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346 Archives ofDisease in Childhood 1996;75:346-350

RECENT ADVANCES Arch Dis Child: first published as 10.1136/adc.75.4.346 on 1 October 1996. Downloaded from

Advances in genetics

Melissa M Lees, Robin M Winter

The contribution of genetics to the under- ment and disease have been gained in standing of paediatric disease has increased this way. An example of this is the of dramatically over recent years. The identifica- DNA repair mechanisms between and tion of disease and the understanding of ."' disease processes at the molecular level have implications for screening, diagnosis, and detection therapeutic manipulation. Inevitably, complex Once a has been isolated, the mutation in ethical issues have arisen from such a rapid rate the gene resulting in the clinical phenotype in of scientific progress, and many ask whether an individual or a family can be sought. Muta- society is prepared for the consequences of tion detection remains an expensive and time such advances. consuming activity in the majority of cases, but This review aims to cover areas of progress it is one that can confirm a clinical diagnosis, within the field of clinical genetics over recent enable prenatal and presymptomatic diagnosis years, and also to discuss future prospects, of an individual in an affected family, and pro- possibilities, and perceived difficulties. vide carrier testing. In some cases a specific test can be used to detect a known common muta- Mapping Project tion, such as in Apert's syndrome, achondro- The Human Genome Mapping Project plasia, and cystic fibrosis. In cystic fibrosis four (HGMP), an international project whose known account for 87% of muta- ultimate aim is to sequence the entire human tions in the northern European population. genome, will lead to understanding about Detection of these mutations is efficient and chromosomal structure, the organisation of the inexpensive to perform, and can be carried out http://adc.bmj.com/ genome, regulation of genes, disease suscepti- on a routine service basis. Other disorders bility, and normal and abnormal human devel- amenable to routine testing include those due opment. The projected completion date is to a common mutational mechanism, such as between 2001 and 2005. The human haploid deletions in Duchenne muscular dystrophy, genome consists of around three billion base and duplications in Charcot-Marie-Tooth dis- pairs of DNA, encoding approximately 50 000 ease. However, in many diseases the causative to 100 000 genes. One major goal of the mutations are unique to each family, and HGMP is to produce a map of the human mutation detection techniques have to be used on September 27, 2021 by guest. Protected copyright. genome, containing 30 000 ordered markers, for each new case. If the gene involved is large, spaced approximately 100 000 base pairs and mutations occur anywhere on that gene, apart.' Expressed sequence tags, which are then localising the mutation may be time con- complementary to the 3' untranslated region of suming. The gene for Marfan's syndrome, mRNA, are also being developed as markers fibrillin-1 (FBN1), is located on for individual genes.2 These resources will aid 1 5q21 and spans approximately 1 10 kb. Muta- positional cloning, where a gene is cloned tions in FBN1 were first detected in patients in using information as to its location on the 1991, and over 50 distinct mutations have chromosome, as well as being a foundation for since been reported,89 each generally unique to the sequencing of the entire genome.3 Other individual families. Identification of an FBN1 projects involve the sequencing of model mutation in a new case is therefore difficult, organisms such as bacteria, yeast, nematodes, and this technique cannot be used as a and mice. DNA sequences that share a diagnostic test. A further example where structural similarity between different species individual mutation detection in a known gene Mothercare Unit of suggest a common ancestral origin. The has proved difficult is provided by the neurofi- Clinical Genetics and of human genes with the genes of bromin in neurofibromatosis type 1 Fetal Medicine, comparison gene Institute of Child simpler model organisms gives insight into (NFl), which spans over 350 kb of genomic Health, 30 Guilford genome structure, and provides valuable ho- DNA in chromosomal region 17ql1.2. Over Street, London WC1N mology data. Having identified a mutant gene 100 disease causing mutations have been iden- 1EH in a 'simple' organism such as the fruit fly dro- tified so far,1' but collectively these are only MM Lees sophila, a short cut to finding human genes responsible for approximately 40% of patients RM Winter exists by searching for sequence similarities with NFl." Correspondence to: through computer databases such as FlyBase.4 Conditions may show genetic heterogeneity, Dr Lees. Surprising insights into mammalian develop- where mutations at a number of different loci Advances in genetics 347

result in the same phenotype. Two loci for chromosome 7 has been reported to be associ- adult onset polycystic kidney disease have been ated with short stature,24 and has also been mapped: polycystic kidney disease 1 gene identified in a number ofpatients with Russell- Arch Dis Child: first published as 10.1136/adc.75.4.346 on 1 October 1996. Downloaded from (PKD 1) on chromosome 16 accounting for Silver syndrome.25 around 85% of cases, and PKD2 on chromo- Mutations in mitochondrial DNA (mtDNA) some 4, 12 accounting for the majority of the can be pathogenic in man.26 27 One example of remaining cases. Two genetic loci have also a disease caused by mtDNA mutations is Leb- been confirmed for tuberous sclerosis, with er's hereditary optic neuropathy (LHON), approximately 50% of familial cases being which is transmitted maternally. Difficulties linked to a on chromosome 9q34 arise, however, in the genetic counselling of (TSC 1), and other cases linked to a locus on this disorder due to the incomplete penetrance, 16pl3.3 (TSC2), closely linked to the PKD1 variable age of onset, and preferential occur- gene. The PKD 1 and TSC1 genes have rence in males. A number of LHON pedigrees been isolated but both are very large. There- are heteroplasmic for the pathogenic mtDNA fore, in isolated cases with either of these disor- mutation, where the mutant coexists with ders, one cannot be certain that one is search- the normal allele in an individual.28 The ing the correct gene for the responsible mutant allele frequency varies between indi- mutation. viduals within a family, giving rise to further counselling difficulties. It has been suggested Unusual inheritance patterns that >70% mutant allele frequency is required A number of diseases have been found to result for a significant risk of visual loss.29 Autosomal from an unstable expansion of a triplet ofbases DNA mutations can give rise to mtDNA rear- within or around a gene, so-called trinucleotide rangements, such as in autosomal dominant repeats. The normal number of repeats is poly- progressive external ophthalmoplegia, a disor- morphic (meaning the existence of two or der with ptosis, weakness of the eye muscles, more with different repeat lengths at and generalised muscle weakness. Affected significant frequency in the population), but a individuals have multiple mtDNA mutations, repeat number above a certain threshold with a pattern of inheritance indicating a results in the clinical phenotype. Fragile X syn- nuclear gene defect.30 drome, Huntington's chorea, and myotonic dystrophy all result from such an expansion.15 16 Friedreich's ataxia, an autosomal recessive Fluorescent in situ hybridisation (FISH) condition, has also recently been found to be FISH is a cytogenetic technique that detects caused by a trinucleotide repeat expansion.'7 In specific DNA sequences, chromosomal sub- this disease, a GAA repeat number of between regions or entire during met- 200 and 900 within the frataxin gene on chro- aphase or interphase of cells, by the use of mosome 9 is seen in 95% of affected individu- fluorescently labelled complementary DNA als, while the normal copy number is between sequences.3' The technique has been enhanced 10 and 21. These diseases are all amenable to by the introduction of multicolour probes http://adc.bmj.com/ direct molecular diagnostic testing by assess- allowing simultaneous examination of a ment of the expansion size. number of sites, and chromosome painting- A number of conditions result from unipa- where consecutive probes spanning an entire rental disomy of an imprinted gene. An chromosome are used. The technique is being imprinted gene is one which is only expressed explored for the rapid prenatal diagnosis of from either the maternal or the paternal copy, aneuploidies, by analysis during interphase, that is the is monoallelic. Uni- giving a result within 48 hours. Some clinical on September 27, 2021 by guest. Protected copyright. parental disomy occurs where both alleles phenotypes result from the microdeletion of a originate from the same parent. Prader-Willi chromosome, resulting in the loss of a number syndrome results from maternal disomy of of genes that are located consecutively on the chromosome 15q11.13 in 20-25% of cases, chromosome. The phenotype in these 'con- and deletion of the same region of the paternal tiguous gene syndromes' varies depending on chromosome 15 in the other cases. Paternal the extent of the deletion, and therefore which disomy of this region results in Angelman syn- genes are missing. FISH techniques are drome in a small number of cases (<5%), but commonly used to determine the presence of more commonly Angelman syndrome arises microdeletions, which are not visible by from the deletion ofpart ofthe maternal 1 5ql 1 conventional cytogenetic means. Examples band (60-75% of cases). At least 20% of include deletion of the elastin gene on 7q in affected individuals have normal chromosomes Williams syndrome,32 22q deletions in velocar- and no evidence of disomy. These cases may be diofacial / DiGeorge's syndrome,33 4p deletions due to mutations in the imprinting mechanism in Wolf-Hirschhorn syndrome, 17p 1 1.2 dele- 18-20 or possibly arise due to point mutations in tions in Smith-Magenis syndrome, and the Angelman gene itself. Differential methyla- 17pl3.3 deletions in Miller-Dieker lissen- tion of genes within the critical region is used cephaly. Many probes used in the clinical as the basis of molecular testing of both disor- setting are available commercially. 'FISHing' ders.2' A number of cases of Beckwith- for microdeletions requires a specific request, Wiedemann syndrome have been described in appropriate to the clinical findings. As the association with uniparental disomy of the HGMP progresses and chromosomal regions paternal copy of distal I lp, possibly related to are delineated by a greater number of probes, overexpression of intrinsic growth factor 2 and advances are made in the computerisation (IGF2). Maternal uniparental disomy of techniques enabling improved image analysis, 348 Lees, Winter

the applications of FISH techniques are likely potentially provide an early, non-invasive to expand. means of prenatal diagnosis.50 51 At present, technical problems exist with the isolation and Arch Dis Child: first published as 10.1136/adc.75.4.346 on 1 October 1996. Downloaded from Prenatal diagnosis enrichment of such cells.52 However there has SCREENING been some success, particularly with the isola- Routinely available prenatal screening in low tion of fetal nucleated red cells. Once detected, risk pregnancies includes serum screening and the application of polymerase chain reaction ultrasonography for fetal anomalies. Second (PCR) or FISH techniques has so far allowed trimester serum screening for the detection of the determination of fetal sex (useful in X Down's syndrome measures the serum levels of linked disorders), aneuploides, and certain ax-fetoprotein, human chorionic gonado- specific mendelian disorders.505354 At present trophin, and unconjugated oestriol. These confirmation of the diagnosis by CVS or parameters are analysed in conjunction with amniocentesis is required, but clinical trials are gestational age to predict high risk pregnancies underway to determine sensitivity and specifi- where diagnostic amniocentesis can be offered. city of these relatively non-invasive methods. A 75% detection rate of Down's syndrome was obtained in a study where over 40 000 PREIMPLANTATION DIAGNOSIS pregnancies were tested, with a false positive This method of diagnosis involves the removal rate of 4%.34 The detection rate in women over of one or two cells from the six to 10 cell 35 was even higher. Studies have indicated that embryo generated by standard in vitro fertilisa- there is a first trimester increase in level of free tion techniques, at around day 3 after insemi- I human chorionic gonadotrophin in trisomic nation, followed by analysis ofthe cells by PCR pregnancies.35 However, first trimester serum or FISH techniques. It was developed in order screening remains at a research stage."6 Fetal to provide the option of healthy embryo selec- nuchal translucency (a measurement of the tion, rather than later termination of abnormal amount of fluid present at the back of the fetal fetuses.55 The technique is established for diag- neck, made by ultrasound scanning at 10-12 nosis of cystic fibrosis using PCR to determine weeks' gestation) of equal to or more than 3 the presence of known parental mutations.56 mm has been reported to be a first trimester Other conditions which have also been de- marker for chromosome abnormality. In one tected at the preimplantation stage include specialist centre 84% of trisomic pregnancies Tay-Sachs disease, Lesch-Nyhan syndrome, were detected in this way, with a false positive and Duchenne muscular dystrophy. Diagnosis rate of 4.5%.37 However, for this to be used as a of some of the triplet repeat expansion diseases screening test, standardised results need to be has been reported, including fragile X and achieved by general hospitals providing myotonic dystrophy.57 Although so far there is antenatal care.'8 no evidence for either a reduction in the The Royal College of Obstetricians and success of the implantation of the embryo, or Gynaecologists currently recommends routine interference with the development of the scanning for fetal abnormality at 18-20 weeks, embryo, the numbers studied are small.56 http://adc.bmj.com/ although its value measured in terms of reduced perinatal morbidity and mortality is Gene therapy controversial.9 40 The sensitivity of ultrasound Although much optimism surrounds this po- in the detection of abnormalities before 24 tentially exciting area, technical and ethical weeks varies. One study reported a 40.9% sen- problems have been encountered when at- sitivity,41 while another reported a 16.6% tempting to manipulate genes. The first genetic sensitivity.42 disorder reported to be treated by gene therapy on September 27, 2021 by guest. Protected copyright. was severe combined immunodeficiency due to CHORIONIC VILLUS SAMPLING (CVS) AND adenosine deaminase deficiency (ADA defi- AMNIOCENTESIS ciency). Retroviral vectors have successfully Tissue suitable for prenatal diagnosis, can be been used to transfer the human ADA obtained in a number of ways. CVS performed minigene, ex vivo, into bone marrow cells and at 10-12 weeks' gestation, and amniocentesis, peripheral blood lymphocytes.58 59 Significant performed from 14 weeks' gestation, are both effort has been directed towards cystic fibrosis, widely used. Fetal karyotyping, molecular where the defect lies in the chloride conduction genetic and biochemical tests can be per- channel.60 Adenovirus vectors were considered formed on the sample obtained. However the suitable vectors to deliver the normal gene to methods described are invasive, and still carry the lungs, but clinical trials have been compli- an associated miscarriage rate of around 2% cated by a high incidence of mucosal inflam- and 1% respectively.4' There have also been mation when high viral doses were used, with reports of limb reduction defects associated no associated evidence for an improvement in with early CVS (<9 weeks),44 4 although the the chloride channel defect.6' significance of this finding has been dis- The gene for Duchenne muscular dystrophy puted.4647 was cloned in 1987, but slow progress is being Less invasive techniques are being devel- made in gene therapy. As the disease gene is oped. Trophoblast cells have been successfully large, it cannot be accommodated by any cultured from endocervical washing during the known viral vector, and attempts have been first trimester,48 though further testing is made at transplanting myoblasts. The myob- required to determine the risks. Isolating fetal lasts from affected individuals have a low cells from the maternal circulation, present as proliferative capacity, and therefore allogenic early as 5-6 weeks' gestation49 could also myoblasts have been used in conjunction with Advances in genetics 349

immunosuppression. However the uptake by influence female sexual orientation remains the host has not only been poor, but the cells unclear. Behavioural genetics is a controversial

have not migrated from their site of injection.62 area that is only beginning to be studied at the Arch Dis Child: first published as 10.1136/adc.75.4.346 on 1 October 1996. Downloaded from One way to get around this problem has been molecular level. It is not easy to predict explored by injecting a recombinant adenovi- changes in social attitudes to specific behaviour rus containing a human dystrophin minigene, patterns, such as criminality, ifthese are shown minidystrophin, into a mouse model. Although to have a significant genetic aetiology. this minidystrophin encodes a truncated pro- Such knowledge raises many ethical and tein, its expression has been shown to protect social issues. To what extent should couples be the muscle fibres against degeneration.6" allowed to choose the genetic make-up of their Alternative approaches of gene therapy are babies? Is presymptomatic testing and carrier currently being developed. A retroviral vector, detection for adult onset disease appropriate in expressing the fumarylacetoacetate hydrolase children? 72 Will the ability to screen for gene (Fah), infused into the portal vein of a 'abnormal' or 'socially undesirable' genes lead mouse model ofthe human liver disease tyrosi- to eugenic policies on the part ofgovernments? naemia type 1 (HT1), has resulted in Fah Should insurance companies have the right to expression in >90% of parenchymal hepato- insist on genetic tests, or to load the policies of cytes and functional correction of the diseased people known to carry specific deleterious liver. The healthy hepatocytes have a high genes? How will the increasing knowledge of regenerative potential, and are selected in vivo behavioural genetics affect our concept of free over the mutant cells.64 This work has promis- will? ing implications for hepatic gene therapy. All these issues must be the subject of informed public debate if the obvious benefit of the HGMP are not to be overshadowed by Databases inappropriate use of this powerful technology. Knowledge about genetic disease, including new syndrome diagnoses, chromosomal locali- sation of disease causing genes, mutation 1 Cox DR, Myers RM. A map to the future. Nat Genet analysis, and genotype-phenotype correlations 1996;12:117-8. 2 Boguski MS, Schuler GD. ESTablishing a human transcript increases daily. The most efficient way to map. Nat Genet 1995;10:369-71. obtain access to such information is via 3 Gibbs RA. Pressing ahead with human genome sequencing. Nat Genet 1995;11:122-5. regularly updated computer databases now 4 Banfi S, Borsani G, Rossi E, et al. Identification and available through the World Wide Web mapping of human cDNAs homologous to mutant genes through EST database searching. Nat Genet (WWW)*.65 Examples of databases of use to the 1996;13: 167-74. paediatrician include the On-line Mendelian 5 Murray JM, Doe CL, Schenk P, et al. Cloning and characterisation of the S pombe radl 5 gene, a homologue Inheritance in Man (OMIM) database and the to the S cerevisiae RAD3 and human ERCC2 genes. Genome Data Base (GDB), which are inter- Nucleic Acids Res 1992;20:2673-8. 6 Bassett DE, Boguski MS, Heiter P. Yeast genes and human national on-line databases of human genetic disease. Nature 1996;379:589-90. data. These allow the users to search for 7 Bronner CE, Baker SM, Morrison PT, Warren G, Smith http://adc.bmj.com/ LG, et al. Mutation in the DNA mismatch repair gene phenotypic descriptions, inheritance patterns, homologue hMLH1 is associated with hereditary non- gene localisation information, and specific polyposis colon cancer. Nature 1994;368:258-60. 8 Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome mutations. Links to genetic databases are avail- caused by a recurrent de novo missense mutation in the able through the UK Medical Research Coun- fibrillin gene. Nature 199 1;352:337-9. 9 Dietz HC, Pyeritz RE. Mutations in the human gene for cil HGMP Resource Centre WW 'home fibrillin-1 (FBN1) in the Marfan syndrome and related dis- page' (http://www.hgmp.mrc.ac.uk/). orders. Hum Mol Genet 1995;4:1799-809.

10 Shen MH, Harper PS, Upadhaya M. Molecular genetics of on September 27, 2021 by guest. Protected copyright. neurofibromatosis type 1 (NF1). 7 Med Genet 1996;33:2- 17. Future advances 11 Upadhaya M, Osborn M, Maynard J, et al. Mutational spec- trum of the neurofibromatosis type 1 (NF1) gene (abst). With the help ofthe HGMP, determining all of EurJIHum Genet 1996;4 (suppl 1):5.084. the genes in gene disorders will 12 Harris PC, Ward CJ, Peral B, Hughes J. Autosomal resulting single dominant polycystic kidney disease: molecular analysis. be a relatively straightforward process. The Hum Mol Genet 1995;4:1745-9. next challenge is to elucidate the genetics of 13 European Chromosome 16 Tuberous Sclerosis Consor- tium. Cell 1993;75:1305-15. common multifactorial disorders, such as heart 14 Webb DW, Osborne JP. Tuberous sclerosis. Arch Dis Child disease, cancer and schizophrenia, where mul- 1995;72:471-4. 15 TurkJ. Fragile X syndrome. Arch Dis Child 1995;72:3-5. tiple genes interact with environmental factors 16 Lindblad K, Zander C, Schalling M, Hudson T. Growing to produce the disease phenotype. Significant triplet repeats. Nat Genet 1994;7:124 17 Campuzano V, Montermini L, Dolores Molto M, Pianese L. progress is being made in unravelling the Friedrich's ataxia: autosomal recessive disease caused by an genetic predisposition to insulin dependant intronic GAA triplet repeat expansion. Science 1996;271: 1423. diabetes mellitus.66 Using genome-wide search 18 Chan C-TJ, Clayton-Smith J, Cheng X-J, et al. Molecular methods on affected sibling pairs, a susceptibil- mechanisms in Angelman syndrome: a survey of 93 patients. I Med Genet 1993;30:895-902. ity locus for Crohn's disease has recently been 19 Nicholis RD. Genomic imprinting and uniparental disomy mapped.67 in Angelman and PraderWilli syndromes: a review. Am J Med Genet 1993;46:16-25. The genetic basis of behaviour is currently 20 Rickard SJ, Gilbert HL, Pembrey ME, Malcolm S, Buxton stirring much interest. One study suggested JL. Molecular characterisation of Angelman syndrome patients. EuJHum Genet 1996;4 (suppl 1):5.164(abst). linkage between defi- 21 Smith A, Prasad M, Deng Z-M, et al. Comparison of high ciency and aggressive behaviour.68 69 The study resolution cytogenetics, fluorescence in situ hybridisation, and DNA studies to validate the diagnosis of Prader-Willi of the genetics of homosexuality has aroused and Angelman's syndromes. Arch Dis Child 1995;72:397- debate. Evidence exists to suggest that male 402. 22 Issa JJ, Baylin S. Altered IGF2 imprinting in somatic homosexuality is influenced by a gene or genes overgrowth provides further evidence for the involvement on Xq,'0 7' although whether genetic factors of in human disease. Nat Med 1996;2:311-6. 350 Lees, Winter

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