Variation du nombre de copies dans 19 familles multiplexes italiennes avec trouble du spectre de l'autisme: Importance des gènes synaptiques et d'élongation des neurites

Aperçu: G.M.

Le trouble du spectre de l'autisme (TSA) est doté d'estimations d'héritabilité impressionnantes et de taux de récidive élevés. Ses fondements génétiques sont néanmoins très hétérogènes, avec des variantes communes et rares qui contribuent à des centaines de loci différents, chacun caractérisé par des niveaux variables de pénétrance. Les familles multiplex d'un seul groupe ethnique représentent un moyen utile de réduire l'hétérogénéité et d'améliorer la charge génétique.Ces résultats fournissent des preuves supplémentaires de l'hétérogénéité génétique dans les TSA, même dans les familles multiplex appartenant à un seul groupe ethnique. Les différences dans la charge de la VCN peuvent probablement contribuer à l'hétérogénéité clinique importante observée entre frères et sœurs affectés

Am J Med Genet B Neuropsychiatr Genet. 2017 Mar 17. doi: 10.1002/ajmg.b.32537.

Copy number variation in 19 Italian multiplex families with autism spectrum disorder: Importance of synaptic and neurite elongation genes

Lintas C¹, Picinelli C², Piras IS², Sacco R¹, Brogna C¹, Persico AM^2,3.

Author information

1

Service for Neurodevelopmental Disorders and Laboratory of Molecular Psychiatry and Neurogenetics, University "Campus Bio-Medico", Rome, Italy.

2

Mafalda Luce Center for Pervasive Developmental Disorders, Milan, Italy.

3

Unit of Child and Adolescent Neuropsychiatry, "Gaetano Martino" University Hospital, University of Messina, Messina, Italy.

Abstract

Autism Spectrum Disorder (ASD) is endowed with impressive heritability estimates and high recurrence rates. Its genetic underpinnings are nonetheless very heterogeneous, with common, and rare contributing variants located in hundreds of different loci, each characterized by variable levels of penetrance. Multiplex families from single ethnic groups represent a useful means to reduce heterogeneity and enhance genetic load. We screened 19 Italian ASD multiplex families (3 triplets and 16 duplets, total N = 41 ASD subjects), using array-CGH (Agilent 180 K). Causal or ASD-relevant CNVs were detected in 36.6% (15/41) of ASD probands, corresponding to 36.8% (7/19) multiplex families with at least one affected sibling genetically positive. However, only in less than half (3/7) of positive families, affected siblings share the same causal or ASD-relevant CNV. Even in these three families, additional potentially relevant CNVs not shared by affected sib pairs were also detected. These results provide further evidence of genetic heterogeneity in ASD even within multiplex families belonging to a single ethnic group. Differences in CNV burden may likely contribute to the substantial clinical heterogeneity observed between affected siblings. In addition, Gene Ontology enrichment analysis indicates that most potentially causal or relevant ASD genes detected in our cohort belong to nervous system-specific categories, especially involved in neurite elongation and synaptic structure/function. These findings point toward the existence of genomic instability in these families, whose underlying genetic and epigenetic mechanisms deserve further scrutiny.

© 2017 Wiley Periodicals, Inc.

PMID: 28304131

DOI: 10.1002/ajmg.b.32537