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



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.



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.



Truncation mutations in SMC1A cause a severe epilepsy phenotype with cluster seizures in females. These mutations are likely to be nonviable in males.
The Paediatric Neurosciences Research Group, Royal Hospital for Children, Queen Elizabeth University Hospitals, Glasgow, United Kingdom.|School of Medicine, University of Glasgow, Glasgow, United Kingdom.
Joseph D
JD
Symonds
West of Scotland Clinical Genetics Service, Glasgow, United Kingdom.
Shelagh
S
Joss
Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.|Division of Evolution and Genomic sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
Kay A
KA
Metcalfe
Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
Suresh
S
Somarathi
Department of Paediatrics, Victoria Infirmary, Kirkcaldy, United Kingdom.
Jamie
J
Cruden
Paediatric Neurology, Great North Children's Hospital, Newcastle Acute Hospitals NHS Trust, Newcastle-upon-Tyne, United Kingdom.
Anita M
AM
Devlin
University of Bristol, Bristol, United Kingdom.
Alan
A
Donaldson
Institute for Clinical Genetics, TU Dresden, Dresden, Germany.
Nataliya
N
DiDonato
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
David
D
Fitzpatrick
Section for Functional Genetics, Institute for Human Genetics, University of Lübeck, Lübeck, Germany.
Frank J
FJ
Kaiser
South East Scotland Clinical Genetic Service, Edinburgh, United Kingdom.
Anne K
AK
Lampe
Clinical Genetics, Great Ormond Street Hospital, London, United Kingdom.
Melissa M
MM
Lees
Department of Paediatric Neurosciences, Royal Hospital for Sick Children, Edinburgh, United Kingdom.
Ailsa
A
McLellan
Institute of Genetic Medicine, Newcastle-upon-Tyne, United Kingdom.
Tara
T
Montgomery
Paediatric Neurology Royal London Hospital, London, United Kingdom.
Vivek
V
Mundada
Department of Paediatrics, Royal Alexandra Hospital, Paisley, United Kingdom.
Lesley
L
Nairn
Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
Ajoy
A
Sarkar
Carl Gustav Carus Hospital, at the TU Dresden, Dresden, Germany.
Jens
J
Schallner
Section for Functional Genetics, Institute for Human Genetics, University of Lübeck, Lübeck, Germany.
Jelena
J
Pozojevic
Section for Functional Genetics, Institute for Human Genetics, University of Lübeck, Lübeck, Germany.
Ilaria
I
Parenti
Paediatric Neurology, Royal Manchester Children's Hospital, Manchester, United Kingdom.
Jeen
J
Tan
Peninsula Genetics, Exeter, United Kingdom.
Peter
P
Turnpenny
Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.|School of Medicine, University of Nottingham, Nottingham, United Kingdom.
William P
WP
Whitehouse
The Deciphering Developmental Disorders study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
The Paediatric Neurosciences Research Group, Royal Hospital for Children, Queen Elizabeth University Hospitals, Glasgow, United Kingdom.|School of Medicine, University of Glasgow, Glasgow, United Kingdom.
Sameer M
SM
Zuberi
D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D004569:Electroencephalography; D004827:Epilepsy / Q000150:complications / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D012640:Seizures / Q000150:complications / Q000235:genetics*; D000098550:Structural Maintenance of Chromosome Protein 1
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000098550:Structural Maintenance of Chromosome Protein 1

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