Soma-to-germline transformation in chromatin-linked neurodevelopmental disorders?

Mutations in numerous chromatin regulators cause neurodevelopmental disorders (NDDs) with unknown mechanisms. Understandably, most research has focused on how chromatin regulators control gene expression that is directly relevant to brain development and function, such as synaptic genes. However, some NDD models surprisingly show ectopic expression of germline genes in the brain. These germline genes are usually expressed only in the primordial germ cells, testis, and ovaries for germ cell development and sexual reproduction. Such ectopic germline gene expression has been reported in several NDDs, including immunodeficiency, centromeric instability, facial anomalies syndrome 1; Kleefstra syndrome 1; MeCP2 duplication syndrome; and mental retardation, X-linked syndromic, Claes-Jensen type. The responsible genes, DNMT3B, G9A/GLP, MECP2, and KDM5C, all encode chromatin regulators for gene silencing. These mutations may therefore lead to germline gene derepression and, in turn, a severe identity crisis of brain cells-potentially interfering with normal brain development. Thus, the ectopic expression of germline genes is a unique hallmark defining this NDD subset and further implicates the importance of germline gene silencing during brain development. The functional impact of germline gene expression on brain development, however, remains undetermined. This perspective article explores how this apparent soma-to-germline transformation arises and how it may interfere with neurodevelopment through genomic instability and impaired sensory cilium formation. Furthermore, we also discuss how to test these hypotheses experimentally to ultimately determine the contribution of ectopic germline transcripts to chromatin-linked NDDs.