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Molecular Diagnosis of Genetic Diseases of the Kidney: Primer for Pediatric Nephrologists

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Pediatric Kidney Disease

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Abstract

In an age of competing medical priorities, why should healthcare professionals who are already overloaded with information develop core competencies in genetics and genomics? [1]

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 helped refine our pathogenetic understanding of many renal diseases, and in many cases, it has directly translated into a concrete improvement of patient care. The recent emergence of next-generation sequencing strategies has dramatically sped up the discovery process and constitutes the cornerstone towards the realization of personalized medicine. This chapter summarizes basic genomic/genetic concepts before delving into recent advances that are pertinent to the practice of contemporary pediatric nephrologists. From laboratory methods to the interpretation of genetic variants, we present every topic within a clinical framework enriched with many examples from the pediatric nephrology literature. The major benefits of genomics to the day-to-day practice of busy clinicians are: it will expedite diagnosis, clarify prognosis, and guide therapeutic choices. Our overarching goals for this chapter were two-fold: 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 providing an accessible port of entry into this complex field.

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Author information

Authors and Affiliations

  1. Paediatric Nephrology, Great Ormond Street Hospital, London, UK

    Aoife Waters

  2. Nephrology, The Hospital for Sick Children, Toronto, ON, Canada

    Mathieu Lemaire

Authors
  1. Aoife Waters
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  2. Mathieu Lemaire
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Corresponding author

Correspondence to Mathieu Lemaire .

Editor information

Editors and Affiliations

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

    Franz Schaefer

  2. Emory School of Medicine, Emory University, Atlanta, GA, USA

    Larry A. Greenbaum

Glossary

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 specifies 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 non-mutational 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.

SNPs (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 a protein is synthesized from an mRNA sequence.

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Waters, A., Lemaire, M. (2023). Molecular Diagnosis of Genetic Diseases of the Kidney: Primer for Pediatric Nephrologists. In: Schaefer, F., Greenbaum, L.A. (eds) Pediatric Kidney Disease. Springer, Cham. https://doi.org/10.1007/978-3-031-11665-0_4

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