{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T06:12:21Z","timestamp":1778739141137,"version":"3.51.4"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>\n                    Rett syndrome, related to methyl-CpG binding protein\n                    <jats:italic>2<\/jats:italic>\n                    (\n                    <jats:italic>MECP2<\/jats:italic>\n                    )\n                    <jats:italic>,<\/jats:italic>\n                    primarily affects females, though recent studies have identified additional causative genes, such as IQ motif and SEC7 domain-containing protein 2 (\n                    <jats:italic>IQSEC2<\/jats:italic>\n                    ), which mainly affect males and are characterized by prominent developmental encephalopathy. Variations in these genes produce clinical manifestations similar to Rett syndrome but do not fully align with it, posing diagnostic challenges. Currently, they are clinically categorized as Rett-like syndromes. The genotype\u2013phenotype relationships in\n                    <jats:italic>IQSEC2<\/jats:italic>\n                    -associated Rett-like syndromes remain poorly characterized. Herein, we describe two brothers with a novel\n                    <jats:italic>IQSEC2<\/jats:italic>\n                    truncating variant and Rett-like syndrome manifestations and, alongside a synthesis of 38 published cases, provide insights into the genotype\u2013phenotype correlations of\n                    <jats:italic>IQSEC2<\/jats:italic>\n                    . Two brothers with a novel\n                    <jats:italic>IQSEC2<\/jats:italic>\n                    variant presented with Rett-like syndrome, exhibiting developmental delay, microcephaly, refractory epilepsy, stereotypic hand movements, and absent speech. Their heterozygous mother displayed mild intellectual disability and late-onset epilepsy. Among the 38 published cases and combined with these siblings, male predominance emerged as a key feature. Regression\u2014unlike in\n                    <jats:italic>MECP2<\/jats:italic>\n                    -related Rett syndrome\u2014occurred inconsistently. We hypothesize that this may represent a phenotype of developmental arrest rather than true regression. All nine missense variants mapped to functionally critical domains of the IQSEC2 protein, whereas 82% of the truncating mutations clustered outside these regions. The patients with large duplications or deletions demonstrated more severe phenotypic variability. Thus, these genotype\u2013phenotype correlations support routine\n                    <jats:italic>IQSEC2<\/jats:italic>\n                    screening in patients with unexplained developmental and epileptic encephalopathy and Rett-like syndrome. Missense and truncated mutations associated with Rett-like syndrome demonstrate a clustered distribution within the IQSEC2 protein. The genotypes and variant locations help explain the phenotypic variation in patients with\n                    <jats:italic>IQSEC2<\/jats:italic>\n                    variants.\n                  <\/jats:p>","DOI":"10.3389\/fped.2026.1786453","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T05:43:30Z","timestamp":1778737410000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["IQSEC2-related developmental and epileptic encephalopathy with a Rett-like phenotype: two cases with novel variants and a review of the literature"],"prefix":"10.3389","volume":"14","author":[{"given":"Li","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Anshun People's Hospital","place":["Anshun, Guizhou, China"]},{"name":"Department of Pediatrics, Guanling County People's Hospital","place":["Anshun, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Guanling County People's Hospital","place":["Anshun, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Guanling County People's Hospital","place":["Anshun, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Guanling County People's Hospital","place":["Anshun, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaobin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Guanling County People's Hospital","place":["Anshun, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengfang","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Guanling County People's Hospital","place":["Anshun, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingtao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Guanling County People's Hospital","place":["Anshun, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maoqiang","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Guanling County People's Hospital","place":["Anshun, Guizhou, China"]},{"name":"Department of Pediatrics, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, Guizhou, 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