{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:05:14Z","timestamp":1790168714119,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>SH2B1<\/jats:italic>\n                      encodes an adaptor protein involved in metabolic regulation and body\u2010weight control. Although\n                      <jats:italic>SH2B1<\/jats:italic>\n                      haploinsufficiency is a recognized contributor to obesity in 16p11.2 deletion syndrome, the relationship between rare monoallelic\n                      <jats:italic>SH2B1<\/jats:italic>\n                      variants and neurodevelopmental disorders (NDDs) remains poorly characterized.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed genetic and clinical data from a cohort of individuals with NDDs. The identified rare\n                      <jats:italic>SH2B1<\/jats:italic>\n                      variants were evaluated using bioinformatic tools and structural modeling. Functional consequences were assessed in\u00a0vitro through analyses of protein expression, subcellular localization, and extracellular signal\u2010regulated kinase (ERK) pathway activation via EGF stimulation assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Five individuals carrying rare monoallelic\n                      <jats:italic>SH2B1<\/jats:italic>\n                      variants presented with syndromic NDDs, including developmental delay, intellectual disability, autism spectrum disorder, dysmorphic features, and hyperphagia. Whole\u2010exome sequencing identified five heterozygous\n                      <jats:italic>SH2B1<\/jats:italic>\n                      variants, including three missense variants (c.52C&gt;G, p.Leu18Val; c.696A&gt;T, p.Arg232Ser; c.1141C&gt;T, p.Pro381Ser) and two truncating variants (c.90_91delTG, p.Cys30Ter; c.121_130dup, p.Arg44LeufsTer30); four of these arose\n                      <jats:italic>de novo<\/jats:italic>\n                      , whereas c.696A&gt;T (p.Arg232Ser) was maternally inherited. The individual carrying the maternally inherited p.Arg232Ser variant presented with elevated BMI and hyperphagia. In overexpression assays, truncating variants showed reduced protein expression and abnormal subcellular localization, whereas missense variants retained comparable protein levels but showed increased EGF\u2010induced ERK phosphorylation in\u00a0vitro, suggesting altered ERK signaling responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study further delineates the clinical spectrum associated with rare monoallelic\n                      <jats:italic>SH2B1<\/jats:italic>\n                      variants in individuals with NDDs. Functional analyses suggest variant\u2010specific effects on protein expression, subcellular localization, and ERK signaling responses. These findings support the consideration of\n                      <jats:italic>SH2B1<\/jats:italic>\n                      in genetic analyses of NDDs, particularly in individuals with co\u2010occurring metabolic abnormalities.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mgg3.70306","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T02:27:22Z","timestamp":1789957642000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Monoallelic\n                    <scp>\n                      <i>SH2B1<\/i>\n                    <\/scp>\n                    Variants in Neurodevelopmental Disorders: Phenotypic Expansion and Functional Characterization of Rare 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