NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations.
The Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphia, upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. Both missense and protein-truncating mutations in NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene, have recently been reported to cause CdLS. The function of NIPBL in mammals is unknown. The Drosophila Nipped-B protein facilitates long-range enhancer-promoter interactions and plays a role in Notch signaling and other developmental pathways, as well as being involved in mitotic sister-chromatid cohesion. We report the spectrum and distribution of NIPBL mutations in a large well-characterized cohort of individuals with CdLS. Mutations were found in 56 (47%) of 120 unrelated individuals with sporadic or familial CdLS. Statistically significant phenotypic differences between mutation-positive and mutation-negative individuals were identified. Analysis also suggested a trend toward a milder phenotype in individuals with missense mutations than in those with other types of mutations.
Gillis
Lynette A
LA
Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA.
McCallum
Jennifer
J
Kaur
Maninder
M
DeScipio
Cheryl
C
Yaeger
Dinah
D
Mariani
Allison
A
Kline
Antonie D
AD
Li
Hui-hua
HH
Devoto
Marcella
M
Jackson
Laird G
LG
Krantz
Ian D
ID
D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins; D017124:Conserved Sequence / Q000235:genetics; D004252:DNA Mutational Analysis; D003635:De Lange Syndrome / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*; D016415:Sequence Alignment
D018797:Cell Cycle Proteins; C487465:NIPBL protein, human; D011506:Proteins