Paulomi Mehta1, Melanie Küspert2, Tejus Bale3, Catherine A Brownstein4,5, Meghan C Towne4,5, Umberto De Girolami3, Jiahai Shi6, Alan H Beggs4,5, Basil T Darras7, Michael Wegner2, Xianhua Piao1, Pankaj B Agrawal1,4,5. 1. Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, 300 Longwood Avenue, Harvard Medical School, Boston, Massachusetts, 02115, USA. 2. Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 3. Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 4. Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 5. The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 6. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong. 7. Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Abstract
INTRODUCTION: Congenital hypomyelinating neuropathy (CHN) is a rare congenital neuropathy that presents in the neonatal period and has been linked previously to mutations in several genes associated with myelination. A recent study has linked 4 homozygous frameshift mutations in the contactin-associated protein 1 (CNTNAP1) gene with this condition. METHODS: We report a neonate with CHN who was found to have absent sensory nerve and compound muscle action potentials and hypomyelination on nerve biopsy. 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. CONCLUSIONS: This report links a missense CNTNAP1 variant to the disease phenotype previously associated only with frameshift mutations. Muscle Nerve 55: 761-765, 2017.
INTRODUCTION:Congenital hypomyelinating neuropathy (CHN) is a rare congenital neuropathy that presents in the neonatal period and has been linked previously to mutations in several genes associated with myelination. A recent study has linked 4 homozygous frameshift mutations in the contactin-associated protein 1 (CNTNAP1) gene with this condition. METHODS: We report a neonate with CHN who was found to have absent sensory nerve and compound muscle action potentials and hypomyelination on nerve biopsy. 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. CONCLUSIONS: This report links a missense CNTNAP1 variant to the disease phenotype previously associated only with frameshift mutations. Muscle Nerve 55: 761-765, 2017.
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