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Case Reports
. 2025 Aug;197(8):e64074.
doi: 10.1002/ajmg.a.64074. Epub 2025 Apr 3.

A Novel Deep Intronic Variant in NSD1 Causing Sotos Syndrome

Alejandro Parra  1   2   3   4 , Mario Cazalla  1   2   3   4 , Juan A Jimenez-Estrada  2 , Cristina Silván  2 , Lucía Miranda-Alcaraz  1   2   3   4 , Natalia Gallego-Zazo  1   2   3 , Mónica Mora-Gómez  1   2   3   4 , Manuel Rodríguez-Canó  1   2   3   4 , Pedro Arias  1   2   3 , Carlos Rodríguez-Antolín  2 , Julián Nevado  1   2   3 , Víctor Luis Ruiz Pérez  1   3   5 , Jair Tenorio-Castano  1   2   3 , Pablo Lapunzina  1   2   3
Affiliations
Case Reports

A Novel Deep Intronic Variant in NSD1 Causing Sotos Syndrome

Alejandro Parra et al. Am J Med Genet A. 2025 Aug.

Abstract

We report a female patient with a de novo deep intronic variant in NSD1 detected by whole genome sequencing (WGS). RNA-seq revealed the creation of a novel exon (exonization), and methylation analysis showed an episignature pattern overlapping with Sotos syndrome patients with well-established pathogenic NSD1 variants, confirming the diagnosis of Sotos syndrome. This patient reinforces the importance of WGS in cases with clear clinical phenotypes and the emerging role of methylation profiling as a diagnostic tool in individuals where conventional approaches failed.

Keywords: NSD1; RNA‐seq; Sotos syndrome; episignature; intronic variant; methylation pattern; whole genome sequencing.

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