Novel susceptibility genes for non-NF2-/LZTR1-/SMARCB1-related hereditary schwannomatosis

Schwannomatosis refers to a group of rare genetic syndromes characterized by a predisposition to develop nerve sheath tumors, specifically schwannomas. Although germline and mosaic (described in the NF2 gene) pathogenic variants in NF2, SMARCB1, and LZTR1 account for the majority of cases, a subset of affected individuals remains without a definitive molecular diagnosis, including those associated with 22q loss of heterozygosity at the tumor level. The absence of a specific disease cause limits effective risk assessment, clinical surveillance, and genetic counselling. In recent years, advances in sequencing technologies have facilitated the identification of novel candidate driver genes. However, the rarity of these findings makes it challenging to establish their pathogenic relevance. This review aims to evaluate the current knowledge of genetic contributors to schwannomatosis in patients for whom routine genetic testing fails to detect a molecular cause in the known associated genes. On chromosome 22, DGCR8 and SOX10 have emerged as novel susceptibility genes, supported by accumulating molecular and clinical data. In addition, genes such as CDKN2A and SMARCA4 may also contribute to schwannomatosis in the context of broader tumor predisposition syndromes. These emerging genetic associations may help explain a proportion of schwannomatosis cases that currently lack a molecular diagnosis, while there is still room for the discovery of non-coding alleles or mosaic forms of known schwannomatosis-related conditions as well as novel genes that could explain unresolved cases.