Premium
Mutation and phenotypic spectrum in patients with cardio‐facio‐cutaneous and Costello syndrome
Author(s) -
Schulz AL,
Albrecht B,
Arici C,
Van Der Burgt I,
Buske A,
GillessenKaesbach G,
Heller R,
Horn D,
Hübner CA,
Korenke GC,
König R,
Kress W,
Krüger G,
Meinecke P,
Mücke J,
Plecko B,
Rossier E,
Schinzel A,
Schulze A,
Seemanova E,
Seidel H,
Spranger S,
Tuysuz B,
Uhrig S,
Wieczorek D,
Kutsche K,
Zenker M
Publication year - 2008
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/j.1399-0004.2007.00931.x
Subject(s) - costello syndrome , phenotype , mutation , genetics , medicine , biology , gene , kras
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.