Co-occurrence of mutations in FOXP1 and PTCH1 in a girl with extreme megalencephaly, callosal dysgenesis and profound intellectual disability.

Heterozygous disruptions in FOXP1 are responsible for developmental delay, intellectual disability and speech deficit. Heterozygous germline PTCH1 disease-causing variants cause Gorlin syndrome. We describe a girl with extreme megalencephaly, developmental delay and severe intellectual disability. Dysmorphic features included prominent forehead, frontal hair upsweep, flat, wide nasal bridge, low-set, abnormally modelled ears and post-axial cutaneous appendages on the hands. Brain MRI showed partial agenesis of the corpus callosum and widely separated leaves of the septum pellucidum. Exome sequencing of a gene set representing a total of 4813 genes with known relationships to human diseases revealed an already known heterozygous de novo nonsense disease-causing variant in FOXP1 (c.1573C>T, p.Arg525Ter) and a heterozygous novel de novo frameshift nonsense variant in PTCH1 (c.2834delGinsAGATGTTGTGGACCC, p.Arg945GlnfsTer22). The composite phenotype of the patient seems to be the result of two monogenic diseases, although more severe than described in conditions due to disease-causing variants in either gene.