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Epilepsia. 2017 Apr;58(4):565-575. doi: 10.1111/epi.13669. Epub 2017 Feb 6.

Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: Detailed phenotyping of 10 new cases.

Author information

1
The Paediatric Neurosciences Research Group, Royal Hospital for Children, Queen Elizabeth University Hospitals, Glasgow, United Kingdom.
2
School of Medicine, University of Glasgow, Glasgow, United Kingdom.
3
West of Scotland Clinical Genetics Service, Glasgow, United Kingdom.
4
Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
5
Division of Evolution and Genomic sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
6
Department of Paediatrics, Victoria Infirmary, Kirkcaldy, United Kingdom.
7
Paediatric Neurology, Great North Children's Hospital, Newcastle Acute Hospitals NHS Trust, Newcastle-upon-Tyne, United Kingdom.
8
University of Bristol, Bristol, United Kingdom.
9
Institute for Clinical Genetics, TU Dresden, Dresden, Germany.
10
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
11
Section for Functional Genetics, Institute for Human Genetics, University of Lübeck, Lübeck, Germany.
12
South East Scotland Clinical Genetic Service, Edinburgh, United Kingdom.
13
Clinical Genetics, Great Ormond Street Hospital, London, United Kingdom.
14
Department of Paediatric Neurosciences, Royal Hospital for Sick Children, Edinburgh, United Kingdom.
15
Institute of Genetic Medicine, Newcastle-upon-Tyne, United Kingdom.
16
Paediatric Neurology Royal London Hospital, London, United Kingdom.
17
Department of Paediatrics, Royal Alexandra Hospital, Paisley, United Kingdom.
18
Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
19
Carl Gustav Carus Hospital, at the TU Dresden, Dresden, Germany.
20
Paediatric Neurology, Royal Manchester Children's Hospital, Manchester, United Kingdom.
21
Peninsula Genetics, Exeter, United Kingdom.
22
School of Medicine, University of Nottingham, Nottingham, United Kingdom.
23
The Deciphering Developmental Disorders study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.

Abstract

OBJECTIVE:

The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X-linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in-frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (CdLS). Recently, protein truncating mutations in SMC1A have been reported in five females, all of whom have been affected by a drug-resistant epilepsy, and severe developmental impairment. Our objective was to further delineate the phenotype of SMC1A truncation.

METHOD:

Female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders (DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). Detailed information on the phenotype in each case was obtained.

RESULTS:

Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of CdLS. They presented with onset of epileptic seizures between <4 weeks and 28 months of age. In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression. Moderate or severe developmental impairment was apparent in all cases.

SIGNIFICANCE:

Truncation mutations in SMC1A cause a severe epilepsy phenotype with cluster seizures in females. These mutations are likely to be nonviable in males.

KEYWORDS:

SMC1A ; Cluster; Epilepsy; Females; Intellectual disability; X-linked

PMID:
28166369
DOI:
10.1111/epi.13669
[Indexed for MEDLINE]
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