Phenotype of CNTNAP1: a study of patients demonstrating a specific severe congenital hypomyelinating neuropathy with survival beyond infancy

Abstract

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 mutations in an adult with Charcot Marie Tooth disease

“…4,9 Survival beyond infancy is rare, with one 15-year-old reported with profound intellectual disability, central hypomyelination, and demyelinating peripheral neuropathy with a homozygous p.Arg714Pro CNTNAP1 substitution. 5 Our patient's NCS results are consistent with a motor>sensory demyelinating polyneuropathy.…”

“…CNTNAP1 encodes a neural immunoglobulin family cell adhesion molecule named contactin‐associated protein 1, or CASPR, which forms a complex with contactin and is essential for normal myelin organization at the node of Ranvier in the peripheral nervous system . Biallelic loss of function variants have been identified in CNTNAP1 in infants with LCCS, a rare form of AMC characterized by decreased fetal movement, polyhydramnios, arthrogryposis, hypotonia, areflexia, respiratory distress, and markedly slowed CVs . Nerve biopsies demonstrate peripheral hypomyelination .…”

“…2 Mutations in CNTNAP1 have been reported to cause lethal congenital contracture syndrome or congenital hypomyelinating neuropathy but have not been reported in CMT patients. [3][4][5] We describe a rare heterozygous missense variant of CNTNAP1 in trans with a pathogenic frameshift mutation in a young man with childhood-onset CMT and mild intellectual disability.…”

CNTNAP1 Mutations and Their Clinical Presentations: New Case Report and Systematic Review

“…To this day, most of the 31 identified patients (11 LCCS7 and 20 CHN3), issued from 20 families, were males and answered to diverse ethnicities (Palestinian, Irish, English, American, Qatari, Lebanese, and French), which brings the number of affected families to twenty [1,2,[6][7][8][9][10][11]. Only seven girls were reported to be affected, three of which were diagnosed with LCCS7 and four with CHN3 [8][9][10]. First degree consanguinity was noted in most families [6][7][8]10].…”

“…Only seven girls were reported to be affected, three of which were diagnosed with LCCS7 and four with CHN3 [8][9][10]. First degree consanguinity was noted in most families [6][7][8]10].…”