A de novo mutation of ADAMTS8 in a patient with Wiedemann-Steiner syndrome.

Background: Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant disorder caused by mutations in the KMT2A gene and is usually characterized by hairy elbows, short stature, developmental delay, intellectual disability and obvious facial dysmorphism.

Case Presentation: Here, we report a 5-year-old girl with clinical features similar to WDSTS, including postnatal growth delay, retarded intellectual development, and ocular hypertelorism. Through whole-exome sequencing (WES), a frameshift variant of KMT2A was found in the patient but not in her parents' genomic DNA. By bioinformatics analysis, the KMT2A variant was demonstrated to be the top candidate pathogenic variant for the clinical phenotype consistent with WDSTS. Moreover, a duplication of exon 1 in ADAMTS8 (belonging to the zinc metalloproteinase family) was found in the genomic DNA of this patient, which may be responsible for the characteristics that are different from those of WDSTS, including early teething, rapid tooth replacement, and dysplastic enamel.

Conclusions: From the above results, we propose that in our patient, the frameshift variant in KMT2A is the main reason for the WDSTS phenotype, and the unreported mutation in ADAMTS8 may be the candidate reason for other characteristics that are different from those of WDSTS. Therefore, this study not only provides a new KMT2A variant associated with WDSTS but is also a reminder that combined mutations may be present in a case with more characteristics than those seen in WDSTS.