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

Abstract

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.

Keywords: Developmental language disorders; Exome sequencing; Neurodevelopmental disorders; Specific learning disorders.

Fig. 1

Proportion of patients with class 4/5 variants, VUS and GUS

Fig. 2

Pedigrees of multiplex families. A, B. and C. patients with inherited pathogenic or likely pathogenic variants; D to Y. Patients with inherited candidate variants. Dark gray: specific learning disorder; black: intellectual disability; light gray: learning difficulties; checkerboard: ADHD; cross-hatched shape: epilepsy; triangle: spontaneous miscarriage. P, pathogenic variant; LP, likely pathogenic variant; VUS, variant of uncertain significance; GUS, gene of unknown significance

Fig. 3

Photographs of patient 6 with SET variant and patient 8 with SMARCC2 variant. A. This patient had morphological features compatible with the ID syndrome associated with the SET gene: asymmetry of the ears, ogival palate, left gibbosity, indented thorax, inward walking, long and thin fingers, hyperlaxity of the elbows and toes, skin elasticity, and white hair. B. This patient had morphological features compatible with Cofin –Siris syndrome: long palpebral fissures, thin upper lip, and particular ears. Written consent was obtained for sharing the facial photographs in the publication