期刊
CLINICAL GENETICS
卷 84, 期 6, 页码 539-545出版社
WILEY-BLACKWELL
DOI: 10.1111/cge.12081
关键词
genotype-phenotype correlation; Kabuki syndrome; MLL2; Niikawa-Kuroki syndrome
资金
- Netherlands Organization for Health Research and Development (ZonMW) [917-66-36, 911-08-025, 917-86-319, 916-12-095]
- EU [Health-F5-2009-223143]
- AnEUploidy project [LSHG-CT-2006-37627]
- SNF
- Gebert grant
- Australian NHMRC [512123]
- Bodossaki Foundation
- Swedish Medical Research Council
- National Institute for Health Research [NF-SI-0507-10379] Funding Source: researchfish
Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median MLL2-Kabuki score' of 5), a significant difference (p<0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.
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