Novel mutation in CNTNAP1 results in congenital hypomyelinating neuropathy

Abstract

Introduction Congenital hypomyelinating neuropathy is a rare congenital neuropathy that presents in the neonatal period and has been linked previously to mutations in a number of genes associated with myelination. A recent study has linked 4 homozygous frameshift mutations in the CNTNAP1 gene with this condition. We report a neonate with congenital hypomyelinating neuropathy who was found to have absent sensory nerve and compound muscle action potentials and hypomyelination on nerve biopsy. Methods/Results On whole exome sequencing we identified a novel CNTNAP1 homozygous missense mutation (p.Arg388Pro) in the proband, and both parents were carriers. Molecular modeling suggests that this variant disrupts a β-strand to cause an unstable structure and likely significant changes in protein function. Discussion This report links a missense CNTNAP1 variant to the disease phenotype previously associated only with frameshift mutations.

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

“…CNTNAP1 involvement in human diseases was first described by Laquérriere in 2014 [6]. 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].…”

“…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].…”

“…Nerve biopsy is now less often performed, as genetic testing in patients with hereditary neuropathies is becoming increasingly used [7,12]. However, sural nerve biopsy is nonspecific and consists mainly of paranodal abnormalities [7,9], along with significant homogeneous axonal loss [1, 6, 9, 11], significant decrease of…”

“…It was first implicated in human disease in 2014, leading to disorders characterized by polyhydramnios, severe neonatal hypotonia, arthrogryposis, facial diplegia, and severe motor paralysis, leading to death in early infancy [6]. ese mutations have been reported in 31 patients, with a wide phenotypic spectrum and promising survival up to early childhood [7][8][9].…”

CNTNAP1 mutations in an adult with Charcot Marie Tooth disease

“…3 The phenotype associated with CNTNAP1 has expanded to include CHN without arthrogryposis and extremely slow CVs. 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.…”