title: Comprehensive mutational analysis of a cohort of Swedish Cornelia de Lange syndrome patients.
abstract: Cornelia de Lange syndrome (CdLS; OMIM 122470) is a rare multiple congenital anomaly/mental retardation syndrome characterized by distinctive dysmorphic facial features, severe growth and developmental delay and abnormalities of the upper limbs. About 50% of CdLS patients have been found to have heterozygous mutations in the NIPBL gene and a few cases were recently found to be caused by mutations in the X-linked SMC1L1 gene. We performed a mutation screening of all NIPBL coding exons by direct sequencing in 11 patients (nine sporadic and two familial cases) diagnosed with CdLS in Sweden and detected mutations in seven of the cases. All were de novo, and six of the mutations have not been previously described. Four patients without identifiable NIPBL mutations were subsequently subjected to multiplex ligation-dependent probe amplification analysis to exclude whole exon deletions/duplications of NIPBL. In addition, mutation analysis of the 5' untranslated region (5' UTR) of NIPBL was performed. Tiling resolution array comparative genomic hybridization analysis was carried out on these four patients to detect cryptic chromosome imbalances and in addition the boys were screened for SMC1L1 mutations. We found a de novo 9p duplication with a size of 0.6 Mb in one of the patients with a CdLS-like phenotype but no mutations were detected in SMC1L1. So far, two genes (NIPBL and SMC1L1) have been identified causing CdLS or CdLS-like phenotypes. However, in a considerable proportion of individuals demonstrating the CdLS phenotype, mutations in any of these two genes are not found and other potential loci harboring additional CdLS-causing genes should be considered.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Karolinska University Hospital Solna, Stockholm, Sweden. jacqueline.schoumans@ki.se
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Schoumans
authors.forename: Josephine
authors.initials: J
authors.lastname: Wincent
authors.forename: Michela
authors.initials: M
authors.lastname: Barbaro
authors.forename: Tatjana
authors.initials: T
authors.lastname: Djureinovic
authors.forename: Paula
authors.initials: P
authors.lastname: Maguire
authors.forename: Lena
authors.initials: L
authors.lastname: Forsberg
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.forename: Ann Charlotte
authors.initials: AC
authors.lastname: Thuresson
authors.forename: Ake
authors.initials: A
authors.lastname: Borg
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
authors.forename: Gunilla
authors.initials: G
authors.lastname: Malm
authors.forename: Britt Marie
authors.initials: BM
authors.lastname: Anderlid
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D043171:Chromosomal Instability; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003635:De Lange Syndrome / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D009693:Nucleic Acid Hybridization; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D013548:Sweden; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D020121:5' Untranslated Regions; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C487465:NIPBL protein, human; D011506:Proteins; D000098550:Structural Maintenance of Chromosome Protein 1