Study of the Value of Trio Exome Sequencing in the Etiological Assessment of Specific Non-syndromic Language and Learning Disorders

Overview

Specific language and learning disorders (SLLD) affect around 5-10% of school-aged children, or 1-2 child(ren) per class. SLLDs correspond to the impairment of a specific cognitive function and are divided into 5 categories: dyslexia, dysphasia, dyspraxia, dyscalculia and attention deficit hyperactivity disorder (ADHD) (DSM-5). In recent years, real progress has been made in their clinical diagnosis and management, thanks to a better description of these disorders in the DSM-5 and the advent of rehabilitative treatments (neuropsychology, speech therapy, occupational therapy, orthoptics, etc.). SLLD can occur in a sporadic or familial context (sibling involvement, a symptomatic parent, other relatives who may mimic dominant inheritance with variable expressivity and incomplete penetrance). It has long been suspected that SLLD is secondary to multifactorial inheritance, with a combination of frequent genetic variations and environmental factors. In France, in the absence of an obvious syndromic diagnosis, the current strategy is to prescribe array CGH, combined in girls with a search for fragile X syndrome (in boys, this syndrome leads to systematic intellectual disability, which does not justify its study in SLLD). A few genes have been described as being specifically involved in a small proportion of SLLD, most often with de novo variations or inherited from a symptomatic parent. There are no distinctive clinical features to guide targeted sequencing of these genes. Moreover, our recent experience shows that genes implicated in intellectual disability may also be involved in SLLD. Very few studies have been published in the literature evaluating the value of exome sequencing in SLLD. Only two studies have been identified, involving 10 and 43 patients with specific SLLD. In view of the roll-out of the French Genomic Medicine Plan (PFMG 2025), it is important to set up a study aimed at assessing the value of genome-wide sequencing in the etiological work-up for SLLD. Participation in the study consists of: * an inclusion visit, where an additional blood sample will be taken during the baseline work-up * a results visit (4 months after the inclusion visit) Optional qualitative study: semi-structured interview 1 year after the inclusion visit proposed to 20 patients or families with a positive result and to 10 patients with a negative result.

Interventions

• Biological Blood samples
  Samples collected during blood sampling for array CGH (1 EDTA tube for index case and 2 biological relatives)
• Other Consultation for results delivery
  at 4 months
• Other Study Humanities and Social Sciences
  Interview offered to 20 families with positive results and 10 families with negative results

Primary outcome measures

• Identification of a genetic cause defined by the presence of at least one ACMG class 4 or 5 variant. [Time frame: Through study completion, an average of 4 months]

Eligibility criteria

Inclusion criteria

• Index case suffering from one or more severe learning disorders (requiring in-school help or intensive rehabilitation), justified by neuropsychological and/or speech therapy and/or occupational therapy assessments, reviewed by experts and supplemented if necessary within the framework of the study, and not yet having undergone genetic testing.
• Index case aged 3 to 40 years
• Sample may be taken from index case and 2 known biological parents
• Consent signed by the parents and by the index case if major
• Index case and parents covered by national health insurance

Exclusion criteria

• Index case and parents have a condition which, in the opinion of the investigator, would contraindicate the subject's participation in the study.
• Intellectual disability confirmed by neuropsychological testing or strongly suspected clinically in the index case and/or his/her parents
• Obvious syndromic diagnosis (syndrome or antecedents having definitely led to a developmental disorder)
• Persons deprived of liberty by judicial or administrative decision,
• Adults under guardianship,
• Persons residing in a health or social establishment
• Patients in critical situations
• Pregnant, parturient or nursing women
• Previous array CGH and/or Fragile X testing or any other targeted genetic examination (except standard karyotype).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Parallel assignment

Masking

Open label

Primary purpose

Diagnostic

Study locations

France · 1 center

• CHU Dijon Bourgogne — Dijon

Identifiers

NCT: NCT05939739 · DELANNE PHRCI 2021

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗