Complexity of Genotype-Phenotype Correlations in Mendelian Disorders: Lessons from Gaucher Disease

  • Nima Moaven
  • Nahid Tayebi
  • Ehud Goldin
  • Ellen SidranskyEmail author
Part of the Advances in Predictive, Preventive and Personalised Medicine book series (APPPM, volume 6)


Mendelian disorders are diseases which occur due to a mutation in the DNA sequence of a single gene. However, as we learn more about these inherited diseases, it is clear that there can be a vast spectrum of associated phenotypes. Gaucher disease is an example of a “simple” monogenic disorder with complex features. It results from the deficiency of the recessively inherited enzyme glucocerebrosidase, and is the most common lysosomal storage disorder. One of the chief clinical challenges facing geneticists and medical practitioners is to assess how adequately one can use genotype data to predict phenotypes. The ability to make such predictions is an essential tenet of individualized medicine and has implications for prenatal decision making. By understanding the limitations of genotype-phenotype correlation in monogenic disorders, we can gain insights that will help us to better understand the complexity in interpreting genetic data in multigene disorders. Factors including genetic modifiers, gene-gene interaction, reduced penetrance, imprinting, processed and non-processed pseudogenes, regulatory polymorphisms, epigenetics and the abundant number of private mutations, provide challenges for those seeking to understand genetic contributions to distinct phenotypes. Through a careful evaluation of one specific Mendelian disorder, Gaucher disease, we can learn lessons directly applicable to other diseases, both rare and common.


Gaucher disease Glucocerebrosidase Mendelian disorder Genotype-phenotype correlation Genetic modifiers Parkinson disease Neurodegeneration 



Online Mendelian Inheritance in Man


Periodic acid-Schiff


International Collaborative Gaucher Group


Lysosomal Storage Disorder


Lysosomal Integral Membrane Protein


Action Myoclonus-Renal Failure


Charcot Marie Tooth


Magnetic Resonance Imaging


Human Gene Mutation Database


Genome Wide Association Studies


Chorionic Villus Sampling


Avascular necrosis


Food and Drug Administration


Enzyme Replacement Therapy


Substrate Reduction Therapy


Central Nervous System



This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health. We acknowledge the assistance of Julia Fekecs in the preparation of the figure.

Glossary of Genetic Terms

Allelic Heterogeneity 

Different mutated alleles in a same gene can result in the same phenotype or symptom of a trait or a disorder.

Autosomal Dominant 

Autosomal dominant disorders occur through the inheritance of a single copy of a mutated gene found on an autosomal chromosome (non-sex chromosome). The single defective allele is sufficient to result in the phenotype.

Autosomal Recessive 

For an autosomal recessive disorder to occur, both copies (alleles) of the gene must be mutated. If only one allele is mutated, the product normal allele is considered to be sufficient to protect the individual from having the disorder, but such individual is considered to be a carrier of the condition.


Co-dominant inheritance occurs when both alleles are expressed, and contribute to a phenotype.


Epigenetics results from changes in the regulation of the expression of a gene without an alteration in the genetic structure. A common epigenetic modification is methylation, where a methyl group binds to segments of DNA and turns off the gene so that no transcription results.


The exome includes all of the coding exons of genes. This accounts for 1.5 % (50 Mb) of the human genome. Whole exome sequencing is used to screen all of a patient’s coding regions to identify mutations in genes.


A specific set of alleles inherited at a locus, or the two alleles inherited for a particular gene.

Genome-Wide Association Study (GWAS) 

An approach to compare genetic variant markers across the complete DNA sequence of a group of patients or with those of appropriate controls to in order to identify genetic associations with recognizable traits or a disease. The markers are usually Single Nucleotide Polymorphism (SNP).

Inherited Diseases 

Diseases caused by mutations in genes or chromosomal abnormalities. A genetic disorder may or may not be a heritable disorder. Some genetic disorders are passed down from the parents’ genes, but others are almost always caused by new mutations or changes in DNA packaging.


Maternal and/or paternal chromosomes are uniquely modified and lead to different expression of a certain gene or genes.

Monogenic Disorder 

These disorders are the result of a single mutated gene that can be passed on to subsequent generations in several ways (recessive, dominant, X-linked and co-dominant).


An alteration in the native sequence of a gene. A mutation may be disease-causing or a benign, normal variant. Mutations can be introduced during cell division by many factors such as radiation, mutagenic chemicals, or from infection by viruses. De novo mutations are new changes in a gene that occur in a germ cell (egg or sperm). Private mutations are mutations that are found in single families or isolated populations.


A condition (most commonly inherited in an autosomal dominant manner) is said to have complete penetrance if clinical symptoms are present in all individuals who have the disease-causing mutation, and to have reduced or incomplete penetrance if clinical symptoms are not always present in all individuals who have the disease-causing mutation.


The entire clinical, biochemical and physiological presentation of an individual determined both by a particular genotype and environmental influences.


Several unrelated physical symptoms caused by a single mutant allele or both alleles.


Natural variations in the DNA sequence of a gene or chromosome that have no adverse effects on the individual, and occur with high frequency in the general population. Polymorphisms involve one of two or more variants of a particular DNA sequence. The most common type of polymorphism is called a single nucleotide polymorphism, or SNP.


An incomplete copy of a gene which it does not have essential DNA sequence segments necessary for being a functional gene. A non-processed pseudogene includes most introns and exons of the gene. Integration of the cDNA (reverse transcription of an mRNA) of a gene into the genomic sequence results in a processed pseudogene and can occur during the course of evolution.

Recombinant Allele 

The result of the exchange of a segment of sister chromatid DNA between two homologous chromosomes during meiosis by a cross-over event, resulting to a new combination of genetic material in the offspring. This phenomenon is an important cause of the genetic variation seen among offspring.

RNA Interference (RNAi) 

An evolutionary process where small, double stranded RNA (dsRNA, 21–23 nucleotides) molecules inhibit or silence the expression or activity of a gene.

Sex-Linked Traits 

The traits or the disorders that their responsible genes are located on the sex chromosome (X or Y). Most of the genes are located on Y chromosome (one of the smallest chromosome) are also present on X chromosome. Therefore, the majority of sex-linked traits or disorders are X-linked. More than 1,000 human X-linked genes are known.

Variable Expressivity 

Individuals with the same mutation, even within a family, may demonstrate variation in clinical features (type and severity) of a genetic disorder.


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Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Nima Moaven
    • 1
  • Nahid Tayebi
    • 1
  • Ehud Goldin
    • 1
  • Ellen Sidransky
    • 1
    Email author
  1. 1.Section on Molecular Neurogenetics, Medical Genetics BranchNational Human Genome Research Institute (NHGRI), National Institutes of Health (NIH)BethesdaUSA

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