Characterisation of CASPR2 deficiency disorder--a syndrome involving autism, epilepsy and language impairment

Abstract

Background: Heterozygous mutations in CNTNAP2 have been identified in patients with a range of complex phenotypes including intellectual disability, autism and schizophrenia. However heterozygous CNTNAP2 mutations are also found in the normal population. Conversely, homozygous mutations are rare in patient populations and have not been found in any unaffected individuals.

Case presentation: We describe a consanguineous family carrying a deletion in CNTNAP2 predicted to abolish function of its protein product, CASPR2. Homozygous family members display epilepsy, facial dysmorphisms, severe intellectual disability and impaired language. We compared these patients with previously reported individuals carrying homozygous mutations in CNTNAP2 and identified a highly recognisable phenotype.

Conclusions: We propose that CASPR2 loss produces a syndrome involving early-onset refractory epilepsy, intellectual disability, language impairment and autistic features that can be recognized as CASPR2 deficiency disorder. Further screening for homozygous patients meeting these criteria, together with detailed phenotypic and molecular investigations will be crucial for understanding the contribution of CNTNAP2 to normal and disrupted development.

Fig. 1

a Clinical picture of the affected probands reported in this study. Note dysmorphic facial phenotype, low forehead and bushy eyebrows. Photos of the patients reported in Orrico et. al. are included for comparison (adapted from [18]) (b) Pedigree of the family showing the two affected siblings (filled symbols; S1 & S2) with homozygous deletions encompassing exons 2–3 of the CNTNAP2 gene. The brother is unaffected (unfilled symbol; S3) and has no detected CNV's. Parents are first cousins and both carry the heterozygous CNTNAP2 deletion (symbols with dots; P), but are phenotypically normal. c PCR gel of the mutant CNTNAP2 gene. A ~700 base pair product spanning the breakpoint could be amplified from the homozygous siblings and heterozygous parent, but not from the unaffected sibling. A Sanger sequencing trace shows the location of the deletion breakpoint. d The wild type CASPR2 protein and predicted functional consequences of CNTNAP2 patient mutations on the CASPR2 protein product. CASPR2 is composed of 1331 amino acids with a number of functional domains including a signal peptide (SP), discoidin/neuropilin homology domain (F5/8 Type C), Laminin G domain (LamG), Epidermal Growth Factor like domain (EGF-like), Fibrinogen domain (Fibrinogen), Transmembrane domain (Transmembrane), and Protein 4.1 homologous binding domain (4.1 m). The exon 2–3 deletion (reported herein), exon 3 deletion [16] and c3709delG mutation [14] all produce truncated proteins due to early stop codons. The exon 2–9 deletion [13] also produces a truncated protein product, however in this case it is due to an in-frame loss of amino acids 33–500