No mutation in RAS‐MAPK pathway genes in 30 patients with Kabuki syndrome

Kabuki (Niikawa-Kuroki) syndrome (KS) is a multiple congenital anomaly/mental retardation (MCA/MR) syndrome characterized by long palpebral fissures with eversion of the lower eyelids, skeletal anomalies, persistence of fingerpads, short stature, joint laxity, and occasional immune abnormalities. Previous molecular cytogenetic approaches including fluorescence in situ hybridization and whole-genome CGH microarray analysis failed to find copy-number changes in the genome of KS patients. Recently, germline mutations in PTPN11/KRAS/SOS1/RAF1, HRAS, and KRAS/BRAF/MEK1/MEK2 were shown to be causes of Noonan syndrome, Costello syndrome and cardio-facio-cutaneous syndrome, respectively. Since KS patients share some phenotypical manifestations with the syndromes above, we hypothesized that KS may be associated with mutations in genes involving the RAS-MAPK pathway. Sixteen genes (PTPN11, GRB2, SOS1, HRAS, ERAS, NRAS, KRAS, ARAF, BRAF, RAF1, MEK1, MEK2, RASA1, RASA2, RASA3, and RASA4) in the pathway were screened for mutations. DNA from 30 KS patients (14 females and 16 males) was sequenced for entire coding regions and splice junctions of the 16 genes. We identified 29 base substitutions in the genes, including 9 nonsynonymous changes, 18 synonymous changes, one in 5’ untranslated region and one at position “-4” in splice acceptor site. But they were almost all confirmed as SNPs listed in the NCBI database or found in 82-89 normal Japanese individuals, while two of them were rare variants with nonsynonymous changes