","family":"Uribe\u2010Salazar","sequence":"additional","affiliation":[{"name":"Genome Center University of California  Davis CA USA"},{"name":"MIND Institute University of California  Davis CA USA"},{"name":"Department of Biochemistry &amp; Molecular Medicine University of California  Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3142-7886","authenticated-orcid":false,"given":"Gulhan","family":"Kaya","sequence":"additional","affiliation":[{"name":"Genome Center University of California  Davis CA USA"},{"name":"MIND Institute University of California  Davis CA USA"},{"name":"Department of Biochemistry &amp; Molecular Medicine University of California  Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Regester","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences University of California  Davis CA USA"},{"name":"MIND Institute University of California  Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1129-3211","authenticated-orcid":false,"given":"Derek Sayre","family":"Andrews","sequence":"additional","affiliation":[{"name":"Autism Research Training Program University of California  Davis CA USA"},{"name":"Department of Psychiatry and Behavioral Sciences University of California  Davis CA USA"},{"name":"MIND Institute University of California  Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1021-4515","authenticated-orcid":false,"given":"Christine Wu","family":"Nordahl","sequence":"additional","affiliation":[{"name":"Autism Research Training Program University of California  Davis CA USA"},{"name":"Department of Psychiatry and Behavioral Sciences University of California  Davis CA USA"},{"name":"MIND Institute University of California  Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1525-8744","authenticated-orcid":false,"given":"David G.","family":"Amaral","sequence":"additional","affiliation":[{"name":"Autism Research Training Program University of California  Davis CA USA"},{"name":"Department of Psychiatry and Behavioral Sciences University of California  Davis CA USA"},{"name":"MIND Institute University of California  Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8502-5420","authenticated-orcid":false,"given":"Megan Y.","family":"Dennis","sequence":"additional","affiliation":[{"name":"Genome Center University of California  Davis CA USA"},{"name":"Autism Research Training Program University of California  Davis CA USA"},{"name":"MIND Institute University of California  Davis CA USA"},{"name":"Department of Biochemistry &amp; 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