{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T06:05:08Z","timestamp":1781244308937,"version":"3.54.1"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T00:00:00Z","timestamp":1653609600000},"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. Genet."],"abstract":"<jats:p>Tuberous sclerosis, also known as tuberous sclerosis complex (TSC), is an autosomal dominant defect characterized by hamartomas in multiple organ systems. Inactivating variants cause this defect in either the <jats:italic>TSC1<\/jats:italic> gene or the <jats:italic>TSC2<\/jats:italic> gene, leading to hamartin or tuberin protein dysfunction, thus resulting in TSC. The diagnostic criteria for TSC suggest that it can be diagnosed by identifying a heterozygous pathogenic variant of <jats:italic>TSC1<\/jats:italic> or <jats:italic>TSC2<\/jats:italic>, even in the absence of clinical signs. In a 4-year-old girl, we identified a splicing variant (NM_000548.4: c.2967-1G&amp;gt;T) that she inherited from her father. Neither the girl (patient) nor her father showed typical features of TSC. This variant is located in a NAGNAG acceptor, which can produce mRNA isoforms that differ by a three-nucleotide indel. Reverse transcription polymerase chain reaction analysis of the patient and both parents\u2019 blood RNA samples suggested two different splicing patterns, and these two splicing patterns differed in the presence or absence of the first codon of exon 27, thus providing two splicing products designated as isoforms A and B, respectively. Furthermore, the proportions of these two patterns varied between the patient and either parent. A minigene assay further confirmed that the c.2967-1G&amp;gt;T variant led to the absence of isoform A (including the first codon of exon 27). The finding of our study demonstrates this variant, c.2967-1G&amp;gt;T, disrupts the balance of an alternative splice event which involves the use of two tandem alternatives acceptors and is not associated with typical symptoms of tuberous sclerosis. Our finding is of importance for genetic counseling and suggests that we need to be vigilant to avoid misdiagnosis when we encounter such a site.<\/jats:p>","DOI":"10.3389\/fgene.2022.904224","type":"journal-article","created":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T06:06:20Z","timestamp":1653631580000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of a Novel Canonical Splice Site Variant TSC2 c.2967-1G&gt;T That is Not Associated With Tuberous Sclerosis Pathogenesis"],"prefix":"10.3389","volume":"13","author":[{"given":"Jing","family":"Duan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanzhen","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanqi","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxiang","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1002\/humu.23626","article-title":"Recommendations for Interpreting the Loss of Function PVS1 ACMG\/AMP Variant Criterion","volume":"39","author":"Abou Tayoun","year":"2018","journal-title":"Hum. 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