Relevance of SOX17 variants for hypomyelinating leukodystrophies and congenital anomalies of the kidney and urinary tract (CAKUT).

The SRY-BOX17 gene (SOX17) encodes a transcription factor playing a key role in different developmental processes including endoderm formation, cardiac myogenesis, kidney/urinary development and differentiation of oligodendrocytes, the brain myelinating cells. In a candidate gene approach, we analyzed the SOX17 gene in hypomyelinating leukodystrophies (HL) characterized by a permanent deficit in the amount of central nervous system myelin. Five genes are involved in the aetiology of HL but 40% of HL remains without known genetic origin (UHL). New sequence variations in SOX17 were identified but all correspond to nonpathogenic variants, suggesting that SOX17 is not involved in UHL phenotype. In one patient, we identified the c.775T>A (p.Tyr259Asn) variation already reported as causative of congenital kidney and urinary tract abnormalities (CAKUT). Nevertheless, since our patient did not present such a phenotype, we propose that this variant may alternatively represent an "at-risk" allele for CAKUT rather than a causative allele. This observation strengthens the idea that caution must be taken when linking genetic variation to disease, especially in discrete phenotypes such as CAKUT.