Cornelia de Lange individuals with new and recurrent SMC1A mutations enhance delineation of mutation repertoire and phenotypic spectrum

Abstract

We report on the clinical and molecular characterization of eight patients, one male and seven females, with clinical diagnosis of Cornelia de Lange syndrome (CdLS), who were found to carry distinct mutations of the SMC1A gene. Five of the eight mutations are novel, with two involving amino acid residues previously described as altered in a different way. The other three have been reported each in a single case. Comparison of pairs of individuals with the same mutation indicates only partial overlap of their clinical phenotypes. The following novel missense mutations, all affecting highly conserved amino acid residues, were found: p.R398G in the N‐terminal coiled‐coil domain, p.V651M in the C‐terminal coiled‐coil/hinge junction, p.R693G in the C‐terminal coiled‐coil, and p.N1166T and p.L1189F in the C‐terminal ABC cassette. The latter is localized in the H‐loop, and represents the first mutation involving a functional motif of SMC1A protein. The effect of the mutations on SMC1A protein function has been predicted using four bioinformatic tools. All mutations except p.V651M were scored as pathogenic by three or four of the tools. p.V651M was found in the only male individual of our cohort, who presented with the most severe phenotype. This raises the issue of gender effect when addressing mutation‐phenotype correlation for genes such as SMC1A, which incompletely escapes X‐inactivation. Our clinical and molecular findings expand the total number of characterized SMC1A‐mutated patients (from 44 to 52) and the restricted repertoire of SMC1A mutations (from 29 to 34), contributing to the molecular and clinical signature of SMC1A‐based CdLS. © 2013 Wiley Periodicals, Inc.

Clinical utility gene card for: Cornelia de Lange syndrome

“…Moreover, 33 larger deletions and one balanced translocation have been reported as well. A much smaller percentage of patients (~4-6%) have mutations in the cohesin complex gene SMC1A, [6][7][8] in which 34 mutations have been identified so far, 9 including missense mutations (82%) or in-frame deletions (18%). No frameshift or nonsense mutations have been reported in this gene, possibly because they are lethal or lead to a different yet unrecognisable phenotype.…”

Two-step ATP-driven opening of cohesin head

“…6c): Smc1A residues K59, R62 and K149, and Smc3 residues H55, R61, K105, K106 and K157. In addition to the presence of Smc3-K105 and Smc3-K106, already involved in acetylation-regulated DNA binding 2, 32, 33, 38 , the presence of three additional amino acids in this group is noteworthy: Smc1A-K59 and Smc1A-R62, deletion of which has been related to CdLS 55, 59, 63 and Smc3-H55, mutation of which to Tyr has been associated with colorectal cancer 22, 54 .…”

“…5a and d). The variant residues Smc1A-N1166T and Smc3-Q1147E have been found in patients with CdLS 12, 55, 56 whereas mutated amino acids Smc3-D1143H and Smc3-A1148T have been related to acute myeloid leukaemia 21, 54 and colorectal cancer 54, 57 , respectively. The mutant Smc3-Q1147E was previously reported to potentially be involved in maintaining the dimerization contact between the Smc1A-head and Smc3-head domains 12 .…”

“…6c). This group includes two Lys residues proposed as involved in acetylation-regulated DNA binding 2, 32, 33, 38 , as well as other positive residues mutation of which has been related to CdLS 55, 59, 63 and cancer 22, 54 . In short, the starting point of our simulation corresponds to the head structure bound to Rad21-Cter, in a position compatible with the DNA-bound condition.…”

Efficient application of next-generation sequencing for the diagnosis of rare genetic syndromes

“…By direct sequencing of exon 9, we confirmed that this variant was present in the four affected sibs and in heterozygous form in the mother. The R469C mutation maps to the junction of the N-terminal coiled coil and the hinge, a region that is remarkably conserved 17 18. The PolyPhen (score=1)15 and SIFT (score=0)16 computer programs classify this missense mutation as damaging.…”