Ann Lab Med.  2015 Nov;35(6):639-642. 10.3343/alm.2015.35.6.639.

Novel Pathogenic Variant (c.3178G>A) in the SMC1A Gene in a Family With Cornelia de Lange Syndrome Identified by Exome Sequencing

• Jang MA
• Lee CW
• Kim JK
• Ki CS

• KMID: 2363269
• DOI: http://doi.org/10.3343/alm.2015.35.6.639

Abstract

Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous congenital anomaly. Mutations in the NIPBL gene account for a half of the affected individuals. We describe a family with CdLS carrying a novel pathogenic variant of the SMC1A gene identified by exome sequencing. The proband was a 3-yr-old boy presenting with a developmental delay. He had distinctive facial features without major structural anomalies and tested negative for the NIPBL gene. His younger sister, mother, and maternal grandmother presented with mild mental retardation. By exome sequencing of the proband, a novel SMC1A variant, c.3178G>A, was identified, which was expected to cause an amino acid substitution (p.Glu1060Lys) in the highly conserved coiled-coil domain of the SMC1A protein. Sanger sequencing confirmed that the three female relatives with mental retardation also carry this variant. Our results reveal that SMC1A gene defects are associated with milder phenotypes of CdLS. Furthermore, we showed that exome sequencing could be a useful tool to identify pathogenic variants in patients with CdLS.

Keyword

Cornelia de Lange Syndrome; Exome sequencing; Mutation; SMC1A

MeSH Terms

Asian Continental Ancestry Group/genetics
Base Sequence
Cell Cycle Proteins/*genetics
Child, Preschool
Chromosomal Proteins, Non-Histone/*genetics
DNA
DNA Mutational Analysis
De Lange Syndrome/diagnosis/*genetics
Female
Heterozygote
Humans
Male
Pedigree
Phenotype
Polymorphism, Single Nucleotide
Proteins/genetics
Republic of Korea
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
DNA
Proteins

Figure

• 

  Fig. 1 Pathogenic SMC1A variant in a CdLS family. (A) Pedigree of the family, with four related cases of CdLS. The arrow indicates the index patient. A black or gray symbol indicates clinically affected family members (gray, mildly affected). (B) Integrative Genomics Viewer snapshot of the novel SMC1A pathogenic variant (NM_006306.3:c.3178G>A, p.Glu1060Lys) identified by exome sequencing (arrow). (C) Sequence analysis of the SMC1A gene. Chromatograms show the hemizygous nonsynonymous variant (c.3178G>A; p.Glu1060Lys) of the SMC1A gene in the proband (III:1), the heterozygous variant in individuals I:2, II:4, and III:2 (II:4 and III:2 are very mildly affected), and the normal sequence in unaffected subjects I:1 and II:3 (arrow).

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