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.
Pasmant
Eric
E
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
Sabbagh
Audrey
A
Spurlock
Gill
G
Laurendeau
Ingrid
I
Grillo
Elisa
E
Hamel
Marie-José
MJ
Martin
Ludovic
L
Barbarot
Sébastien
S
Leheup
Bruno
B
Rodriguez
Diana
D
Lacombe
Didier
D
Dollfus
Hélène
H
Pasquier
Laurent
L
Isidor
Bertrand
B
Ferkal
Salah
S
Soulier
Jean
J
Sanson
Marc
M
Dieux-Coeslier
Anne
A
Bièche
Ivan
I
Parfait
Béatrice
B
Vidaud
Michel
M
Wolkenstein
Pierre
P
Upadhyaya
Meena
M
Vidaud
Dominique
D
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