title: De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy-resistant epilepsy in females: expanding the phenotypic spectrum.
abstract: De novo missense mutations and in-frame coding deletions in the X-linked gene SMC1A (structural maintenance of chromosomes 1A), encoding part of the cohesin complex, are known to cause Cornelia de Lange syndrome in both males and females. For a long time, loss-of-function (LoF) mutations in SMC1A were considered incompatible with life, as such mutations had not been reported in neither male nor female patients. However, recently, the authors and others reported LoF mutations in females with intellectual disability (ID) and epilepsy. Here we present the detailed phenotype of two females with de novo LoF mutations in SMC1A, including a de novo mutation of single base deletion [c.2364del, p.(Asn788Lysfs*10)], predicted to result in a frameshift, and a de novo deletion of exon 16, resulting in an out-of-frame mRNA splice product [p.(Leu808Argfs*6)]. By combining our patients with the other recently reported females carrying SMC1A LoF mutations, we ascertained a phenotypic spectrum of (severe) ID, therapy-resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet. Our data show the existence of a novel phenotypic entity - distinct from CdLS - and caused by de novo SMC1A LoF mutations.
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Jansen
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: M H
authors.initials: MH
authors.lastname: Willemsen
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: de Vries
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: J Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands. bert.devries@radboudumc.nl.
authors.forename: B B A
authors.initials: BB
authors.lastname: de Vries
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: L E L M
authors.initials: LE
authors.lastname: Vissers
mesh_terms: D000293:Adolescent; D018797:Cell Cycle Proteins / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D003635:De Lange Syndrome / Q000235:genetics* / Q000503:physiopathology; D004351:Drug Resistance / Q000235:genetics; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D005091:Exons / Q000235:genetics; D005260:Female; D050172:Genes, X-Linked; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D017384:Sequence Deletion; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D012333:RNA, Messenger; D000098550:Structural Maintenance of Chromosome Protein 1
keywords: Cornelia de Lange syndrome; SMC1A; epilepsy; intellectual disability; loss-of-function