New variant in KITLG shapes the pathogenesis of familial progressive hyper- and hypo-pigmentation.

Familial progressive hyper- and hypo-pigmentation (FPHH) is a pigmentary disorder characterized by a mixture of hypo- and hyper-pigmentation lesions, brown spots, and hypo-pigmentation gray leaf spots. This disease had previously been reported to be associated with the KITLG gene. In this study, whole exome sequencing was performed to identify the gene mutation in two patients suspected with FPHH. Functional changes were explored at a cellular level with the help of adenine base editors, and the differentially expressed genes in the melanin pathway were detected through RNA-sequencing. Mutations were identified in two patients at exon 4 of KITLG (NM_000899.4): [c.329 A > T] and [c.329 A > G]. The c.329 A > G is a de novo mutation. The two variations were located in a conservative region and were predicted to be likely pathogenic mutations. For de novo c.329 A > G mutation, results showed that the mutation broadly affected the transcription and translation of genes responsible for melanin synthesis, especially the melanin gene MITF. These results indicated that the conservative locus c.329 A had an important function to KITLG, mutations [c.329 A > T] and [c.329 A > G] in KITLG could result FPHH. Based on the functional tests, c.329 A > G could be pathogenic mutant. This study has an important clinical significance, and it would extend the mutation spectrum of KITLG gene. It would improve the disease knowledge base and offer a reliable reference for the clinical diagnosis and prevention of FPHH.