Psychiatrie et Génétique

Bertrand Isidor

Service de Génétique Médicale

CHU Nantes

LES MALADIES GENETIQUES

•  Anomalies chromosomiques : –  Nombre: Trisomie 21 –  Structure: Délétion, Duplication

•  Maladies génétiques monogéniques : –  ex: Mucoviscidose, Huntington, PKD

•  Maladies multifactorielles à prédisposition génétique: –  ex: Diabète, Polyarthrite rhumatoïde, spondylarthrite

ankylosante

1. Les maladies psychiatriques ont elles une origine génétique? 2. Les patients atteints de maladies génétiques développent ils des troubles psychiatriques?

•  48,XXYY group has increased risk for anxiety, withdrawal, somatic complaints, and attention problems.

•  In the externalizing subdomain, increases are found in aggressive and delinquent behaviors. Significant difference is seen in the social subdomain with 48,XXYY having higher risk for social difficulty.

•  48,XXYY subjects show elevated scores in anxiety, frustration, order, and vengeance domains compared to 48,XXXY and 49,XXXXY.

CNVs et Psychiatrie

CNVs et Psychiatrie

1/identifiction of de novo CNVs by analysing 9,878 transmissions from parents to offspring genome-wide we analysed data from a population-based sample (2,160 trios (two parents and one offspring) and 5,558 parent–offspring pairs, none of which was known to have schizophrenia):66 CNVs de novo identified

2/The 66 de novo CNVs identified were tested for association in a sample of

1,433 schizophrenia cases and 33,250 controls. 3 deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with

schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II).

All three deletions significantly associate with schizophrenia and related psychoses in the combined sample.

The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 × 10−5, OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort.

The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample.

A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 × 10−7), bipolar disorder (P = 0.017) and autism (P = 1.9 × 10−7).

In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 × 10−13).

Microduplications at 7q36.3 were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample.

All duplications overlapped or were located within 89 kilobases upstreamof the vasoactive intestinal peptide receptor gene VIPR2.

VIPR2 transcription and cyclic-AMPsignalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3.

These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs

Mefford HC, et al

•  25/5218 patients avec délétion de 1.35-Mb délétion 1q21.1. –  8 de novo, –  3 héritées d’un parent avec signes modérés –  6 hérités parent asymptomatique –  8 origine indéterminée,

•  Délétion absente chez 4737 sujets contrôles (P = 1.1×10−7). •  Phénotype :

–  grande variabilité d’expression, –  retard mental léger à sévère, –  malformations cardiaques, –  microcéphalie et cataracte

Mefford HC, et al

•  21/16557 patients avec del 1q21.1 •  15/16557 avec dup 1q21.1

Brunetti-Pierri N et al

Pénétrance incomplète

•  Héritées d’un parent dans la plupart des cas: –  14/ 17 microdeletion –  11/ 12 microduplication.

•  1q21.1 CNVs absents chez 550 sujets contrôles

Problème du conseil génétique

•  Ancien dogme: –  Réarrangement déséquilibré hérité d’un parent non

atteint = polymorphisme –  Réarrangement déséquilibré de novo = pathogène

•  Notion nouvelle pour les syndromes microdélétionnels de pénétrance incomplète et d’ expressivité variable –  Problème pour le diagnostic prénatal –  Il existe néanmoins probablement une probabilité

forte pour l’enfant à naitre d’avoir un phénotype anormal

Quelque soit le mode de transmission

Boycott et al., Nature Reviews Genetics, 2013

Sequencing the exomes of 53 sporadic cases, 22 unaffected controls and their parents. We identified 40 de novo mutations in 27 cases affecting 40 genes, including a potentially disruptive mutation in DGCR2, a gene located in the schizophrenia-predisposing 22q11.2 microdeletion region.

•  sequenced the exomes of 14 schizophrenia probands and their parents.

•  We identified 15 de novo mutations (DNMs) in 8 probands,

Psychiatrie et génétique

•  Déficience intellectuelle

•  Syndromes microdélétionnels: 22q11.2, Williams Beuren, Prader Willi,…

•  Souvent peu ou pas abordé…

•  Troubles psychiatriques

•  ATCD Familiaux? •  ATCD personnels: malformation? •  Troubles cognitifs: Age de la marche,

Langage, scolarité , diplôme •  Examen physique complet: mesure du PC

Est ce que c’est génétique? ATCD familiaux? non oui

Troubles cognitifs ? + Malformation(s)? Anomalies morphologiques?

Oui Non

CGH Array CGH array? Panel de gènes/exome? FMR1( X fragile) Analyse ciblée ( FISH, séquencage)

Exome

Consultation GénoPsy Nantes

•  Objectifs

•  Bilan d’activité: 2-3 patients/3mois,stable

Psychiatrie et génétique

•  Vulnérabilité biologique: multifactoriel vs monogénique (symptômes psychiatriques d’une maladie neurologique avec un déterminisme génétique)

•  Classification moléculaire/physiopathologique

•  Nouvelles thérapies ciblées/cf oncogénétique