Cortical Dysplasia-Focal Epilepsy Syndrome via the CNTNAP2 Gene

Cortical dysplasia-focal epilepsy syndrome (CDFE) or Pitt-Hopkins like syndrome 1 (PTHSL1; OMIM:610042) is a neurodevelopmental disorder characterized by intractable seizures and severe intellectual disability. Patients show normal development prior to seizure onset at 14-20 months (Strauss et al. N Engl J Med 354(13):1370-1377, 2006). Following seizure onset, there is mental regression as well as deterioration of social behavior and language skills reminiscent of Autism Spectrum Disorders (ASD) (Zweier et al. Am J Hu Gen 85(5):655-666, 2009). CDFE patients suffer from frequent focal seizures throughout childhood and seizures often become intractable with age. Variable features of CDFE include hyperactivity, hyperbreathing and neonatal hypotonia (Zweier et al., 2009).

CDFE is inherited in an autosomal recessive manner and is caused by loss-of-function mutations in the CNTNAP2 gene. The c.3709delG mutation has been identified as a founder mutation in Old Order Amish families (Strauss et al., 2006; Jackman et al. Pediatr Neurol 40(4):310-313, 2009). Heterozygous variants in CNTNAP2 have been associated with some cases of Autism Spectrum Disorder (ASD), however no direct causative link has been demonstrated (Bakkaloglu et al. Am J Hu Genet 82(1):165-173, 2008).

CNTNAP2 encodes the protein CASPR2. CASPR2 is a neuronally expressed transmembrane protein. CASPR2 is important for mediating axo-glial interactions as well as for the proper clustering of K+ channels in juxtaparanodal regions along myelinated axons (Poliak et al. J Cell Biol.162(6):1149-1160, 2003). CNTNAP2 knockout mice phenocopy CDFE patients and have defects in neuronal migration, suggesting a possible etiology (Penagarikano et al. Cell 147(1):235-246, 2011).

While a variety of mutation types have been reported in CNTNAP2, approximately 50% of the reported disease causing variants are point mutations or small deletions and approximately 50% are large deletions (Human Gene Mutation Database).

Approximately 50% of the reported disease causing variants in CNTNAP2 are point mutations or small deletions that would be detectable via sequencing (Zweier et al. Am J Hu Genet 85(5):655-666, 2009; Strauss et al. N Engl J Med 354(13):1370-1377, 2006). CNTNAP2 mutations were found in <1% of patients diagnosed with Pitt-Hopkins syndrome, but who lacked a TCF4 mutation (Zweier et al., 2009).

Approximately 50% of the reported disease causing variants in CNTNAP2 are large deletions (Zweier et al., 2009; Strauss et al., 2006).

This test provides full coverage of all coding exons of the CNTNAP2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.