Novel mutation in CNTNAP1 results in congenital hypomyelinating neuropathy.
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.



We report a neonate with CHN who was found to have absent sensory nerve and compound muscle action potentials and hypomyelination on nerve biopsy.



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.



This report links a missense CNTNAP1 variant to the disease phenotype previously associated only with frameshift mutations. Muscle Nerve 55: 761-765, 2017.
Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, 300 Longwood Avenue, Harvard Medical School, Boston, Massachusetts, 02115, USA.
Paulomi
P
Mehta
Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Melanie
M
Küspert
Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Tejus
T
Bale
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Catherine A
CA
Brownstein
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Meghan C
MC
Towne
Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Umberto
U
De Girolami
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong.
Jiahai
J
Shi
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Alan H
AH
Beggs
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Basil T
BT
Darras
Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Michael
M
Wegner
Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, 300 Longwood Avenue, Harvard Medical School, Boston, Massachusetts, 02115, USA.
Xianhua
X
Piao
Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, 300 Longwood Avenue, Harvard Medical School, Boston, Massachusetts, 02115, USA.|Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Pankaj B
PB
Agrawal
D000200:Action Potentials / Q000502:physiology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D004576:Electromyography; D017809:Fatal Outcome; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009046:Motor Neurons / Q000502:physiology; D020125:Mutation, Missense; D009431:Neural Conduction / Q000502:physiology
C491323:CNTNAP1 protein, human; D015816:Cell Adhesion Molecules, Neuronal
CNTNAP1; congenital neuropathy; exome sequencing; hypomyelination; missense mutation; nerve conduction
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