Monogenic Disorders
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J Med Genet: first published as 10.1136/jmg.14.5.316 on 1 October 1977. Downloaded from Journal ofMedical Genetics 1977, 14, 316-320 Monogenic disorders C. 0. CARTER From the MRC Clinical Genetics Unit, Institutte of Child Health, London In comparison with chromosomal anomalies or the Table I a Estimates ofbirth frequencies ofsome more more common congenital malformations there are common dominant conditions in European derivedpopu- special difficulties in establishing the total frequency lations per 1000 livebirths of monogenic disorders. There are very many Nervous system conditions, most ofwhich are individually rare. Many Huntington's chorea 0 5 (Shokeir, 1975) of them are not manifest at birth and many present Neurofibromatosis 0 4 (Crowe et al., 1956) Myotonic dystrophy 0-2 (Grimm, 1975; Klein, 1958) difficulties in diagnosis. There are two possible Intestines approaches: collating studies of the frequencies of Multiple polyposis coli 0-1 (Veale, 1965; Reed and Neel, 1958) individual conditions which have been carried out by Kidney individual workers with a special interest in the Polycystic disease of kidneys 0-8 (Dalgaard, 1957) condition using all possible means of ascertainment; Locomotor system Diaphysial aclasia 0 5 (Murken, 1963) or surveillance studies attempting to pick up all Sight monogenic disorders in a particular population. A Dominant forms of blindness 0-1 (Fraser and Friedmann, 1967) Hearing valuable pioneer study ofthe second type was that by Dominant forms of early 0-1 (Stevenson and Cheeseman, Stevenson from Northern Ireland (1959). The study, childhood onset deafness 1955; Chung et al., 1958) was incomplete and several Dominant otosclerosis 1-0 (Morrison, 1967) however, evidently (adult onset) disorders were regarded as monogenic, which would Circulation copyright. now not be so classified. Nevertheless, the total Monogenic hypercholesterol- 2-0 (Heiberg and Berg, 1976) aemia frequency suggested was of the right order. A current Teeth surveillance study is from the British Columbia Dentinogenesis imperfecta 0-1 (Witkop, 1973) Blood Register (Trimble and Doughty, 1974). This also, 0-2 et 1962) however, is evidently incomplete. In particular Congenital spherocytosis (Morton al., relatively common conditions of adult onset are represented and even a common relatively Table lb Some less common dominants hardly http://jmg.bmj.com/ diagnosed autosomal recessive disorder with onset in childhood, cystic fibrosis, is recorded at a frequency Nervous system Tuberous sclerosis 0-01 (Borberg, 1951) ofless than halfthat indicated by adhoc and neonatal Basilar impression 0 03 (Haslam, 1973) screening studies. However, the continuation of such Skeleton Thanatophoric dwarfism 0-08 (Harris and Paton, 1971) a registry is well worth while and it is likely to become Osteogenesis imperfecta 0 04 (Smars, 1961) more complete and accurate with time. Therefore, it is Marfan sydrome 0 04 (Lynas, 1958) first Achondroplasia 0-02 (Verschuer, 1962) necessary to rely largely on studies of the type Ehlers-Danlos syndrome 0-01 (Beighton, 1970) attempting to make due allowance for their limita- Osteopetrosis tarda 0 01 (Salzano, 1961) on September 25, 2021 by guest. Protected tions. A limitation of either type of survey is that Sight Retinoblastoma 0 03 (Macklin, 1960) birth frequencies in any one country may be atypical. Face Most of the surveys have come from north-west Cleft lip and/or palate with 0 01 (Cervenka et al., 1967) mucous pits oflip European populations. Metabolism Acute intermittent porphyria 0-01 (Tschudy, 1973) Dominant conditions Variegate porphyria 0-01 (Tschudy, 1973) Teeth Amelogenesis imperfecta 0-02 (Witkop, 1973) Dominant conditions have special importance in radiation genetics. The relation between mutation and birth frequency is relatively direct, the theoretical increase in the birth frequency of fresh cases of such equilibrium birth frequency being the product of dominant conditions born to unaffected parents. twice the mutation rate and the mean persistence in Table la summarises data on birth frequencies terms of generations of each mutant gene. Any from ad hoc surveys of some of the more common increase in mutation rate will be reflected at once by an dominant conditions giving frequencies of 0-1 per 316 J Med Genet: first published as 10.1136/jmg.14.5.316 on 1 October 1977. Downloaded from Monogenic disorders 317 1000 births or more. A birth frequency is the pro- reduced by two-thirds in Table la so as to include portion of children born who will at some stage in only the more severe cases. their lives develop the condition, that is the pro- The reason for the relatively high frequency of portion of children who are born heterozygous for these dominant conditions is probably largely a the gene involved. Table lb summarises findings on reflection of their relatively small effect on repro- some less common dominant conditions with esti- ductive fitness. There is no need to postulate an mated frequencies between 0 1 and 001 per 1000 improbably high mutation rate for them, nor to births. postulate, as some have suggested, that in some Monogenic hypercholesterolaemia is outstanding circumstances those who possess the gene have an in Table la. Evidence for such a monogenic entity above average reproductive fitness. In the case of among the largely multifactorially determined monogenic hypercholesterolaemia however it may hyperlipidaemias has been increasing over the past well be that the much increased risk of early death in 20 years, and recently Brown and Goldstein (1974) men did not apply in a less civilized environment. have probably identified the specific basic biochemical The somewhat less common dominants listed in defect in fibroblast culture, though there may be more Table lb also present no special problems. Thana- than one variant. The combined birth frequency of tophoric dwarfism, the most frequent in the table, heterozygotes is not well established, but is perhaps should not perhaps be included as it is not yet proven not likely to be less than 1 or more than 4 per 1000. that it is a dominant condition. Moreover, unlike the The condition is serious since it is estimated that about other conditions listed it results in stillbirth or neo- a halfofheterozygous men have their first coronary by natal death. Most estimates of the 'birth frequency' 50 years and about half are dead by 60 years (Slack, of achondroplasia have been estimates of the birth 1969). A case has been made for an even more com- frequency largely of thanatophoric dwarfism and mon monogenic form of hyperlipidaemia, with both indeed the paediatric pathologist's concept of the hypercholesterolaemia and hypertriglyceridaemia histology of achondroplasia is often that of this (Goldstein et al., 1973), also associated with early condition. Classical achondroplastics seldom die in onset ischaemic heart disease; but I do not think the infancy and so do not provide the pathologist with case is proven. histological material. Nevertheless, classical achon- copyright. Adult onset dominant otosclerosis has a birth droplasia is not an uncommon condition, perhaps the frequency ofthe order of 3 0 per 1000 and the onset is most common of the dozen or so forms of surviving usually below 40 years. short limbed dwarfism apparent at birth. The adult form of polycystic disease of the kidneys There are many more well-known dominant had a birth frequency of nearly 1 per 1000 in Dal- conditions. Some of which should perhaps have gaard's Danish survey (1957). It is certainly a re- appeared in Table lb, if there had been an adequate latively common condition in nephrology clinics. survey. These include familiar conditions such as http://jmg.bmj.com/ Though sometimes benign, the condition usually cleido-cranial dysostosis, Apert syndrome, Crouzon causes clinical trouble before the 4th decade and may disease, dominant myotonia congenita, dominant cause death in childhood. The condition has been facio-scapula-humeral muscle dystrophy, dominant recognized in twin fetuses aborted at 16 weeks (Blyth forms of neurogenic, muscular atrophy, split-hand and Ockenden, 1971). and foot, von Willebrand's disease, Treacher Collins There have been numerous prevalence studies of syndrome, multiple epiphysial dysplasia, and many Huntington's chorea. The most complete of these in others. However none of these I think will prove to north-west Europeans tends to give an estimate of have frequency which would put them into Table la. on September 25, 2021 by guest. Protected 0 05 to 0-1 per 1000 population. With an estimated Any further conditions likely to go into Table la are mean survival after onset of the disease of 15 years, those, like perhaps combined hypercholesterolaemia this implies a birth frequency of about 0 5, especially and hypertriglyceridaemia, if that exists as a mono- as some cases still remain undiagnosed. The estimate genic disorder, which have not yet been recognized. for neurofibromatosis is an old one, but the frequency The total frequency of dominant conditions in with which the condition is seen, especially in ortho- Table la is 6 per 1000, with a third of this caused by paedic clinics, indicates that this old estimate may be monogenic hypercholesterolaemia. The conditions in near the mark. Table lb only total 0 3 per 1000. Perhaps 7 per 1000 The other conditions listed largely speak for would be a reasonable figure for all presently known themselves. Some have regarded multiple exostosis as serious dominant conditions. But there may well be a trivial condition. However, it may cause embarras- others which are not yet recognized. Stevenson's singly short stature, restrict joint mobility, and per- estimate for Northern Ireland was similar, 9 5 per haps 1 in 20 patients develop sarcoma. The birth 1000, but Trimble and Doughty's only 0-8 per frequency of dominant otosclerotic deafness has been 1000. J Med Genet: first published as 10.1136/jmg.14.5.316 on 1 October 1977. Downloaded from 318 C.