{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:59:57Z","timestamp":1790315997276,"version":"4.1.0"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"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":"\n Background<\/jats:title>\n \n The homozygous or compound heterozygous missense variants in the\n SLC6A9<\/jats:italic>\n gene (OMIM*601019) are associated with autosomal recessive glycine encephalopathy with normal serum glycine (OMIM#617301). Fewer than ten\n SLC6A9<\/jats:italic>\n variants have been reported to date. Neonates harboring pathogenic variants in the\n SLC6A9<\/jats:italic>\n gene exhibited a mortality rate of up to 75% during the first 7 months of life. We reported the first documented case of neonate death in China attributable to compound heterozygous missense\n SLC6A9<\/jats:italic>\n variants.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Trio-based whole-exome sequencing (trio-WES) was performed on genomic DNA (gDNA) of amniotic fluid cells and parental peripheral blood samples. Two mutant\n SLC6A9<\/jats:italic>\n expression vectors, namely pCMV-Flag-Neo(EGFP)-\n SLC6A9<\/jats:italic>\n -m1 and pCMV-Flag-Neo(EGFP)-\n SLC6A9<\/jats:italic>\n -m2 (\n SLC6A9<\/jats:italic>\n -m1\/m2), and wild-type pCMV-Flag-Neo(EGFP)-\n SLC6A9<\/jats:italic>\n -wt (\n SLC6A9<\/jats:italic>\n -wt) mammalian expression vectors were constructed. All vectors were subsequently transformed into HEK293T cells. Assays measuring the relative expression of\n SLC6A9<\/jats:italic>\n gene mRNA and SLC6A9 protein were performed. Concurrently, we conducted a systematic review of previously reported\n SLC6A9<\/jats:italic>\n -related cases with accessible clinical data, encompassing relevant genetic testing findings and prenatal\/postnatal clinical manifestations.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Trio-WES identified novel compound heterozygous missense variants c.859C\u2009&gt;\u2009T (p.Arg287Trp) and c.1120T\u2009&gt;\u2009C (p.Cys374Arg) in the\n SLC6A9<\/jats:italic>\n gene (NM_201649.4).\n In vitro<\/jats:italic>\n functional studies demonstrated that neither variant caused a reduction in the expression of mutant mRNA, but both led to a significant decrease in the expression of mutant SLC6A9 protein. After reviewing the current literature, we found that fetuses with\n SLC6A9<\/jats:italic>\n gene variants commonly presented with increased nuchal translucency (NT), polyhydramnios and talipes equinovarus (clubfoot). Pathogenic\n SLC6A9<\/jats:italic>\n variants exhibited complete penetrance and a relatively consistent phenotypic spectrum characterized by developmental delay, facial dysmorphism, clubfoot, and a high neonatal mortality rate. The characteristic phenotype in affected infants was characterized by elevated cerebrospinal fluid (CSF) glycine concentrations, with or without concurrent elevation in serum glycine levels.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Preliminary evidence from\n in vitro<\/jats:italic>\n functional studies suggested that the pathogenic mechanism of\n SLC6A9<\/jats:italic>\n -related glycine encephalopathy may be associated with the loss-of-function (LoF) effect caused by\n SLC6A9<\/jats:italic>\n gene variants. This study also expanded the mutational spectrum of the\n SLC6A9<\/jats:italic>\n gene.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fped.2026.1945449","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:32:29Z","timestamp":1790314349000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Neonatal lethality caused by novel compound heterozygous missense variants of SLC6A9 gene"],"prefix":"10.3389","volume":"14","author":[{"given":"Jianbin","family":"Liu","sequence":"first","affiliation":[{"name":"Pediatric Rehabilitation Department, Quzhou Maternal and Child Health Care Hospital","place":["Quzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Wu","sequence":"additional","affiliation":[{"name":"Laboratory of Prenatal Diagnosis Center, Quzhou Maternal and Child Health Care Hospital","place":["Quzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ni","sequence":"additional","affiliation":[{"name":"Women\u2019s Health Department, Quzhou Maternal and Child Health Care Hospital","place":["Quzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e2254069","DOI":"10.1001\/jamanetworkopen.2022.54069","article-title":"Reclassification of the etiology of infant mortality with whole-genome sequencing","volume":"6","author":"Owen","year":"2023","journal-title":"JAMA Netw Open"},{"key":"B2","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/s41525-020-00155-8","article-title":"Measurement of genetic diseases as a cause of mortality in infants receiving whole genome sequencing","volume":"5","author":"Kingsmore","year":"2020","journal-title":"NPJ Genom 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