Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity.
Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering and identified 5 novel candidate genes (RBM48, FAM186B, PIAS1, INCENP, and RCOR1) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis, and allows identification of novel candidate genes.
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Daniela A
DA
Braun
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Markus
M
Schueler
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jan
J
Halbritter
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Heon Yung
HY
Gee
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jonathan D
JD
Porath
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jennifer A
JA
Lawson
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Rannar
R
Airik
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Shirlee
S
Shril
Department of Pediatrics, University of Michigan, Michigan, USA.
Susan J
SJ
Allen
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Deborah
D
Stein
Department of Genetics, Sultan Qaboos University Hospital, Sultanate of Oman.
Adila
A
Al Kindy
Institute for Human Genetics, University of Cologne, Germany.
Bodo B
BB
Beck
Baskent University, School of Medicine, Adana Medical Training and Research Center, Department of Pediatric Nephrology, Adana, Turkey.
Nurcan
N
Cengiz
Department of Pediatric Nephrology, National Institute of Child Health, Karachi 75510, Pakistan.
Khemchand N
KN
Moorani
Faculty of Medicine, Department of Pediatric Nephrology, Hacettepe University, Ankara, Turkey.|Nephrogenetics Laboratory, Faculty of Medicine, Department of Pediatric Nephrology, Hacettepe University, Ankara, Turkey.|Center for Biobanking and Genomics, Hacettepe University, Ankara, Turkey.
Fatih
F
Ozaltin
Department of Pediatric Nephrology, Sindh Institute of Urology and Transplantation, SIUT, Karachi, Pakistan.
Seema
S
Hashmi
Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle NE1 3BZ, UK.
John A
JA
Sayer
University College London, Institute of Child Health and Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Detlef
D
Bockenhauer
Department of Pediatrics, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt.|Egyptian Group for Orphan Renal Diseases (EGORD), Cairo, Egypt.
Neveen A
NA
Soliman
Department of Pediatrics, University of Michigan, Michigan, USA.
Edgar A
EA
Otto
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.|Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, Connecticut, USA.|Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Richard P
RP
Lifton
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Friedhelm
F
Hildebrandt
D017668:Age of Onset; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D059472:Exome; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000151:congenital / Q000235:genetics; D051436:Renal Insufficiency, Chronic / Q000000981:diagnostic imaging / Q000235:genetics*