Approximately 20% of cases of chronic kidney disease (CKD) that manifest before the age of 25 years are caused by single gene mutations in any one of >200 different genes
Molecular genetic diagnostics can provide patients with a molecular diagnosis for their disease and can generate new insights into disease mechanisms
Molecular genetic diagnostics might also have consequences for personalized treatment and prevention of CKD
Indication-driven mutation analysis panels are available to guide the genetic diagnosis of common early-onset kidney diseases, such as congenital anomalies of the kidneys and urinary tract, steroid-resistant nephrotic syndrome, ciliopathies and nephrolithiasis
The primary causes of chronic kidney disease (CKD) in children differ from those of CKD in adults. In the USA the most common diagnostic groups of renal disease that manifest before the age of 25 years are congenital anomalies of the kidneys and urinary tract, steroid-resistant nephrotic syndrome, chronic glomerulonephritis and renal cystic ciliopathies, which together encompass >70% of early-onset CKD diagnoses. Findings from the past decade suggest that early-onset CKD is caused by mutations in any one of over 200 different monogenic genes. Developments in high-throughput sequencing in the past few years has rendered identification of causative mutations in this high number of genes feasible. Use of genetic analyses in patients with early onset-CKD will provide patients and their families with a molecular genetic diagnosis, generate new insights into disease mechanisms, facilitate aetiology-based classifications of patient cohorts for clinical studies, and might have consequences for personalized approaches to the prevention and treatment of CKD. In this Review, we discuss the implications of next-generation sequencing in clinical genetic diagnostics and the discovery of novel genes in early-onset CKD. We also delineate the resulting opportunities for deciphering disease mechanisms and the therapeutic implications of these findings.
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The authors' work described in this Review was supported by grants from the NIH (R01-DK088767 to F.H.) and by the March of Dimes Foundation (6FY11-241). A.V. is a recipient of the Fulbright postdoctoral scholar award for 2013 and is also supported by grants from the Manton Center Fellowship Program, Boston Children's Hospital, Boston, Massachusetts, USA, and the Mallinckrodt Research Fellowship Award.
F.H. receives royalties for a mutation analysis panel that is licensed to Claritas Genomics. A.V. declares no competing interests.
The proportion of individuals who express a certain phenotype in relation to the number of individuals that carry the pathogenic variant(s). Incomplete penetrance refers to the observation that some individuals with the mutation do not develop the disease phenotype.
- Next-generation sequencing
A DNA sequencing method that enables simultaneous sequencing of multiple DNA segments in a high-throughput manner. Also known as massively parallel sequencing.
- Whole exome sequencing
Targeted capture and sequencing of the exome using next-generation sequencing. This method offers a powerful approach towards the identification of monogenic disease-causing genes.
A difference in a DNA sequence compared to a 'normal' reference sequence. A variant can be benign (for example, a single nucleotide polymorphism) or disease-causing (for example, a mutation).
Specific DNA sequence variant in a given gene. Alleles can be designated according to their frequency as common or rare alleles.
The observable characteristics of an individual as a morphological, clinical or biochemical trait. A phenotype can also be the presence or absence of a disease.
The set of alleles (variants of genes) that structure an individual's genetic makeup.
Variation of the expression of the phenotype among affected individuals with the same genotype. Variable expressivity refers to different degrees of severity and/or organ involvement in different affected individuals that carry an identical mutation.
The protein coding part of a gene. Exons are spliced together following gene transcription to form mRNA, which is translated into protein.
The protein coding sequences of the entire genome (comprising ∼1% of the human genome).
- Variant filtering
The process of excluding variants as disease-causing. For instance, very common variants and variants that do not alter the protein sequence are excluded.
- Homozygosity mapping
A technique in which the homozygous regions across the genome are identified. This strategy is effective for the discovery of autosomal recessive monogenic disease genes in consanguineous families.
A variation in a phenotype of given trait that can mimick a different trait.
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Vivante, A., Hildebrandt, F. Exploring the genetic basis of early-onset chronic kidney disease. Nat Rev Nephrol 12, 133–146 (2016). https://doi.org/10.1038/nrneph.2015.205
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