Dominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children.

TitleDominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children.
Publication TypeJournal Article
Year of Publication2019
AuthorsVivante, A, Chacham, OStaretz, Shril, S, Schreiber, R, Mane, SM, Pode-Shakked, B, Soliman, NA, Koneth, I, Schiffer, M, Anikster, Y, Hildebrandt, F
JournalPediatr Nephrol
Date Published2019 Apr 17

BACKGROUND: Heterozygous PAX2 mutations cause renal coloboma syndrome (RCS) [OMIM no. 120330]. RCS is a renal syndromic disease encompassing retinal coloboma and sensorineural hearing loss. Recently, a causative role for PAX2 was reported in adult-onset nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS). However, the prevalence of PAX2 mutations among large cohort of children with steroid-resistant nephrotic syndrome (SRNS) and FSGS has not been systematically studied.

METHODS: We employed whole-exome sequencing (WES) to identify the percentage of SRNS cases explained by monogenic mutations in known genes of SRNS/FSGS. As PAX2 mutations are not an established cause of childhood FSGS, we evaluated a cohort of 215 unrelated families with SRNS, in whom no underlying genetic etiology had been previously established.

RESULTS: Using WES, we identified 3 novel causative heterozygous PAX2 mutations in 3 out of the 215 unrelated index cases studied (1.3%). All three cases were detected in individuals from families with more than one affected and compatible with an autosomal dominant mode of inheritance (3/57 familial cases studied (5.2%)). The clinical diagnosis in three out of four pediatric index patients was done during routine medical evaluation.

CONCLUSIONS: Our findings demonstrate high frequency of PAX2 mutations in familial form of SRNS (5.2%) and further expand the phenotypic spectrum of PAX2 heterozygous mutations to include autosomal dominant childhood-onset FSGS. These results highlight the importance of including PAX2 in the list of genes known to cause FSGS in children.

Alternate JournalPediatr. Nephrol.
PubMed ID31001663
Grant ListR01 DK076683 / DK / NIDDK NIH HHS / United States
R01-DK076683 / / National Institutes of Health /
UM1 HG008900 to DGM and HLR and U54 HG006504 to RPL) / / National Institutes of Health /