Phenotype of FOXP2 haploinsufficiency in a mother and son

Abstract

Disruptions in FOXP2, a transcription factor, are the only known monogenic cause of speech and language impairment. We report on clinical findings for two new individuals with a submicroscopic deletion of FOXP2: a boy with severe apraxia of speech and his currently moderately affected mother. A 1.57 Mb deletion on chromosome 7q31 was detected by array comparative genomic hybridization (aCGH). In addition to FOXP2, the patients' deletion involves two other genes, MDFIC and PPP1R3A, neither of which has been associated with speech or language disorders. Thus, findings for these two family members provide informative phenotypic information on FOXP2 haploinsufficiency. Evaluation by a clinical geneticist indicated no major congenital anomalies or dysmorphic features. Evaluations by a clinical psychologist and occupational therapist indicated cognitive-linguistic processing and sensorimotor control deficits, but did not support a diagnosis of autism spectrum disorder. Evaluation by clinical and research speech pathologists confirmed that both patients' speech deficits met contemporary criteria for apraxia of speech. Notably, the patients were not able to laugh, cough, or sneeze spontaneously, replicating findings reported for two other FOXP2 cases and a potential diagnostic sign of nonsyndromic apraxia of speech. Speech severity findings for the boy were not consistent with the hypothesis that loss of maternal FOXP2 should be relatively benign. Better understanding of the behavioral phenotype of FOXP2 disruptions will aid identification of patients, toward an eventual understanding of the pathophysiology of syndromic and nonsyndromic apraxia of speech.

Figure 1

Patient 1 at 4 years, 10 months of age. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 2

Graphic representation of the data from the ISCA 105K oligo-aCGH analysis. A: Ideogram of chromosome 7, with the the symbol on the right side of the image showing the position of the deleted region. B: Chromosome 7 findings from aCGH analysis software (OneClick CGH, InfoQuant, London, UK). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 3

A screenshot from the UCSC genome browser showing the deleted region at cytogenetic location 7q31.2q31.2, from 112,946,520 to 114,520,576 based on the Human Genome March 2006 (hg18) assembly. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 4

WAIS-III Performance and Verbal IQ scores for Patient 2 in comparison to B and T [Tomblin et al., 2009] and the means and standard deviations for the 13 affected members of the KE family [Watkins et al., 2002].

Figure 5

WAIS-III subtest scale scores (10 = average, 3 =SD) for Patient 2 in comparison with the scores for B and T [Tomblin et al., 2009] and the means for the 13 affected members of the KE family [Watkins et al., 2002]. Scores above the solid line are within the normal range.