A Study of the Value of Trio Genome Sequencing in the Etiological Evaluation of Early-Onset and/or Atypical Psychiatric Disorders Without Intellectual Disability or Congenital Anomalies

A Study of the Value of Trio Genome Sequencing in the Etiological Evaluation of Early-Onset and/or Atypical Psychiatric Disorders Without Intellectual Disability or Congenital Anomalies

According to the World Health Organization, one in eight people worldwide has a mental disorder, defined as a significant impairment in thinking, emotional regulation, or behavior. These disorders are classified according to the DSM-5. These psychiatric disorders may be atypical in terms of their age of onset, course of the illness, unusual response to treatment, or classification (significant impact but classified as a "disorder not otherwise specified" by the DSM-5). These disorders can occur sporadically or run in families.

In France, there are no genetic testing recommendations for these patients. A CGH-array analysis may be ordered as part of patient care, as may testing for Fragile X syndrome, depending on the clinical context.

The main hypothesis is that atypical psychiatric disorders result from multifactorial inheritance, involving a combination of common genetic variations and environmental factors. Pangenomic association studies and twin studies have already demonstrated heritability in these psychiatric disorders. It has now been shown that some neurodevelopmental disorders (NDDs) and psychiatric disorders-such as autism spectrum disorders or schizophrenia, for which similar hypotheses were proposed in the past-may result from monogenic inheritance. Furthermore, preliminary indications now allow for the prescription of genome sequencing on the platforms of the France Genomic Medicine Plan 2025.

To date, no study has evaluated the role of high-throughput sequencing in an etiological approach to atypical, non-syndromic psychiatric disorders. Through this study, we aim to assess whether genome sequencing (GS) could be relevant for atypical, non-syndromic psychiatric disorders, which would be the case if it leads to an etiological diagnosis in at least 12% of cases.

The establishment of the GénoPsy network (Centers of Excellence for Behavioral Disorders in Developmental Disorders) creates an environment that is highly conducive to the development of this project.

Inclusion Criteria:

• Index case with one or more psychiatric disorders confirmed by a psychiatrist and/or child psychiatrist, whose evaluations may be supplemented as needed as part of their care, and who meets at least ONE of the following criteria for atypicality:
• Early age of onset
• Unusual course of the disorder (polymorphic/fluctuating)
• Treatment resistance
• Disorder classified as "unspecified" by the DSM-5 with significant functional impact
• Index case aged 3 to 50 years, inclusive
• Consent signed by the biological parents and by the "index case, if of legal age"
• Index case and their parents enrolled in or eligible for a social security program
• Sample collection possible from the index case and their two known biological parents

Exclusion Criteria:

• Genetic testing previously performed (CGH array, targeted gene testing, gene panel, etc.)
• Parent(s) and/or the index case subject to a court-ordered protective measure
• The index case and his or her parents have a condition that, in the investigator's opinion, would contraindicate the subject's participation in the study
• Presence of an intellectual developmental disorder confirmed by a neuropsychological test or strongly suspected clinically in the index case and/or their parents
• Index case with a clear syndromic diagnosis
• Index case with a psychiatric disorder already covered by a pre-indication under PFMG2025.