A De Novo FOXP1 Truncating Mutation in a Patient Originally Diagnosed as C Syndrome

Abstract

De novo FOXP1 mutations have been associated with intellectual disability (ID), motor delay, autistic features and a wide spectrum of speech difficulties. C syndrome (Opitz C trigonocephaly syndrome) is a rare and genetically heterogeneous condition, characterized by trigonocephaly, craniofacial anomalies and ID. Several different chromosome deletions and and point mutations in distinct genes have been associated with the disease in patients originally diagnosed as Opitz C. By whole exome sequencing we identified a de novo splicing mutation in FOXP1 in a patient, initially diagnosed as C syndrome, who suffers from syndromic intellectual disability with trigonocephaly. The mutation (c.1428 + 1 G > A) promotes the skipping of exon 16, a frameshift and a premature STOP codon (p.Ala450GLyfs*13), as assessed by a minigene strategy. The patient reported here shares speech difficulties, intellectual disability and autistic features with other FOXP1 syndrome patients, and thus the diagnosis for this patient should be changed. Finally, since trigonocephaly has not been previously reported in FOXP1 syndrome, it remains to be proved whether it may be associated with the FOXP1 mutation.

Figure 1

FOXP1 domain organization (for UniProt Q9H334). Point mutations associated with intellectual disability (ID) with language delay, with or without autistic features are shown. In bold, the mutation found in the patient described here.

Figure 2

Main features of the patient. (A–B) Neonatal CT scan. Trigonocephaly is clearly appreciated. For a control CT scan, see Khanna et al. (C–E) Facial dysmorphisms at 2 and 23 years of age. Hypertelorism, convergent strabismus, down slanted palpebral fissures, epicanthus, prominent nasal root and ante-verted nostrils and (F) arched palate and hypertrophy of the alveolar processes are appreciated. (G–H) Foot phenotype with metatarsal flat-footedness and clinodactyly. All images are shared by the family with explicit permission to publish.