title: Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients.
abstract: Cornelia de Lange syndrome (CdLS) is a rare multisystemic congenital anomaly disorder that is characterised by intellectual disability and growth retardation, congenital heart defects, intestinal anomalies, facial dysmorphism (including synophyris and high arched eyebrows) and limb reduction defects. Mutations in three cohesin-associated genes encoding a key regulator (NIPBL, chr 5p13.2) and one structural component of the cohesin ring (SMC1A, chr Xp11) occur in about 65% of CdLS patients. NIPBL is the major causative gene, and accounts for 40-60% of CdLS patients as shown by a number of mutational screening studies that indicate a wide mutational repertoire of mainly small deletions and point mutations. Only a few data are available concerning the occurrence of large NIPBL rearrangements or intragenic deletions or duplications involving whole exons. We used multiplex ligation-dependent probe amplification (MLPA) to study 132 CdLS patients negative to the standard mutation NIPBL test out of a cohort of 200 CdLS patients. A total of 7 out of 132 patients were found to carry NIPBL alterations, including two large gene deletions extending beyond the gene, four intragenic multi- or single-exon deletions and one single-exon duplication. These findings show that MLPA leads to a 5.3% increase in the detection of mutations when used in addition to the standard NIPBL scan, and contributes per se to the molecular diagnosis of 3.5% (7/200) of clinically diagnosed CdLS patients. It is recommended that MLPA be included in the CdLS diagnostic flow chart.
authors.affiliation: Laboratory of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, Milan, Italy. s.russo@auxologico.it
authors.forename: Silvia
authors.initials: S
authors.lastname: Russo
authors.forename: Maura
authors.initials: M
authors.lastname: Masciadri
authors.forename: Cristina
authors.initials: C
authors.lastname: Gervasini
authors.forename: Jacopo
authors.initials: J
authors.lastname: Azzollini
authors.forename: Anna
authors.initials: A
authors.lastname: Cereda
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Oskar
authors.initials: O
authors.lastname: Haas
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Scarano
authors.forename: Maja
authors.initials: M
authors.lastname: Di Rocco
authors.forename: Palma
authors.initials: P
authors.lastname: Finelli
authors.forename: Romano
authors.initials: R
authors.lastname: Tenconi
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
mesh_terms: D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis / Q000379:methods*; D003635:De Lange Syndrome / Q000175:diagnosis / Q000235:genetics*; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D020440:Gene Duplication; D015321:Gene Rearrangement; D005820:Genetic Testing / Q000379:methods*; D015894:Genome, Human; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D011506:Proteins / Q000235:genetics*; D012680:Sensitivity and Specificity; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C487465:NIPBL protein, human; D011506:Proteins; D000098550:Structural Maintenance of Chromosome Protein 1