Among autistic individuals, a subphenotype with brain enlargement disproportionate to height (autism with disproportionate megalencephaly, or ASD-DM) seen at three years of age is associated with co-occurring intellectual disability and poorer prognoses later in life. However, many of the genes contributing to ASD-DM have yet to be delineated. In this study, we aim to identify additional ASD-DM associated genes to better define the genetic etiology of this subphenotype of autism. Here, we expand the previously studied sample size of ASD-DM 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 153 candidate ASD-DM genes harboring de novo protein-impacting variants. Our findings include thirteen high confidence autism genes and seven genes previously associated with DM. Five impacted genes have previously been associated with both autism and DM, including CHD8 and PTEN. By performing functional network analysis, we also narrowed in on additional candidate genes, including one previously implicated in ASD-DM (PIK3CA) as well as 184 additional genes previously implicated in ASD or DM alone. Using zebrafish as a model, we performed CRISPR gene editing to generate knockout animals for seven of candidate genes and assessed head-size and induced seizure activity differences. From this analysis, we identified significant morphological changes in zebrafish knockout models of two genes, ythdf2 and ryr3. While zebrafish knockout mutants model haploinsufficiency of assayed genes, we identified a de novo tandem duplication impacting YTHDF2 in an ASD-DM proband. Therefore, we also transiently overexpressed YTHDF2 by injection of in vitro transcribed human mRNA to simulate the patient-identified duplication. Following this, we observed increased head and brain size in the YTHDF2 overexpression zebrafish matching that of the proband, providing a functional link between YTHDF2 mutations and DM. Though discovery of additional mutations of ASD-DM candidate genes are required in order to fully elucidate the genetics associated with this severe form of autism, our study was able to provide support for YTHDF2 as a novel putative ASD-DM gene.