Dominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children.
- Vivante A Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA.
- Chacham OS Metabolic Clinic, Pediatric Division, Soroka University Medical Center, Ben-Gurion University, Beer Sheva, Israel.
- Shril S Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA.
- Schreiber R Faculty of Health Sciences, Pediatric Nephrology Clinic, Pediatric Division, Soroka University Medical Center, Ben-Gurion University, 84101, Beer Sheva, Israel.
- Mane SM Department of Genetics, Yale University School of Medicine, New Haven, CT, 06510, USA.
- Pode-Shakked B 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.
- Soliman NA Department of Pediatrics, Kasr Al Ainy School of Medicine, Cairo, Egypt and Egyptian Group for Orphan Renal Diseases (EGORD), Cairo University, Cairo, Egypt.
- Koneth I Department of Nephrology and Transplantation Medicine, Kantonsspital St. Gallen, St. Gallen, Switzerland.
- Schiffer M Clinic for Nephrology and Hypertension Ulmenweg 18, 91054, Erlangen, Germany.
- Anikster Y 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.
- Hildebrandt F Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA. friedhelm.hildebrandt@childrens.harvard.edu.
- 2019-04-20
Published in:
- Pediatric nephrology (Berlin, Germany). - 2019
Congenital anomalies of the kidneys and urinary tract (CAKUT)
FSGS
SRNS and PAX2
Adolescent
Age of Onset
Child
Child, Preschool
Cohort Studies
DNA Mutational Analysis
Drug Resistance
Female
Genetic Predisposition to Disease
Genetic Testing
Glomerulosclerosis, Focal Segmental
Glucocorticoids
Heterozygote
Humans
Infant
Male
Mutation
Nephrotic Syndrome
PAX2 Transcription Factor
Pedigree
Whole Exome Sequencing
Young Adult
English
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.
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.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1007/s00467-019-04256-0
- PMID 31001663
- Persistent URL
- https://sonar.ch/global/documents/628
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