Chiari I malformation, delayed gross motor skills, severe speech delay, and epileptiform discharges in a child with FOXP1 haploinsufficiency

Abstract

Human FOXP2 deficiency has been identified as a cause of hereditary developmental verbal dyspraxia. Another member of the same gene family, FOXP1, has expression patterns that overlap with FOXP2 in some areas of the brain, and FOXP1 and FOXP2 have the ability to form heterodimers. These findings suggest the possibility that FOXP1 may also contribute to proper speech development. However, no such role of FOXP1 has been established to date. Recently, a child was reported who presented with a 3p13-14.1 deletion of four genes, including FOXP1, and a constellation of deficits that included speech delay. In this study, we report the case of a patient with a single deletion of FOXP1. This patient presented with speech and motor developmental delays, a Chiari I malformation, and epileptiform discharges. The nature of the speech deficit is different from the primary oromotor verbal dyspraxia found in patients with FOXP2 deficiency. The patient's developmental deficits may support a role for FOXP1 in the development of verbal and motor skills.

Figure 1

MRI showing the patient's Chiari I malformation.

Figure 2

The patient's dysmorphology includes a broad forehead, orbital hypertelorism, down-slanting palpebral fissures, bilateral ptosis, short nose, broad nasal tip, smooth philtrum, and slightly down-turned corners of the mouth. Facial photos demonstrate the evolution of the facial phenotype from (a) 10 months to (b) 20 months to (c) 46 months.

Figure 3

The deletion of FOXP1 at 3p14.1. (a) Array results for the proband are shown above the ideogram of chromosome 3. Each dot is an oligonucleotide probe; those with normal copy number have a log2 ratio of ∼0, whereas those in the deleted region have a log2 of less than −0.32. The deleted region is boxed. (b) UCSC Genome Browser view of the FOXP1 deletion. The deletion described in this report and a similar larger deletion from a previous study are shown as red bars. Probes on the whole-genome array and FOXP1-targeted array appear as black vertical lines. Deletions (red bars) and duplications (green bars) found in apparently normal control individuals from a previous study are also displayed. The minimal deleted region is chr3:70 549 923–71 618 670; the maximum deleted region is chr3:70 508 118–71 618 932. The color reproduction of this figure is available on the html full text version of the manuscript.