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Background <p>Specific learning disorders (SLDs) affect approximately 5% of school-age children. In France, genetic investigations of complex non-syndromic SLD cases include chromosomal microarray analysis and fragile X syndrome testing. However, the examples of genes being described in intellectual disability or autism spectrum disorder and also reported in patients with complex and severe SLDs are multiplying. International efforts using exome sequencing have identified monogenic diseases that explain severe SLDs in some instances. The aim of our study was to investigate the value of exome sequencing in children with SLDs without intellectual disability and autism spectrum disorder.</p> Methods <p>We initiated a prospective study using exome sequencing in patients with well-documented, severe SLD.</p> Results <p>Analysis of 82 patients revealed pathogenic/likely pathogenic variants in 11 (13.4%) patients (<i>ADNP</i>, <i>BRAF</i>,<i> CREBBP</i>,<i> KCNN2</i>,<i> KIF1A</i>,<i> RERE</i>,<i> SCN8A</i>,<i> SET</i>,<i> SMARCC2</i> (x2), <i>TRIO</i>). In addition, 38 variants of uncertain significance in candidate genes for severe neurodevelopmental disorders (NDDs) or in genes of unknown significance that could contribute to the phenotype were identified in 30 patients.</p> Limitations <p>The study of 82 patients does not provide sufficient statistical power to conclude that exome testing adds value over chromosomal microarray analysis, or to determine which patient profiles are more likely to benefit from genetic testing. Studies with larger patient numbers are needed to increase statistical power.</p> Conclusions <p>This study confirms the involvement of NDD genes in milder phenotypes and suggests the potential of exome sequencing for diagnosing severe SLDs. Further research on larger samples is required to determine which SLDs are most likely to benefit from pangenomic explorations and to clarify the implication of candidate variants.</p>

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Exome sequencing in severe non-syndromic specific learning and language disorders in a French cohort

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月30日

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  • Eléonore Viora-Dupont,
  • Julian Delanne,
  • Aurore Garde,
  • Sophie Nambot,
  • Estelle Colin,
  • Marie Bournez,
  • Clémence Fauconnier-Fatus,
  • Caroline Racine,
  • Clément Simao De Souza,
  • Céline Bernard,
  • Agnès Maurer,
  • Aurélie Espitalier,
  • Christine Binquet,
  • Marion Bouctot,
  • Marie-Laure Humbert,
  • Anne-Sophie Briffaut,
  • Véronique Darmency,
  • Patricia Plumet,
  • Audrey Cotinaud-Ricou,
  • Noémie Relin,
  • Patrick Callier,
  • Anne-Laure Mosca-Boidron,
  • Nathalie Marle,
  • Frederic Tran Mau-Them,
  • Anne-Sophie Denommé-Pichon,
  • Hana Safraou,
  • Antonio Vitobello,
  • Christophe Philippe,
  • Yannis Duffourd,
  • Ange-Line Bruel,
  • Christel Thauvin-Robinet,
  • Laurence Faivre

摘要

Background

Specific learning disorders (SLDs) affect approximately 5% of school-age children. In France, genetic investigations of complex non-syndromic SLD cases include chromosomal microarray analysis and fragile X syndrome testing. However, the examples of genes being described in intellectual disability or autism spectrum disorder and also reported in patients with complex and severe SLDs are multiplying. International efforts using exome sequencing have identified monogenic diseases that explain severe SLDs in some instances. The aim of our study was to investigate the value of exome sequencing in children with SLDs without intellectual disability and autism spectrum disorder.

Methods

We initiated a prospective study using exome sequencing in patients with well-documented, severe SLD.

Results

Analysis of 82 patients revealed pathogenic/likely pathogenic variants in 11 (13.4%) patients (ADNP, BRAF, CREBBP, KCNN2, KIF1A, RERE, SCN8A, SET, SMARCC2 (x2), TRIO). In addition, 38 variants of uncertain significance in candidate genes for severe neurodevelopmental disorders (NDDs) or in genes of unknown significance that could contribute to the phenotype were identified in 30 patients.

Limitations

The study of 82 patients does not provide sufficient statistical power to conclude that exome testing adds value over chromosomal microarray analysis, or to determine which patient profiles are more likely to benefit from genetic testing. Studies with larger patient numbers are needed to increase statistical power.

Conclusions

This study confirms the involvement of NDD genes in milder phenotypes and suggests the potential of exome sequencing for diagnosing severe SLDs. Further research on larger samples is required to determine which SLDs are most likely to benefit from pangenomic explorations and to clarify the implication of candidate variants.