Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome.
Cardio-facio-cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of the RAS-RAF-MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF, MAP2K1, MAP2K2 and KRAS, HRAS alterations are almost exclusively associated with CS. We carried out a comprehensive mutation analysis in 51 CFC-affected patients and 31 individuals with CS. Twelve different BRAF alterations were found in twenty-four patients with CFC (47.0%), two MAP2K1 mutations in five (9.8%) and two MAP2K2 sequence variations in three CFC-affected individuals (5.9%), whereas three patients had a KRAS alteration (5.9%). We identified four different missense mutations of HRAS in twenty-eight cases with CS (90.3%), while KRAS mutations were detected in two infants with a phenotype meeting criteria for CS (6.5%). In 14 informative families, we traced the parental origin of HRAS alterations and demonstrated inheritance of the mutated allele exclusively from the father, further confirming a paternal bias in the parental origin of HRAS mutations in CS. Careful clinical evaluation of patients with BRAF and MAP2K1/2 alterations revealed the presence of slight phenotypic differences regarding craniofacial features in MAP2K1- and MAP2K2-mutation positive individuals, suggesting possible genotype-phenotype correlations.
Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
A L
AL
Schulz
B
B
Albrecht
C
C
Arici
I
I
van der Burgt
A
A
Buske
G
G
Gillessen-Kaesbach
R
R
Heller
D
D
Horn
C A
CA
Hübner
G C
GC
Korenke
R
R
König
W
W
Kress
G
G
Krüger
P
P
Meinecke
J
J
Mücke
B
B
Plecko
E
E
Rossier
A
A
Schinzel
A
A
Schulze
E
E
Seemanova
H
H
Seidel
S
S
Spranger
B
B
Tuysuz
S
S
Uhrig
D
D
Wieczorek
K
K
Kutsche
M
M
Zenker
D000015:Abnormalities, Multiple / Q000235:genetics*; D000328:Adult; D002648:Child; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities; D019066:Facies; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D048370:MAP Kinase Kinase 2 / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012868:Skin Abnormalities / Q000235:genetics*; D013577:Syndrome; D018631:ras Proteins / Q000235:genetics
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins