NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype.
In 5-10% of patients, neurofibromatosis type 1 (NF1) results from microdeletions that encompass the entire NF1 gene and a variable number of flanking genes. Two recurrent microdeletion types are found in most cases, with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion). A more severe phenotype is usually associated with NF1 microdeletion patients than in those with intragenic mutations. We characterized NF1 microdeletions in 70 unrelated NF1 microdeleted patients using a high-resolution NF1 custom array comparative genomic hybridization (CGH). Genotype-phenotype correlations were studied in 58 of these microdeletion patients and compared to 389 patients with intragenic truncating NF1 mutations and phenotyped in the same standardized way. Our results confirmed in an unbiased manner the existence of a contiguous gene syndrome with a significantly higher incidence of learning disabilities and facial dysmorphism in microdeleted patients compared to patients with intragenic NF1 mutations. Microdeleted NF1 patients also showed a trend toward significance for childhood overgrowth. High-resolution array-CGH identified a new recurrent approximately 1.0 Mb microdeletion type, designated as type-3, with breakpoints in the paralogous regions middle NF1-REP-b and distal NF1-REP-c.
UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 av. de l'Observatoire, 75006, Paris, France. eric.pasmant@etu.univ-paris5.fr
Eric
E
Pasmant
Audrey
A
Sabbagh
Gill
G
Spurlock
Ingrid
I
Laurendeau
Elisa
E
Grillo
Marie-José
MJ
Hamel
Ludovic
L
Martin
Sébastien
S
Barbarot
Bruno
B
Leheup
Diana
D
Rodriguez
Didier
D
Lacombe
Hélène
H
Dollfus
Laurent
L
Pasquier
Bertrand
B
Isidor
Salah
S
Ferkal
Jean
J
Soulier
Marc
M
Sanson
Anne
A
Dieux-Coeslier
Ivan
I
Bièche
Béatrice
B
Parfait
Michel
M
Vidaud
Pierre
P
Wolkenstein
Meena
M
Upadhyaya
Dominique
D
Vidaud
D000328:Adult; D055028:Comparative Genomic Hybridization; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics*; D010641:Phenotype; D012044:Regression Analysis; D017384:Sequence Deletion; D055815:Young Adult
D025542:Neurofibromin 1