Loss of function of ADNP by an intragenic inversion.

ADNP is a well-known gene implicated in intellectual disability and its molecular spectrum consists mainly in loss of function variant in the ADNP last and largest exon. Here, we report the first description of a patient with intellectual disability identified with an intragenic inversion in ADNP. RNAseq experiment showed a splice skipping of the inversed exons. Moreover, in-silico analysis of initiating ATGs in the mutated transcript using contextual Kozak score suggested that several initiating ATGs were likely used to translate poisonous out-of-frame ORFs and would lead to the suppression of any in-frame rescuing translation, thereby causing haploinsufficiency. As constitutive Alu sequences with high homology were identified at both breakpoints in reversed orientation in the reference genome, we hypothesized that Alu-mediated non-allelic-homologous recombination was responsible for this rearrangement. Therefore, as this inversion is not detectable by exome sequencing, this mechanism could be a potential underdiagnosed recurrent mutation in ADNP-related disorders.