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 Sep

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
PubMed Central IDPMC6660980
Grant ListR01 DK076683 / DK / NIDDK NIH HHS / United States
S10 OD018521 / OD / NIH HHS / United States
R01-DK076683 / NH / NIH HHS / United States
UM1 HG008900 to DGM and HLR and U54 HG006504 to RPL) / NH / NIH HHS / United States