Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations.

Sotos syndrome is an overgrowth syndrome with characteristic facial dysmorphism, variable severity of learning disabilities and macrocephaly with overgrowth. Haploinsufficiency of the nuclear receptor SET domain-containing protein 1 (NSD1) gene located on 5q35 has been implicated as the cause of Sotos syndrome. This study was performed to investigate the mutation spectrum of NSD1 abnormalities and meaningful genotype-phenotype correlations in Korean patients with Sotos syndrome. Eighteen unrelated Korean patients with Sotos syndrome were enrolled for clinical and molecular analyses. Cytogenetic studies were performed to confirm 5q35 microdeletion, and NSD1 sequencing analysis was performed to identify intragenic mutations. NSD1 abnormalities were identified in 15 (83%) patients. Among them, eight patients (53%) had 5q35 microdeletions and the other seven patients (47%) had seven different NSD1 intragenic mutations including four novel mutations. The mutation spectrum of Korean patients with Sotos syndrome was similar to that of previous studies for Japanese patients. Height was significantly shorter and age of walking alone was significantly older in the microdeletion group compared with those in the intragenic mutation group. No significant differences were observed for other clinical characteristics between the microdeletion and intragenic mutation groups. Further studies with a larger number of patients will be necessary to draw conclusive genotype-phenotype correlations.

Molecular genetic analysis of TWIST1 and FGFR3 genes in Korean patients with coronal synostosis: identification of three novel TWIST1 mutations.

BACKGROUND: Craniosynostosis is very heterogeneous in terms of its causes, presentation, and management. In particular, coronal synostosis evidences a higher tendency to be genetically caused, and TWIST1 and FGFR3 have been identified as major causative genes. The authors analyzed the clinical and molecular characteristics of Korean patients with coronal synostosis in this study. METHODS: Forty-three Korean patients with unicoronal or bicoronal synostosis were included in this study. All samples were first screened for TWIST1 and FGFR3 mutation hot spots, and the negative samples were subsequently screened for FGFR2. The patients' clinical features were analyzed and compared. RESULTS: Seven sequence alterations (six in TWIST1 and one in FGFR3) were identified in 11 patients (25.6 percent). Three novel TWIST1 mutations were detected, and p.P250R was the only mutation in FGFR3. Bicoronal cases evidenced a much higher mutation detection rate (52.9 percent) than unicoronal cases (7.7 percent). In the TWIST1 group, five patients had Saethre-Chotzen syndrome, and one was nonsyndromic. In the FGFR3 group, four patients had Muenke syndrome, and one was nonsyndromic. The majority of associated anomalies, with the exception of psychomotor retardation and Chiari malformation, were detected more frequently in TWIST1 patients than in FGFR3 p.P250R patients. CONCLUSIONS: This study is, to the best of the authors' knowledge, the first to illustrate the frequency and spectrum of mutations in TWIST1 and FGFR3 in Korea. Considering that molecular diagnosis techniques can prove helpful in providing adequate genetic counseling and guidance, genetic screening for TWIST1 and FGFR3 p.P250R in cases of coronal synostosis is recommended.

Mutation spectrum of the TYR and SLC45A2 genes in patients with oculocutaneous albinism.

Oculocutaneous albinism (OCA) is a group of inherited disorders characterized by defective melanin biosynthesis. OCA1, the most common and severe form, is caused by mutations in the tyrosinase (TYR) gene. OCA4, caused by mutations in the SLC45A2 gene, has frequently been reported in the Japanese population. To determine the mutational spectrum in Korean OCA patients, 12 patients were recruited. The samples were first screened for TYR mutations, and negative samples were screened for SLC45A2 mutations. OCA1 was confirmed in 8 of 12 (66.7%) patients, and OCA4 was diagnosed in 1 (8.3%) patient. In the OCA1 patients, a total of 6 distinct TYR mutations were found in 15 of 16 (93.8%) alleles, all of which had been previously reported. Out of the 6 alleles, c.929insC was the most frequently detected (31.3%), and was mainly associated with OCA1A phenotypes. Other TYR mutations identified included c.1037-7T>A/c.1037-10delTT, p.D383N, p.R77Q and p.R299H. These largely overlapped with mutations found in Japanese and Chinese patients. The SLC45A2 gene analysis identified 1 novel mutation, p.D93N, in 1 patient. This study has provided information on the mutation spectrum in Korean OCA patients, and allows us to estimate the relative frequencies of OCA1 and OCA4 in Korea.