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Genetic Diagnosis of Renal Diseases: Basic Concepts and Testing

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Pediatric Kidney Disease

Abstract

The genomic architecture of kidney disease has fascinated developmental biologists and human geneticists for over four decades. Seminal discoveries of note include the discovery of genes implicated in autosomal dominant/recessive polycystic kidney disease, nephronophthisis and nephrotic syndrome. Uncovering disease-causing genes has not only helped refine our pathogenetic understanding of many renal diseases, but in many cases it has directly translated into concrete improvement of patient care. The recent emergence of next generation sequencing strategies has dramatically accelerated the discovery process, and constitutes the cornerstone towards the realization of personalized medicine. This chapter provides a brief overview of basic genomic/genetic concepts before delving into recent advances that are pertinent to the practice of contemporary pediatric nephrologists. From laboratory methods to interpretation of genetic variants, every topic is presented within a clinical framework and is enriched with numerous examples from the pediatric nephrology literature. The major benefits of genomics on the day-to-day practice of busy clinicians are as follows: it will expediate diagnosis, clarify prognosis and guide therapeutic choices. Our overarching goals for this chapter were twofolds: to first convince clinicians “already overloaded with information” that learning about genomics is a worthwhile investment that will pay dividends in the short-term, while at the same time providing an accessible port of entry into this complex field.

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Author information

Authors and Affiliations

  1. Department of Nephrology, Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK

    Aoife Waters

  2. Division of Nephrology, The Hospital for Sick Children Scientist-track Investigator, Sick Kids Research Institute, 686 BAy street, Toronto, M5G0A4, Canada

    Mathieu Lemaire

Authors
  1. Aoife Waters
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  2. Mathieu Lemaire
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Correspondence to Aoife Waters or Mathieu Lemaire .

Editor information

Editors and Affiliations

  1. Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada

    Denis F. Geary

  2. Division of Pediatric Nephrology, University of Heidelberg, Heidelberg, Germany

    Franz Schaefer

Glossary of Terms

Alleles

Alternative forms of a gene at the same locus

Alternative splicing

Formation of diverse mRNAs through differential splicing of an mRNA precursor

Autosome

Any chromosome (1–22) other than the sex chromosomes X and Y

cDNA, complementary DNA

DNA sequence that contains only exonic sequences and was made from an mRNA molecule

Centimorgan

Length of DNA that on average has 1 crossover per 100 gametes

Cis

Location of two genes/changes on the same chromosome

Codon

Three consecutive bases/nucleotides in DNA/RNA that specify an amino acid

Compound heterozygote

Individual with two different mutant alleles at a locus

Consanguineous

Mating between individuals who share at least one common ancestor

Conservation

Sequence similarity for genes present in two distinct organisms or for gene families; can be detected by measuring the sequence similarity at the nucleotide (DNA or RNA) or amino acid (protein) level

Crossover

Exchange of genetic material between homologous chromosomes during meiosis

Digenic inheritance

Two genes interacting to produce a disease phenotype

Diploid

Chromosome number of somatic cells

Domain

Segment of a protein associated with a specialized structure or function

Dominant

Trait expressed in the heterozygote

Downstream

Sequence that is distal or 3′ from the reference point

Empiric risk

Recurrence risk based on experience rather than calculation

Epigenetics

Term describing nonmutational phenomena (e.g., methylation and acetylation) that modify the expression of a gene

Euchromatin

Majority of nuclear DNA that remains relatively unfolded during most of the cell cycle and is therefore accessible to transcriptional machinery

Exon

Segment of a gene (usually protein coding) that remains after splicing of the primary RNA transcript

Expressivity

Variation in the severity of a genetic trait

Genotype

Genetic constitution of the organism; usually refers to a particular pair of alleles the individual carries at a given locus of the genome

Germline

Cell lineage resulting in eggs or sperm

Germline mutation

Any detectable, heritable variation in the lineage of germ cells transmitted to offspring while those in somatic cells are not

Gonadal (germline) mosaicism

Occurrence of more than one genetic constitution in the precursor cells of eggs or sperm

Haplotype

Group of nearby, closely linked alleles inherited together as a unit

Heterozygote

Person with one normal and one mutant allele at a given locus on a pair of homologous chromosomes

Homozygote

Person with identical alleles at a given locus on a pair of homologous chromosomes

Imprinting

Parent-specific expression or repression of genes or chromosomes in offspring

Intron

Segment of a gene transcribed into the primary RNA transcript but excised during exon splicing, thus does not code for a protein

Isodisomy, uniparental

Inheritance of two copies of one homologue of a chromosome from one parent, with loss of the corresponding homologue from the other parent

Karyotype

Classified chromosome complement of an individual or a cell

Lyon hypothesis (X inactivation)

Principle of inactivation of one of the two X chromosomes in normal female cells (first proposed by Dr. Mary Lyon)

Mendelian

Following patterns of inheritance originally proposed by Gregor Mendel

Monogenic disorder

Caused by mutations in a single gene

Mosaicism

Occurrence of more than one genetic constitution arising in an individual after fertilization

Multifactorial disorder

Caused by the interaction of multiple genetic and environmental factors

Mutation

Change from the normal to an altered form of a particular gene that has harmful; pathogenic effects

Oligogenic inheritance

Character that is determined by a small number of genes acting together

Penetrance

Frequency with which a genotype manifests itself in a given phenotype

Phenotype

Visible expression of the action of a particular gene; the clinical picture resulting from a genetic disorder

Pleiotropy

Multiple effects of a single gene

Polymerase chain reaction (PCR)

Amplification of DNA using a specific technique that allows analysis of minute original amounts of DNA

Polymorphism

Usually used for any sequence variant present at a frequency greater than 1 % in a population

Recessive

A trait expressed only when both alleles at a given genetic locus are altered

Recombination

Separation of alleles that are close together on the same chromosome by crossing over of homologous chromosomes at meiosis

SNP (single nucleotide polymorphism)

Usually used for any sequence variant present at a frequency greater than 1 % in a population

Somatic

Involving the body cells rather than the germline

Syndrome, genetic

Nonrandom combination of features

Teratogen

Any agent causing congenital malformations

Trans

Location of two genes/changes on opposite chromosomes of a pair

Transcription

Production of mRNA from the DNA template

Translation

The process by which protein is synthesized from an mRNA sequence

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Waters, A., Lemaire, M. (2016). Genetic Diagnosis of Renal Diseases: Basic Concepts and Testing. In: Geary, D., Schaefer, F. (eds) Pediatric Kidney Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-52972-0_4

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