PNPT1 and Alexander disease: This enrichment was 30-fold when focusing on WM-PVS loci only, comprising several genes involved in early-onset leukodystrophies: GFAP (chr17q21.31), mutations of which cause Alexander disease, a rare neurodegenerative disorder of astrocytes leading to psychomotor regression and death; SLC13A3 (chr20q13.12), causing acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate; and PNPT1 (chr2p16.1), causing Aicardi–Goutières syndrome and cystic leukoencephalopathy (Methods, Extended Data Fig. 4 and Supplementary Table 22).