CHN is genetically heterogeneous and its genetic basis is difficult to determine on features alone. CNTNAP1 encodes CASPR, integral in the paranodal junction high molecular mass complex. Nineteen individuals with biallelic variants have been described in association with severe congenital hypomyelinating neuropathy, respiratory compromise, profound intellectual disability and death within the first year. We report 7 additional patients ascertained through exome sequencing. We identified 9 novel CNTNAP1 variants in 6 families: three missense variants, four nonsense variants, one frameshift variant and one splice site variant. Significant polyhydramnios occurred in 6/7 pregnancies. Severe respiratory compromise was seen in 6/7 (tracheostomy in 5). A complex neurological phenotype was seen in all patients who had marked brain hypomyelination/demyelination and profound developmental delay. Additional neurological findings included cranial nerve compromise: orobulbar dysfunction in 5/7, facial nerve weakness in 4/7 and vocal cord paresis in 5/7. Dystonia occurred in 2/7 patients and limb contractures in 5/7. All had severe gastroesophageal reflux, and a gastrostomy was required in 5/7. In contrast to most previous reports, only one patient died in the first year of life. Protein modelling was performed for all detected CNTNAP1 variants. We propose a genotype–phenotype correlation, whereby hypomorphic missense variants partially ameliorate the phenotype, prolonging survival. This study suggests that biallelic variants in CNTNAP1 cause a distinct recognisable syndrome, which is not caused by other genes associated with CHN. Neonates presenting with this phenotype will benefit from early genetic definition to inform clinical management and enable essential genetic counselling for their families.

CNTNAP1 (OMIM # 602346) encodes rat contactin-associated protein (CASPR) and was first implicated in human disease in 2014.1 CASPR2, forms part of a high molecular mass complex in the paranodal junction and interacts with contactin. Normal paranodal junctions do not form if CASPR is absent and this occurs in conjunction with disruption of the paranodal loops. Using a whole exome sequencing (WES) approach in 31 non-syndromic arthrogryposis multiplex congenital families, Laquerriere et al identified four unrelated familes with homozygous frameshift mutations in CNTNAP1. Death occurred within the first 40 days of life in all four cases. CNTNAP1 has since been described in association with a severe congenital hypomyelinating neuropathy (CHN) in a further 5 patients in the literature. We describe the clinical findings in 6 further patients extending the phenotype beyond that of neonatal lethality. We report neuropathological findings on muscle and nerve biopsy of 3 of the patients. Further molecular genetic analysis is ongoing and the results will be reported. Our findings demonstrate that CNTNAP1 causes a reproducible specific phenotype of polyhydramnios with associated premature birth, severe central hypotonia from birth with severe demyelinating peripheral neuropathy, cranial nerve involvement including orobulbar dysfunction, vocal cord palsy, severe respiratory distress from birth with associated requirement for tracheostomy and profound intellectual disability. Onion bulb fibres were noted on neuropathological specimens concurring with previous reports, although not specific to CNTNAP1. Brain MRI demonstrated a varying combination of central hypomyelination, delayed myelination and loss of white matter bulk. This specific clinical pattern has not been previously reported in association with any of the other genes associated with CHN and should guide clinical management and genetic counselling.