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

Roser Urreizti,Lluïsa Vilageliu,Bru Cormand,Sarah Damanti,Giovanni Neri,Héctor Franco-Valls,Carla Esteve,Susana Balcells,Laura Castilla-Vallmanya,Raul Tonda,Daniel Grinberg,John M Opitz

doi:10.1038/s41598-017-19109-9

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.

Highlights

FOXP1 is one of the genes recently found mutated in a Mendelian developmental disorder
Foxp[1] and Foxp[2] have been shown to be co-expressed in several brain regions[12] as well as in perichondrial skeletal progenitors and proliferating chondrocytes during endochondral ossification and they act as coordinators of osteogenesis and chondrocyte hypertrophy in the developing long bones[13]
FOXP2 is involved in a rare form of speech and language disorder with developmental verbal dyspraxia

Summary

Diagnosed as C Syndrome

Roser Urreizti[1], Sarah Damanti[2,3], Carla Esteve[1], Héctor Franco-Valls[1], Laura Castilla-Vallmanya[1], Raul Tonda[4,5], Bru Cormand[1], Lluïsa Vilageliu[1], John M. The main diagnostic tools include a great variety of molecular tests (karyotype, array CGH and Sanger sequencing of putative candidate genes) together with multiple clinical evaluations by highly specialized physicians and a variety of complementary tests, some of them invasive, such as neuroimaging, metabolic evaluation or cerebrospinal fluid examination[1] After this “diagnostic odyssey” more than a half of the patients are still miss- or undiagnosed[2] and this situation is worsened in patients suffering from rare diseases clinically and genetically heterogeneous or with unclear or atypical presentations[2,3]. We present an adult patient with developmental delay, trigonocephaly, speech impairment and ID who was diagnosed as Opitz C syndrome early in life, in whom we have identified by WES a novel splicing mutation in the FOXP1 gene and provide a detailed clinical description, in comparison to so far reported patients identified carrying deleterious FOXP1 mutations

Results and Discussion

Srivastava Song

Material and Methods

Author Contributions

Additional Information