Elucidating the pathogenesis of Kabuki syndrome and a possible molecular genetic link between the two malformation syndromes CHARGE and Kabuki

• Applicants: Professorin Dr. Annette Borchers; Professorin Dr. Silke Pauli
• Subject Area: Human Genetics
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 281662349

Kabuki and CHARGE syndrome are two complex malformation syndromes. Due to clinical overlaps, a common pathogenesis has been suggested. During the first funding period, we showed that Kabuki syndrome, like CHARGE syndrome, belongs to the neurocristopathies, as neural crest development was likewise impaired. In addition, we were able to show that the proteins KMT2D and CHD7, involved in Kabuki and CHARGE syndrome, interact with each other and are members of the same chromatin modification and remodeling machinery. Using RNA sequencing, we identified common target genes and showed that CHD7 and KMT2D regulate each other. Interestingly, a novel syndromic phenotype has recently been described, which is caused by missense mutations in exons 38 and 39 of the KMT2D gene. The phenotype differs from the classic Kabuki and CHARGE syndrome by specific malformations that do not occur in these syndromes. However, it also shows characteristics of both syndromes. Thus, in the follow-up application, we will characterize this new syndrome using our established animal models and proteomics knowledge. In addition, we will perform studies using neural crest cells (isolated from Xenopus as well as generated from human iPS cells) to understand the pathogenesis – as well as the similarities to Kabuki and CHARGE syndrome – of this new disease. The understanding of the respective pathogenesis with genotype-phenotype correlation will provide important insights into clinical and molecular genetic diagnostics, as well as enable prognostic and preventive assistance for the affected patients and their families.

• DFG Programme: Research Grants