Amino-Terminal Microdeletion within the CNTNAP2 Gene Associated with Variable Expressivity of Speech Delay

Abstract

The contactin-associated protein-like 2 (CNTNAP2) gene is highly expressed in the frontal lobe circuits in the developing human brain. Mutations in this gene have been associated with several neurodevelopmental disorders such as autism and specific language impairment. Here we describe a 450 kb deletion within the CNTNAP2 gene that is maternally inherited in two male siblings, but with a variable clinical phenotype. This variability is described in the context of a limited number of other cases reported in the literature. The in-frame intragenic deletion removes a critical domain of the CNTNAP2 protein, and this case also highlights the challenges of correlating genotype and phenotype.

Figure 1

Schematic of the chromosome 7 region encompassing the CNTNAP2 gene. (a) shows an ideogram of chromosome 7, together with the location of the CNTNAP2 gene. (b) shows the exonic organisation of the CNTNAP2 gene and the location and extent of the deletion detected in the proband (indicated by an asterisk), his brother and his mother, together with deletions reported by Gregor et al. [15] (patients reported as C5 and C6 with deletions of exons 2-3 and 3-4, resp.), and Mefford et al. [16] (patient reported as K034 with a deletion of exons 2–4; coordinates taken from Figure 2 of this publication), which lie in the same region of the CNTNAP2 gene. The images presented here are taken from the UCSC genome browser (http://genome.ucsc.edu/).

Figure 2

Pedigree of proband and copy number changes. The copy number changes detected in all members of the pedigree are shown; the common deletion detected in the CNTNAP2 gene is shown in grey, and the proband is indicated by an arrow.