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.
| Original language | English |
|---|---|
| Pages (from-to) | 2909-2919 |
| Number of pages | 11 |
| Journal | American Journal of Medical Genetics, Part A |
| Volume | 161 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 2013 |
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Keywords
- Cornelia de Lange syndrome
- Gender effect
- Genotype-phenotype correlations
- In silico prediction tools
- SMC1A mutations
ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Cornelia de Lange individuals with new and recurrent SMC1A mutations enhance delineation of mutation repertoire and phenotypic spectrum. / Gervasini, Cristina; Russo, Silvia; Cereda, Anna; Parenti, Ilaria; Masciadri, Maura; Azzollini, Jacopo; Melis, Daniela; Aravena, Teresa; Doray, Bérénice; Ferrarini, Alessandra; Garavelli, Livia; Selicorni, Angelo; Larizza, Lidia.
In: American Journal of Medical Genetics, Part A, Vol. 161, No. 11, 11.2013, p. 2909-2919.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Cornelia de Lange individuals with new and recurrent SMC1A mutations enhance delineation of mutation repertoire and phenotypic spectrum
AU - Gervasini, Cristina
AU - Russo, Silvia
AU - Cereda, Anna
AU - Parenti, Ilaria
AU - Masciadri, Maura
AU - Azzollini, Jacopo
AU - Melis, Daniela
AU - Aravena, Teresa
AU - Doray, Bérénice
AU - Ferrarini, Alessandra
AU - Garavelli, Livia
AU - Selicorni, Angelo
AU - Larizza, Lidia
PY - 2013/11
Y1 - 2013/11
N2 - 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.
AB - 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.
KW - Cornelia de Lange syndrome
KW - Gender effect
KW - Genotype-phenotype correlations
KW - In silico prediction tools
KW - SMC1A mutations
UR - http://www.scopus.com/inward/record.url?scp=84886314760&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84886314760&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.36252
DO - 10.1002/ajmg.a.36252
M3 - Article
C2 - 24124034
AN - SCOPUS:84886314760
VL - 161
SP - 2909
EP - 2919
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
SN - 1552-4825
IS - 11
ER -