Girirajan S, Rosenfeld JA, Cooper GM, Antonacci F, Siswara P, Itsara A, Vives L, Walsh T, McCarthy SE, Baker C, Mefford HC, Kidd JM, Browning SR, Browning BL, Dickel DE, Levy DL, Ballif BC, Platky K, Farber DM, Gowans GC, Wetherbee JJ, Asamoah A, Weaver DD, Mark PR, Dickerson J, Garg BP, Ellingwood SA, Smith R, Banks VC, Smith W, McDonald MT, Hoo JJ, French BN, Hudson C, Johnson JP, Ozmore JR, Moeschler JB, Surti U, Escobar LF, El-Khechen D, Gorski JL, Kussmann J, Salbert B, Lacassie Y, Biser A, McDonald-McGinn DM, Zackai EH, Deardorff MA, Shaikh TH, Haan E, Friend KL, Fichera M, Romano C, Gécz J, DeLisi LE, Sebat J, King MC, Shaffer LG, Eichler EE.
A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet.
2010 Feb 14
Comments on News and Primary Papers
Comment by: Ben Pickard
Submitted 25 February 2010
Posted 25 February 2010
In their Nature Genetics paper, Girirajan et al. contribute to the slow shift of focus in the field of complex genetic disorders, away from population risks towards the risks specific to the individual. The driving force of this shift is the ongoing discovery of mutations more penetrant than the common single nucleotide polymorphisms (SNPs) studied in case-control association studies. Copy number variants (CNVs) and coding variants are the two principal classes of these mutations, typified by their relative rarity, frequent familiality, and generally higher odds ratio (OR) values indicative of their impact.
Considerable evidence from increased levels of comorbidity, dysmorphic features, brain structural changes, and latent endophenotypes suggests that early neurodevelopmental deficits can predispose to later neuropsychiatric conditions (Ross et al., 2006). This paper demonstrates how the phenotype in a single individual can be more closely linked with the causative genotype when the simultaneous action of two CNVs is considered. This provides some concrete evidence to explain how seemingly disparate diagnoses (for example, epilepsy, autism, schizophrenia and mental retardation) and variable penetrance can occur in different individuals who ostensibly carry the same pathogenic CNV (van Bon et al., 2009; Mefford et al., 2008)—specifically, it appears that a second CNV can translate a generalized neurodevelopmental pathology into a more specific, severe, and reproducible final clinical endpoint. Hence, the authors invoke a “two-hit” hypothesis, as originally applied by Knudson to explain the observed progression of familial forms of cancer (Knudson, 1971).
From a semantic point of view, the use of the “two-hit” terminology is a little loosely applied here. Originally, this described an inherited predisposition to cancer in the form of a tumor suppressor mutation which was coupled with a later, somatic, “second hit” oncogenic mutation that resulted in the tumor. In the current application of the term, both mutational changes are germline, present from the outset, and even a single CNV “hit” can still produce a phenotype. However, the comprehensive data in the paper and the analogy used are thought-provoking, as they highlight three etiological issues, outlined below, which may have wide applicability to complex genetic disorders.
1. A key observation from this paper is that the hypothetical Venn diagrams illustrating the overlapping relationships between the varied diagnoses and also between diagnoses and genomic variation would be highly complex. The phenotypic reach of each CNV may also be considerably greater than we currently suppose—limited by the developmental or neurological conditions that have yet to be comprehensively studied by comparative genomic hybridization. Conversely, the interpretation of shared genetic risk in association and epidemiological studies may have to be reassessed in the light of this paper’s findings. For example, the demonstration of a component of genetic contribution shared between bipolar disorder and schizophrenia may not be such a simple story (Lichtenstein et al., 2009). That component may be just a genetic contribution to generalized neurodevelopmental failure which predisposes to neuropsychiatric disorders in the context of “second hit,” disease-specific mutations (schizophrenia or bipolar disorder, in this case). Can a gene truly be called a “schizophrenia gene” if you haven’t discounted its role in other conditions first? This is reminiscent of the shared genetic contribution to underlying autoimmunity processes which is emerging from the genomewide association studies of diagnostically discrete disorders such as type I diabetes, Crohn’s disease, and rheumatoid arthritis (Baranzini, 2009).
2. The two-hit terminology and the involvement of neurodevelopmental deficits clearly imply a sequential pattern of CNV effect—early predisposition followed by later resolution of diagnosis. Mouse gene knockouts have shown that such staged action is indeed possible, and its confounding effects on animal models of disease led to the development of spatially and temporally controllable transgenic technologies (Gingrich et al., 1998). However, to prove this in the context of the CNV model will require both the individual spatiotemporal expression profiles of the deleted genes and also some measure of individual gene dosage sensitivity to be correlated with the apparent mode of CNV action (developmental or “modifier”).
3. The model’s restriction to just two contributory CNVs as presented here is, in my opinion, a by-product of CNV scarcity, visibility, and sample size, rather than a genuine biological phenomenon. As the authors state, the accuracy of genotype-phenotype correlations at the level of the individual will undoubtedly increase when common and rare SNP variation is also taken into account—potentially to the point where predictive diagnosis is realistic. Likewise, the authors’ suggestion that the second CNV has a “modifier” effect on the foundation CNV is enticing, and backed up by the ubiquity of the 16p12.1 across several genomic disorders, but it is still difficult at this stage to discount the equally compelling explanation that two CNVs just represent a simple increase in mutational load. However, this latter explanation has its own problems, as it suggests a continuum of illness dictated by additive genetic risk. Does this continuum start with mild developmental delay and end with neuropsychiatric illness—or vice versa?
Finally, it must not be forgotten that schizophrenia, bipolar, autism, and epilepsy can exist without comorbid traits and without evidence for developmental issues. Is this, then, an important dimension to be considered in the future sub-categorization of these disorders?
Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron . 2006 Oct 5 ; 52(1):139-53. Abstract
van Bon BW, Mefford HC, Menten B, Koolen DA, Sharp AJ, Nillesen WM, Innis JW, de Ravel TJ, Mercer CL, Fichera M, Stewart H, Connell LE, Ounap K, Lachlan K, Castle B, Van der Aa N, van Ravenswaaij C, Nobrega MA, Serra-Juhé C, Simonic I, de Leeuw N, Pfundt R, Bongers EM, Baker C, Finnemore P, Huang S, Maloney VK, Crolla JA, van Kalmthout M, Elia M, Vandeweyer G, Fryns JP, Janssens S, Foulds N, Reitano S, Smith K, Parkel S, Loeys B, Woods CG, Oostra A, Speleman F, Pereira AC, Kurg A, Willatt L, Knight SJ, Vermeesch JR, Romano C, Barber JC, Mortier G, Pérez-Jurado LA, Kooy F, Brunner HG, Eichler EE, Kleefstra T, de Vries BB. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet . 2009 Aug 1 ; 46(8):511-23. Abstract
Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, Devriendt K, Bongers EM, de Leeuw N, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Räber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A, Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, Eichler EE. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med . 2008 Oct 16 ; 359(16):1685-99. Abstract
Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A . 1971 Apr 1 ; 68(4):820-3. Abstract
Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet . 2009 Jan 17 ; 373(9659):234-9. Abstract
Baranzini SE. The genetics of autoimmune diseases: a networked perspective. Curr Opin Immunol . 2009 Dec 1 ; 21(6):596-605. Abstract
Gingrich JR, Roder J. Inducible gene expression in the nervous system of transgenic mice. Annu Rev Neurosci . 1998 Jan 1 ; 21():377-405. Abstract
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