Medical College of Wisconsin
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Novel SMC1A frameshift mutations in children with developmental delay and epilepsy. Eur J Med Genet 2015 Oct;58(10):562-8



Pubmed ID




Scopus ID

2-s2.0-84945963620   24 Citations


Cornelia de Lange syndrome (CdLS) is a rare dominantly inherited genetic multisystem developmental condition with considerable phenotypic and allelic heterogeneity. Missense and in-frame deletions within the SMC1A gene can be associated with epilepsy and milder craniofacial features. We report two females who presented with developmental delay and developed isolated medically refractory seizures with unrevealing initial laboratory, imaging and genetic evaluations. Whole exome sequencing (WES) analyses were performed and were instrumental in uncovering the genetic etiology for their conditions. WES identified two novel de novo heterozygous frameshift mutations in the SMC1A gene [c.2853_2856delTCAG (p.Ser951Argfs*12) and c.3549_3552dupGGCC (p.Ile1185Glyfs*23)]. We also observed marked skewing of X-inactivation in one patient. The individual with the p.Ser951Argfs*12 mutation represents an extreme on the CdLS phenotypic spectrum, with prominent neurological involvement of severe developmental delay and refractory epilepsy, with mild craniofacial features. Both individuals eventually had incomplete clinical responses to therapy with valproic acid. We review previous reports of SMC1A mutations with epilepsy. SMC1A should be included in clinical gene panels for early infantile and early childhood epileptic encephalopathy.

Author List

Goldstein JH, Tim-Aroon T, Shieh J, Merrill M, Deeb KK, Zhang S, Bass NE, Bedoyan JK


Nancy Bass MD Professor in the Neurology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Base Sequence
Cell Cycle Proteins
Child, Preschool
Chromosomal Proteins, Non-Histone
De Lange Syndrome
Developmental Disabilities
Frameshift Mutation
Molecular Sequence Data