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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620656
Title:
Phenotype of CNTNAP1: a study of patients demonstrating a specific severe congenital hypomyelinating neuropathy with survival beyond infancy.
Authors:
Low, K J; Stals, Karen; Caswell, R; Wakeling, M; Clayton-Smith, J; Donaldson, A; Foulds, N; Norman, A; Splitt, M; Urankar, K; Vijayakumar, K; Majumdar, A; Study, Ddd; Ellard, Sian ( 0000-0002-7620-5526 ) ; Smithson, S F
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.
Citation:
Phenotype of CNTNAP1: a study of patients demonstrating a specific severe congenital hypomyelinating neuropathy with survival beyond infancy. 2018 Eur. J. Hum. Genet.
Publisher:
Nature
Journal:
European journal of human genetics : EJHG
Issue Date:
6-Mar-2018
URI:
http://hdl.handle.net/11287/620656
DOI:
10.1038/s41431-018-0110-x
PubMed ID:
29511323
Additional Links:
http://dx.doi.org/10.1038/s41431-018-0110-x
Type:
Journal Article
Language:
en
ISSN:
1476-5438
Appears in Collections:
Molecular Genetics; 2018 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorLow, K Jen
dc.contributor.authorStals, Karenen
dc.contributor.authorCaswell, Ren
dc.contributor.authorWakeling, Men
dc.contributor.authorClayton-Smith, Jen
dc.contributor.authorDonaldson, Aen
dc.contributor.authorFoulds, Nen
dc.contributor.authorNorman, Aen
dc.contributor.authorSplitt, Men
dc.contributor.authorUrankar, Ken
dc.contributor.authorVijayakumar, Ken
dc.contributor.authorMajumdar, Aen
dc.contributor.authorStudy, Ddden
dc.contributor.authorEllard, Sianen
dc.contributor.authorSmithson, S Fen
dc.date.accessioned2018-03-27T13:01:49Z-
dc.date.available2018-03-27T13:01:49Z-
dc.date.issued2018-03-06-
dc.identifier.citationPhenotype of CNTNAP1: a study of patients demonstrating a specific severe congenital hypomyelinating neuropathy with survival beyond infancy. 2018 Eur. J. Hum. Genet.en
dc.identifier.issn1476-5438-
dc.identifier.pmid29511323-
dc.identifier.doi10.1038/s41431-018-0110-x-
dc.identifier.urihttp://hdl.handle.net/11287/620656-
dc.description.abstractCHN 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.en
dc.language.isoenen
dc.publisherNatureen
dc.relation.urlhttp://dx.doi.org/10.1038/s41431-018-0110-xen
dc.rightsArchived with thanks to European journal of human genetics : EJHGen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titlePhenotype of CNTNAP1: a study of patients demonstrating a specific severe congenital hypomyelinating neuropathy with survival beyond infancy.en
dc.typeJournal Articleen
dc.identifier.journalEuropean journal of human genetics : EJHGen
dc.type.versionIn press (epub ahead of print)en

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