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 mutations in SMC1A were considered incompatible with life, as such mutations had not been reported in neither male or female patients. However, recently we and others reported loss-of-function mutations in females with ID and epilepsy.

Here we present the detailed phenotype of two females with de novo loss-of-function 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 loss-of-function 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 loss-of-function mutations.

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