Complexity of Genotype-Phenotype Correlations in Mendelian Disorders: Lessons from Gaucher Disease
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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.
KeywordsGaucher disease Glucocerebrosidase Mendelian disorder Genotype-phenotype correlation Genetic modifiers Parkinson disease Neurodegeneration
Online Mendelian Inheritance in Man
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
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
Different mutated alleles in a same gene can result in the same phenotype or symptom of a trait or a disorder.
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.
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.
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).
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.
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.
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.
An evolutionary process where small, double stranded RNA (dsRNA, 21–23 nucleotides) molecules inhibit or silence the expression or activity of a gene.
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.
Individuals with the same mutation, even within a family, may demonstrate variation in clinical features (type and severity) of a genetic disorder.
- 8.Gaucher PCE (1882) De l’epithelioma primitif de la rate, hypertrophie idiopathique de la rate sans leucemie. Thesis, University of Paris, ParisGoogle Scholar
- 12.Barton NW, Brady RO, Dambrosia JM, Di Bisceglie AM, Doppelt SH, Hill SC, Mankin HJ, Murray GJ, Parker RI, Argoff CE, Grewal RP, Yu KT (1991) Replacement therapy for inherited enzyme deficiency–macrophage-targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med 324(21):1464–1470PubMedCrossRefGoogle Scholar
- 13.Beutler E, Grabowski G (2001) Gaucher disease. In: Scriver CR, Beaudet al, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 3635–3668Google Scholar
- 24.Cox TM, Aerts JM, Belmatoug N, Cappellini MD, vom Dahl S, Goldblatt J, Grabowski GA, Hollak CE, Hwu P, Maas M, Martins AM, Mistry PK, Pastores GM, Tylki-Szymanska A, Yee J, Weinreb N (2008) Management of non-neuronopathic Gaucher disease with special reference to pregnancy, splenectomy, bisphosphonate therapy, use of biomarkers and bone disease monitoring. J Inherit Metab Dis 31(3):319–336PubMedCrossRefGoogle Scholar
- 26.Lewis S (2001) Gaucher’s disease. Nose bleeds and bruising. Lancet 358 Suppl:S30Google Scholar
- 27.Zimran A, Morris E, Mengel E, Kaplan P, Belmatoug N, Hughes DA, Malinova V, Heitner R, Sobreira E, Mrsić M, Granovsky-Grisaru S, Amato D, vom Dahl S (2009) The female Gaucher patient: the impact of enzyme replacement therapy around key reproductive events (menstruation, pregnancy and menopause). Blood Cells Mol Dis 43(3):264–288PubMedCrossRefGoogle Scholar
- 29.Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Dürr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 361(17):1651–1661PubMedCentralPubMedCrossRefGoogle Scholar
- 33.Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF, Morris CM, Theuns J, Crosiers D, Cras P, Engelborghs S, De Deyn PP, Van Broeckhoven C, Mann DM, Snowden J, Pickering-Brown S, Halliwell N, Davidson Y, Gibbons L, Harris J, Sheerin UM, Bras J, Hardy J, Clark L, Marder K, Honig LS, Berg D, Maetzler W, Brockmann K, Gasser T, Novellino F, Quattrone A, Annesi G, De Marco EV, Rogaeva E, Masellis M, Black SE, Bilbao JM, Foroud T, Ghetti B, Nichols WC, Pankratz N, Halliday G, Lesage S, Klebe S, Durr A, Duyckaerts C, Brice A, Giasson BI, Trojanowski JQ, Hurtig HI, Tayebi N, Landazabal C, Knight MA, Keller M, Singleton AB, Wolfsberg TG, Sidransky E (2013) A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol 70:727–735PubMedCrossRefGoogle Scholar
- 36.Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368(2):107–116PubMedCentralPubMedCrossRefGoogle Scholar
- 46.Lo SM, Choi M, Liu J, Jain D, Boot RG, Kallemeijn WW, Aerts JM, Pashankar F, Kupfer GM, Mane S, Lifton RP, Mistry PK (2012) Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis. Blood 119(20):4731–4740PubMedCentralPubMedCrossRefGoogle Scholar
- 52.Barneveld RA, Keijzer W, Tegelaers FP, Ginns EI, Geurts van Kessel A, Brady RO, Barranger JA, Tager JM, Galjaard H, Westerveld A, Reuser AJ (1993) Assignment of the gene coding for human beta-glucocerebrosidase to the region q21-q31 of chromosome 1 using monoclonal antibodies. Hum Genet 64:227–231CrossRefGoogle Scholar
- 56.Tayebi N, Walker J, Stubblefield B, Orvisky E, LaMarca ME, Wong K, Rosenbaum H, Schiffmann R, Bembi B, Sidransky E (2003) Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol Genet Metab 79(2):104–109PubMedCrossRefGoogle Scholar
- 67.Wolf U (1991) Identical mutations and phenotypic variation. Hum Genet 100(3–4):305–321Google Scholar
- 78.Salvioli R, Tatti M, Scarpa S, Moavero SM, Ciaffoni F, Felicetti F, Kaneski CR, Brady RO, Vaccaro AM (2005) The N370S (Asn370 > Ser) mutation affects the capacity of glucosylceramidase to interact with anionic phospholipid-containing membranes and saposin C. Biochem J 390(Pt 1):95–103PubMedCentralPubMedGoogle Scholar
- 81.Chabás A, Cormand B, Grinberg D, Burguera JM, Balcells S, Merino JL, Mate I, Sobrino JA, Gonzàlez-Duarte R, Vilageliu L (1995) Unusual expression of Gaucher’s disease: cardiovascular calcifications in three sibs homozygous for the D409H mutation. J Med Genet 32(9):740–742PubMedCentralPubMedCrossRefGoogle Scholar
- 87.Panicker LM, Miller D, Park TS, Patel B, Azevedo JL, Awad O, Masood MA, Veenstra TD, Goldin E, Stubblefield BK, Tayebi N, Polumuri SK, Vogel SN, Sidransky E, Zambidis ET, Feldman RA (2012) Induced pluripotent stem cell model recapitulates pathologic hallmarks of Gaucher disease. Proc Natl Acad Sci U S A 109(44):18054–18059PubMedCentralPubMedCrossRefGoogle Scholar
- 96.Zhang CK, Stein PB, Liu J, Wang Z, Yang R, Cho JH, Gregersen PK, Aerts JM, Zhao H, Pastores GM, Mistry PK (2012) Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation. Am J Hematol 87(4):377–383PubMedCentralPubMedCrossRefGoogle Scholar
- 100.McEachern KA, Fung J, Komarnitsky S, Siegel CS, Chuang WL, Hutto E, Shayman JA, Grabowski GA, Aerts JM, Cheng SH, Copeland DP, Marshall J (2007) A specific and potent inhibitor of glucosylceramide synthase for substrate reduction therapy of Gaucher disease. Mol Genet Metab 91(3):259–267PubMedCrossRefGoogle Scholar