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Pediatr Nephrol. 2019 Sep;34(9):1607-1613. doi: 10.1007/s00467-019-04256-0. Epub 2019 Apr 17.

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

Author information

1
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA.
2
Department of Pediatrics B and Pediatric Nephrology unit, Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
3
Metabolic Clinic, Pediatric Division, Soroka University Medical Center, Ben-Gurion University, Beer Sheva, Israel.
4
Faculty of Health Sciences, Pediatric Nephrology Clinic, Pediatric Division, Soroka University Medical Center, Ben-Gurion University, 84101, Beer Sheva, Israel.
5
Department of Genetics, Yale University School of Medicine, New Haven, CT, 06510, USA.
6
Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
7
Department of Pediatrics, Kasr Al Ainy School of Medicine, Cairo, Egypt and Egyptian Group for Orphan Renal Diseases (EGORD), Cairo University, Cairo, Egypt.
8
Department of Nephrology and Transplantation Medicine, Kantonsspital St. Gallen, St. Gallen, Switzerland.
9
Clinic for Nephrology and Hypertension Ulmenweg 18, 91054, Erlangen, Germany.
10
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA. friedhelm.hildebrandt@childrens.harvard.edu.

Abstract

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.

KEYWORDS:

Congenital anomalies of the kidneys and urinary tract (CAKUT); FSGS; SRNS and PAX2

PMID:
31001663
PMCID:
PMC6660980
[Available on 2019-10-01]
DOI:
10.1007/s00467-019-04256-0

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