496

safety of home births cannot be settled by statistics,obstetricians should look to ways of improving theparents’ satisfaction under conditions they believe tobe safe: for those who want it, the birthroom seems areasonable compromise.

MOLECULAR GENETICS AND OSTEOGENESISIMPERFECTA

MUCH has been written on the impact of molecularbiology in medicine and unquestionably more will follow.Progress has been achieved at a staggering pacel in a subjectwhich transcends traditional medical boundaries and

promises to revolutionise clinical and laboratory sciencessuch as haematology, immunology, microbiology, andoncology.2-4 However, it is in the study and management ofsingle-gene disease that the "new genetics" has made itsgreatest impression.The new techniques have the enormous advantage that

knowledge of the basic defect at the biochemical level is not aprerequisite. All that is necessary for preclinical or prenataldiagnosis is demonstration of close linkage of the diseasewith a polymorphic DNA marker, identified by means ofrestriction endonucleases and a radiolabelled gene-probederived from a known gene locus or from anonymous DNA

fragments. 5 This approach has proved fruitful for

Huntington’s chorea autosomal dominant polycystickidney disease cystic fibrosis,8 and to a lesser extentDuchenne muscular dystrophy, which appears to have apeculiarly large and complex locus.9 If the basic defect isknown but difficult to demonstrate in vitro, as is the casewith phenylketonuria, then the gene can be cloned and usedwith appropriate restriction enzymes to achieve prenataldiagnosis in genetically informative families.10

Demonstration of linkage of a disease with the genecoding for its putative miscreant protein not only provides ahandle of great clinical value, but also offers confirmation ofthe suspected causal relation. This point is well illustrated bythe studies on osteogenesis imperfecta (01) lately presentedby Sykes and his colleagues in Oxford."’ Collagen has longbeen implicated as the repository of the basic defect in mostforms of 01,12 but the obvious limitations imposed byobtaining suitable tissue for study have made it difficult toestablish that the error lies in the genes coding for collagenrather than in those responsible for its complex post-translational modification. The Oxford group are first pastthe post in the race to identify restriction enzyme

polymorphisms linked to the COL1A1 locus. At a stroke,they have provided confirmation that mutations in or closeto the genes coding for type I collagen are responsible for

1. Weatherall DJ. The new genetics and clinical practice. 2nd ed. Oxford OxfordUniversity Press, 1985.

2 Gordon H. Oncogenes. Mayo Clin Proc 1985; 60: 697-713.3. Editorial Genetic probes for immunological diseases. Lancet 1986; i: 1071-72.4 Editorial. Molecular mechanisms of tumour evolution. Lancet 1986, i: 780-81.5. Editorial. Molecular genetics for the clinician. Lancet 1984; i: 257-59.6 Gusella JF, Wexler NS, Conneally PM, et al. A polymorphic DNA marker genetically

linked to Huntington’s disease. Nature 1983; 306: 234-38.7. Reeders ST, Zerres K, Gal A, et al. Prenatal diagnosis of autosomal dominant

polycystic kidney disease with a DNA probe Lancet 1986; ii: 6-8.8. Farrall M, Law H-Y, Rodeck CH, et al. First-trimester prenatal diagnosis of cystic

fibrosis with linked DNA probes. Lancet 1986; i: 1402-05.9. Kunkel LM, Hejtmancik JF, Caskey CT, et al. Analysis of deletions in DNA from

patients with Becker and Duchenne muscular dystrophy. Nature 1986; 322: 73-77.10. Woo SLC, Lidsky AS, Guttler F, Chandra T, Robson KJH Cloned human

phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection ofclassical phenylketonuna. Nature 1983; 306: 151-55

11. Sykes B, Ogilvie D, Wordsworth P, Anderson J, Jones N Osteogenesis imperfecta islinked to both type I collagen structural genes Lancet 1986; ii: 69-72.

12. Smith R, Francis MJO, Bauze RJ. Osteogenesis unperfecta: A clinical and biochemicalstudy of a generalised connective tissue disorder. Quart J Med 1975; 44: 555-73.

many, if not all, of the more common dominantly inheritedforms of 01, whilst at the same time opening up possibleavenues for prenatal diagnosis.The approach of Sykes et al also obviates the need for

knowledge of the specific defect in the particular collagengene. Thus, the underlying abnormality may be a pointmutation, deletion, insertion, or regulatory mutation and itmay well be that no two families with 01 have exactly thesame genetic error. Experience at the biochemical levelsuggests that this may well be So.13 However, these factorswill be of no consequence, since it is a tightly linked DNAmarker which is being tracked through the family ratherthan the fundamental genetic abnormality.

Prenatal diagnosis is an emotive subject and some familieswith 01 will find the suggestion distasteful. For those whoexpress interest it would be incorrect to indicate that

prenatal diagnosis is now widely or readily available. AsSykes and co-workers point out, it is premature to drawconclusions until further studies have confirmed the Oxfordexperience and excluded other loci as possible causativeagents. False alarms in which probable lengthpolymorphisms have been causally implicated in lethal Op4and Marfan’s syndrome15 illustrate the need for caution.Each family in which 01 is segregating will have to becarefully evaluated, both clinically and in the laboratory,before any clear statement about prenatal diagnosis can bemade for that family. The use of the hypervariableminisatellite probes16 to confirm paternity would seem aprudent precaution in these family studies.

In many instances, possibly the majority, prenataldiagnosis will not be possible, either because the family isnot genetically informative or because blood cannot beobtained from crucial individuals who have died or refusevenesection. These families will have to wait for direct

diagnosis based on precise knowledge of the basic defect.Prenatal diagnosis for families in which healthy parents havehad an infant with one of the more severe and possibly lethalvariants of 01 is much more likely to be based on secondtrimester ultrasonography than on molecular geneticanalysis. 17

Nevertheless, the results of Sykes and colleaguesrepresent a major landmark in the long and tortuous historyof this potentially disabling group of heterogeneousdisorders. Further analysis of 01 at the molecular level mayprovide us with an insight into the hitherto completemysteries of gene expression, modification, and regulation.For example, it is curious that polymorphic restrictionenzyme cutting sites linked to the COL1A1 locus haveproved so elusive, an observation which suggests that theintegrity of this gene and its flanking sequences may be ofcrucial evolutionary significance and biological importance.Ultimately it must be hoped that the collective efforts ofmolecular biologists and clinicians working in harmony willlead to strategies for effective therapy. The dawn of themolecular era is now truly upon US.18

13. Pope FM, Nicholls AC, McPheat J, Talmud P, Owen R. Collagen genes and proteinsin osteogenesis imperfecta. J Med Genet 1985; 22: 466-78.

14. Sykes BC, Ogilvie DJ, Wordsworth BP. Lethal osteogenesis imperfecta and a collagengene deletion. Length polymorphism provides an alternative explanation HumGenet 1985; 70: 35-37.

15. Dalgleish R, Williams G, Hawkins JR. Length polymorphism in the pro &agr;2 (I)collagen gene: An alternative explanation in a case of Marfan syndrome. Hum Genet1986; 73: 91-92

16. Jeffreys AJ, Wilson V, Them SL. Hypervariable ’minisatellite’ regions in humanDNA. Nature 1985; 314: 67-73.

17. Shapiro JE, Phillips JA, Byers PH, et al. Prenatal diagnosis of lethal perinatalosteogenesis imperfecta (OI type II). J Pediatr 1982; 100: 127-33.

18. Hams R. Molecular euphoria. J Med Genet 1986; 23: 97-98.