{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:23:28Z","timestamp":1787027008250,"version":"build-2736575974"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T00:00:00Z","timestamp":1691366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000269","name":"Economic and Social Research Council","doi-asserted-by":"publisher","award":["ES\/T013435\/1"],"award-info":[{"award-number":["ES\/T013435\/1"]}],"id":[{"id":"10.13039\/501100000269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012116","name":"EMBL-EBI","doi-asserted-by":"publisher","award":["HICF-1009-003"],"award-info":[{"award-number":["HICF-1009-003"]}],"id":[{"id":"10.13039\/100012116","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Gain a better understanding of sex-specific differences in individuals with global developmental delay (GDD), with a focus on phenotypes and genotypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using the Deciphering Developmental Disorders (DDD) dataset, we extracted phenotypic information from 6,588 individuals with GDD and then identified statistically significant variations in phenotypes and genotypes based on sex. We compared genes with pathogenic variants between sex and then performed gene network and molecular function enrichment analysis and gene expression profiling between sex. Finally, we contrasted individuals with autism as an associated condition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified significantly differentially expressed phenotypes in males vs. females individuals with GDD. Autism and macrocephaly were significantly more common in males whereas microcephaly and stereotypies were more common in females. Importantly, 66% of GDD genes with pathogenic variants overlapped between both sexes. In the cohort, males presented with only slightly increased X-linked genes (9% vs. 8%, respectively). Individuals from both sexes harbored a similar number of pathogenic variants overall (3) but females presented with a significantly higher load for GDD genes with high intolerance to loss of function. Sex difference in gene expression correlated with genes identified in a sex specific manner. While we identified sex-specific GDD gene mutations, their pathways overlapped. Interestingly, individuals with GDD but also co-morbid autism phenotypes, we observed distinct mutation load, pathways and phenotypic presentation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study shows for the first time that males and females with GDD present with significantly different phenotypes. Moreover, while most GDD genes overlapped, some genes were found uniquely in each sex. Surprisingly they shared similar molecular functions. Sorting genes by predicted tolerance to loss of function (pLI) led to identifying an increased mutation load in females with GDD, suggesting potentially a tolerance to GDD genes of higher pLI compared to overall GDD genes. Finally, we show that considering associated conditions (for instance autism) may influence the genomic underpinning found in individuals with GDD and highlight the importance of comprehensive phenotyping.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fped.2023.1172154","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T14:17:41Z","timestamp":1691417861000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Sex difference contributes to phenotypic diversity in individuals with neurodevelopmental 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