Genotype Phenotype Correlation in Patients with Synaptic Genes Mutations

Background:  The phenotypical heterogeneity is observed in ASD even in patients carrying gene mutations in the same gene. In 2004 and 2009 we reported two ASD cases, one familial  and one sporadic, carrying a deleterious different mutation in the NLGN4X gene (Laumonnier et al, 2004; Daoud et al, 2009).

Objectives:  To evidence genotype phenotype correlation in patients carrying NLGN4X gene mutations.

Methods:  We  performed the whole exome sequencing (WES) of these 2 individuals with ASD and 1 uncle.  Phenotypic characterization of patients and relatives included behavioural, cognitive, electrophysiological and MRI evaluations.

Results:  We discovered a second truncating mutation affecting either (i) the GLRB gene encoding a postsynaptic receptor interacting with NLGN4X in the family described in Laumonnier et al (2004), (ii) or the MLL3 gene, previously involved in ASD/ID, for the sporadic case (Daoud et al, 2009). The combination of the NLGN4X mutation and the second truncated gene was specific to patients with ASD and was absent in controls as well as relatives with ID only . Complete phenotypic evaluation of the pedigrees has evidenced within these two ASD cases common autistic behavioural features and neurophysiological pattern (ie abnormal Mismatch Negativity on auditory ERP) but different developmental trajectories and cognitive profiles. Furthermore the ASD case within the multiplex family had a different cognitive profile from members carrying the NLGN4X mutation only.

Conclusions:  These results illustrate, to our knowledge, for the first time that the phenotypic variability present in ASD multiplex families or in different families that include patients having a similar deleterious mutation in a candidate gene (such as NLGN4X), is caused by the combinatory effect of at least a second mutation in another gene.