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De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy-resistant epilepsy in females: expanding the phenotypic spectrum.
- Source :
-
Clinical genetics [Clin Genet] 2016 Nov; Vol. 90 (5), pp. 413-419. Date of Electronic Publication: 2016 Feb 14. - Publication Year :
- 2016
-
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.<br /> (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Subjects :
- Adolescent
De Lange Syndrome physiopathology
Drug Resistance genetics
Epilepsy drug therapy
Epilepsy physiopathology
Exons genetics
Female
Genes, X-Linked
Humans
Intellectual Disability physiopathology
Male
Middle Aged
Phenotype
RNA, Messenger genetics
Sequence Deletion
Cell Cycle Proteins genetics
Chromosomal Proteins, Non-Histone genetics
De Lange Syndrome genetics
Epilepsy genetics
Intellectual Disability genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1399-0004
- Volume :
- 90
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Clinical genetics
- Publication Type :
- Academic Journal
- Accession number :
- 26752331
- Full Text :
- https://doi.org/10.1111/cge.12729