Annals of the Rheumatic Diseases 1994; 53: 787-788 787 Ann Rheum Dis: first published as 10.1136/ard.53.12.787 on 1 December 1994. Downloaded from Genetic anticipation and musculoskeletal disease

In 1985, Strom et al described two families in which with the age of onset.9 '5 Molecular biology has provided rheumatoid arthritis (RA) appeared in several members an objective marker of the epidemiological observation of over three consecutive generations.' Although these pedi- anticipation in these monogenic diseases. grees taken alone could implicate dominant inheritance, The majority of common rheumatological diseases, such the overall picture with RA pedigrees indicates a complex as RA, are not monogenic in their aetiology, with multicase mode of inheritance, with incomplete penetrance of families such as the two pedigrees described by Strom et predisposing genes and probably several genes being al being the exception rather than the rule. Is there any involved in the diseases process. In addition, an interesting evidence that genetic anticipation operates in genetically observation in both pedigrees described by Strom's group more complex diseases? Disorders in which the aetiology and one which is difficult to understand in terms of is multifactorial, and yet in familial cases there is good classical Mendelian genetics is that the disease tended to evidence for increasing severity and decreasing age of onset start progressively earlier over the generations (60 to 81 over the generations include bipolar affective disorder,'6 years in the grandparents, 36 to 47 in the parents, and 12 schizophrenia,'7 testicular germ cell tumours,'8 and hyper- to 28 in the probands). For both families, the clinical trophic cardiomyopathy.'9 In these diseases, the epidemio- details of the individuals suggested that not only was the logical evidence for genetic anticipation is already leading disease starting earlier, but it was also becoming more to searches for unstable genetic elements, such as severe over the generations.' Is there any possible expanded trinucleotide repeats, which might account for explanation for this observation, and does this anecdote at least part of their genetic aetiology. have any potential repercussions for our understanding of The table lists the features of RA (as well as many of the the genetics of the rheumatic diseases? other complex musculoskeletal diseases) which are difficult There are a number of monogenic diseases in which to understand in terms of Mendelian genetics. These various aspects of increasing severity and earlier age of features could have a number of genetic and epidemio- onset from generation to generation (an epidemiological logical explanations, but could also lend themselves to a observation known as 'genetic anticipation') are now well model in which unstable genetic elements play a part.2 24 established. Examples of such disorders, for which In diseases in which unstable trinucleotide repeats have unstable trinucleotide repeats close to or within the disease been demonstrated, such as myotonic dystrophy and predisposing gene have been demonstrated include: fragile Huntingtons's disease, the paternal age at which the X syndrome,2 myotonic dystrophy,3 Huntington's disease,4 affected individual is conceived has been shown to predict spinobulbar muscular atrophy,5 and spinocerebellar age of onset in the patient, with older fathers tending to atrophy type 16 (for general reviews see references 7-10). have children with a younger age of onset of disease.25 This http://ard.bmj.com/ For one ofthese diseases, myotonic dystrophy (MD), there may reflect ongoing mitoses throughout the lifetime of the was considerable debate from the beginning of the 20th paternal germ cells, with increasing chances of unstable century whether genetic anticipation was a true premutant alleles expanding over time. Ova do not phenomenon, or a bias of ascertainment (principally undergo further mitoses after the birth of the female, so because families in which parents started with the disease that it can be predicted that increased mitoses in male germ early in life and offspring late in life are intuitively more cells should give an increase in the mutation rate for fathers difficult to find than those families in which the opposite versus mothers. There are, however, examples of unstable on September 30, 2021 by guest. Protected copyright. applies). " What managed to convince the anticipation alleles being maternally transmitted. The unstable sceptics of their misplaced cynicism was the description in trinucleotide repeat in fragile X syndrome appears to be 1992 of a molecular correlate for the epidemiological restricted to maternal transmissions,26 and congenital observation. It was found that at the 3' non-coding region myotonic dystrophy occurs only in the offspring of affected of the MD-predisposing gene (found by linkage studies to mothers, not of fathers." The mechanisms for maternal be a protein kinase gene on chromosome 19) there is a transmissions are currently elusive. CTG trinucleotide repeat. This is present in all What are the repercussions of this developing area for individuals, but the number of repeating CTG copies in the common, multifactorial musculoskeletal diseases? The normal populations is distributed in a Gaussian fashion epidemiological phenomenon of genetic anticipation can between six and 30 copy numbers.3 This is transmitted be better understood now that important breakthroughs stably from generation to generation. However, if an have occurred in the molecular basis of this observation. increase beyond 30 copy numbers takes place, this appears Consequently, any evidence for anticipation in diseases to produce an allele which acts in an unstable fashion in such as RA may lead to a similar search for unstable genetic its transmission. If premutant marginally expanded alleles elements. In this issue ofthe Annals we present preliminary (not associated with disease phenotype) are transmitted in evidence in RA to suggest that anticipation may not be germline cells, they seem capable of undergoing large expansions in early zygotic cell divisions.'2-14 Features ofrheumatoid arthritis and other complex musculoskeletal diseases Similarly, unstable trinucleotide repeats have been that are consistent with unstable genetic elements (references arefor rheumatoid arthritis) described in the other diseases listed above. There are many unanswered questions, both as to what defect in Variable familiarity20 Variable age of onset2' DNA replication leads to these expansions, and as to how Variable disease severity, even within families22 the increases in copy numbers lead to disease phenotypes. Higher sibling concordance rates in families with more severe disease23 ? Parental ages at proband conception influence proband age of onset in However, in the diseases listed there is variable evidence familial RA24 of a direct correlation between the size of the expansion ? Disease becomes more severe and starts earlier in consecutively affected 24 and the severity of the disease, and an inverse correlation generations' 788 Deighton, Thomson

restricted to the two families described by Strom et al, but region exhibiting length variation in fragile X syndrome. Cell 1991; 65: Ann Rheum Dis: first published as 10.1136/ard.53.12.787 on 1 December 1994. Downloaded from 905-14. may occur in most families in which consecutive 3 Brook J D, McCurrach M E, Harley H G, et al. Molecular basis of myotonic generations are affected.24 We also suggest that within dystrophy: expansion of a trinucleotide repeat (CTG) at the 3' end of a transcript encoding a protein kinase family member. Cell 1992; 68: pedigrees in which mothers and offspring are affected by 799-808. RA, the parental ages of conception may have predictive 4 Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on value in the proband age of RA onset.24 As has been argued Huntington's disease chromosomes. Cell 1993; 72: 971-83. exhaustively over this century with respect to myotonic 5 La Spada A R, Wilson E M, Lubahn D B, Harding A E, Fischbeck K H. Androgen receptor gene mutations in X-linked spinal and bulbar dystrophy, these observations are prone to ascertainment muscular atrophy. Nature 1991; 352: 77-9. bias and need to be confirmed in larger and more detailed 6 Orr H T, Chung M, Banfi S, et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nature Genetics 1993; 4: studies. However, we feel that our first step in this direction 221-6. has been sufficiently encouraging to warrant further 7 Richards R I, Sutherland G R. Heritable unstable DNA sequences. Nature Genetics 1992; 1: 7-9. epidemiological studies, as well as searches for unstable 8 Caskey C T, Pizzuti A, Fu Y H, Fenwick R G, Nelson D L. Triplet repeat genetic elements in the DNA of families with evidence of mutations in human disease. Science 1992; 256: 784-9. 9 Ross C A, McInnis M G, Margolis R L, Li S H. Genes with triplet repeats: vertical disease transmission. The epidemiology is equally candidate mediators of neuropsychiatric disorders. Trends Neurosci 1993; applicable to other multifactorial musculoskeletal diseases, 16: 254-60. 10 Nelson D L, Warren S T. Trinucleotide repeat instability: when and where? such as familial forms of osteoarthritis and the seronegative Nature Genetics 1993; 4:107-8. spondarthropathies. 11 Harper PS, Harley H G, Reardon W, Shaw D J. Anticipation in myotonic dystrophy: new light on an old problem. Ami J Hum Genet 1992; 51: Our understanding of the complexities of molecular 10-16. biology is proceeding rapidly. A recent review drew the 12 Buxton J, Shelbourne P, Davies J,et al. Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy. Nature 1992; attention of rheumatologists to two newly recognised 355: 547-8. genetic mechanisms that may be relevant in musculo- 13 Harley H G, BrookJ D, Rundle S A, et al. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Natuire 1992; 355: skeletal disease:27 genetic imprinting, in which the parental 545-6. origin of an allele is critical in its expression, and X 14 Aslandis C, Jansen G, Amemiya C, et al. Cloning of the essential myotonic dystrophy region and mapping of the putative defect. Nature 1992; 355: chromosome inactivation, with which differences in the 548-51. proportion of parental X chromosomes inactivated in 15 Harley H G, Rundle S A, MacMillan J C, et al. Size of the unstable CTG repeat sequence in relation to phenotype and parental transmission in females may be influential in disease states. We would like myotonic dystrophy. Am JHum Genet 1993; 52: 1164-74. to suggest that genetic anticipation also merits the 16 McInnis M G, McMahon F J, Chase G A, Simpson S G, Ross C A, De Paulo J R. Anticipation in bipolar affective disorder. Amii7 Hum Getnet attention of rheumatologists. Epidemiological phenomena 1991; 53: 385-90. in monogenic diseases eventually led to molecular corre- 17 Bassett A S, Honer W G. Evidence for anticipation in schizophrenia. Am J7Hum Genet 1994; 54: 864-70. lates. A similar line of enquiry in musculoskeletal diseases 18 Dieckmann K P, Klan R, Bunte S. HLA antigens, Lewis antigens, and blood may produce further understanding of their complex groups in patients with testicular germ-cell tumours. Oncolog, 1993; 50: 252-8. clinical and genetic features. 19 Gregor P, Cemy M. A genetic studv in hypertrophic cardiomvopathies (Czech population). Cor Vasa 1992; 34: 218-26. Department of Rheumatology, CHRIS M DEIGHTON 20 Deighton C M, Walker D J. The familial nature of rheumatoid arthritis. Ann City Hospital, Rheum Dis 1991; 50: 62-5. Nottingham NG5 21 Hazes J M W, Silman A J. Review of UK data on the rheumatic diseases-2. IPB, Rheumatoid arthritis. Br]7 Rheumatol 1990; 29: 310-2. United Kingdom 22 Silman A J, Ollier W E R, Currey H L F. Failure to find disease similarity in sibling pairswith rheumatoid arthritis. Annii Rheum71 Dis 1987; 46: Department of Integrative Biology, GLENYS THOMSON 135-8. http://ard.bmj.com/ University of California at Berkeley, 23 Deighton C M, Roberts D F, Walker D J. Effect of disease severity on Berkeley, CA 94720, USA rheumatoid arthritis concordance in same sexed siblings. Ann Rheum Dis 1992; 51: 943-5. Correspondence ro: Dr C M Deighton. 24 Deighton C M, Heslop P, McDonagh J, Walker D, Thomson G. Does genetic anticipation occur in familial rheumatoid arthritis? Ann Rheum Dis 1994; 53: 833-5. Dr C M Deighton was supported by a Medical Research Council Travelling 25 Zheng C-J, Byers B, Moolgavkar S H. Allelic instability in mitosis: a Dr G Thomson is NIH Grant unified Fellowship. supported by HD 12731. model for dominant disorders.Proc Natl Acad Sci USA 1993; 90: 10178-82.

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