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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 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- 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 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 . 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 , 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. 0. Carter Recessive conditions Table 2 Estimates ofbirth frequencies ofsome more common recessive conditions in Britain per 1000 livebirths Autosomal recessive conditions are of less interest to Metabolism radiation biologists. The interval between gene muta- Cystic fibrosis 0-5 (Hall and Simpkiss, 1968; Wright, 1969; Stephen et al., tion and patient may be lengthy, centuries, or even 1975) millennia. The full effect of an increase in mutation Phenylketonuria classical 01 (Carter, 1973) Nervous system rate would not be seen for many generations. For Neurogenic muscle atrophies 0-1 (Pearn, 1973; Pearn and example the gene frequency of phenylketonuria in Wilson, 1973) north-west Europe is about 1 in 100. If the mutation Red blood cells Sickle-cell anemia 01 (Carter, 1973) rate was, say, 1 in 50 000 this would imply a mean Endocrine glands survival time of each mutation of some 500 gener- Adrenal hyperplasias 0 1 (Hubble, 1966; Rosenbloom and Smith, 1966) ations, that is about 12 000 years. This would be Hearing shortened, however, if, as is likely, the higher birth Severe congenital deafness 0-2 (Stevenson and Cheeseman the of 1955; Chung et al., 1958) frequency in Europe is to some extent result Sight founder effect and drift. Recessive forms of blindness 0-1 (Fraser and Friedmann, 1967) Each population appears to have its own pattern of Mental retardation severe recessive disorders occurring at relatively high fre- Non-specific recessive forms 0 5 (Carter, personal estimate) quencies. Birth frequencies ofrecessive disorders may be much influenced by heterozygote advantage. There Isles, with a cline ofincreasing frequency as one moves is the opportunity for the relatively high frequencies north and west from about 1 in 15 000 in the southeast of one or two out of the many hundred individual to 1 in 7000 in Ireland and West Scotland. It will be recessive to develop as a result offounder effect interesting to see how the pattern of frequency deve- and drift in a particular population. The population lops in Europe as the results of neonatal screening geneticists do not yet appear to have worked out that come in. Poland appears to have a high frequency. frequency of a recessive gene in a particular size of Finland has such a low frequency that the value of population at which it is no longer reasonable to neonatal screening is in doubt. The neurogenic muscle invoke founder effect and drift and so necessary to atrophies certainly are common and include 2 andcopyright. invoke heterozygote advantage. The high frequency perhaps 3 distinct conditions, distinguishable by of tyrosinosis in French Canadians is obviously the age of onset and the rapidity with which paralysis result of founder effect, of Tay-Sach's disease in develops. Sickle-cell anaemia is confined to immi- Ashkenazi Jews is acceptable also as the result of grants to Britain from West and Central Africa, but founder effect and drift, of phenylketonuria through- there are sufficient of these to give a figure of 0-1 per out Europe with localized specially high frequencies 1000 for births in Britain. This would drop rapidly is perhaps just acceptable. But the apparently con- with intermarriage of these migrants with those ofhttp://jmg.bmj.com/ sistent high frequency of cystic fibrosis of about 1 in other races. The adrenal hypoplasias include 3 2000 births over much of Europe is, in my opinion, varieties, though 2 of these may involve the same difficult to visualise as the result of such chance enzyme. It has been estimated that recessive con- influences and requires a small degree ofheterozygote genital deafness perhaps includes at least 5 different advantage. forms, though these are not distinguishable clinically. Autosomal recessive conditions which appear to Recessive blindness includes several different forms have birth frequencies in Britain of about or greater many of which are distinguishable. than 0-1 per 1000 births are listed in Table 2. Cystic A list of autosomal recessives with frequencies on September 25, 2021 by guest. Protected fibrosis is outstanding for a condition where repro- between 0-1 and 0-01 per 1000 would include with ductive fitness is near zero and yet has a high birth their approximate birth frequencies: among the frequency. Recent neonatal screening surveys by lysozymal enzyme deficiencies-Tay Sach's disease Stephan's method on albumin in meconium, checked (0 04), 1 (0-02), mucopoly- by sweat electrolyte, in Dublin, Cardiff, and in one or saccharidosis 2 (0 01), metachromatic leucodystrophy two German cities has indicated that the birth fre- (0-02); among errors of metabolism affecting carbo- quency may be 1 in 1600 rather than 1 in 2000. The hydrate metabolism-galactokinase deficiency (0-01) indications are that the relatively high frequency andgalactosaemia(0 02); among errors of amino acid obtains from Ireland across to Russia and perhaps in metabolism-homocystinuria(0 01),cystinuria(0 06), southern Europe too, but more data are needed. The cystinosis (0 01); among syndromes-Smith-Lemli- condition is rare outside Europe and populations Opitz syndrome (0'01). derived from Europe. Phenylketonuria is also rare There are also some hundreds of probably rarer except in Europe and migrants from Europe, but recessive conditions. shows distinct variations even within the British The total frequency of conditions listed in Table 2 J Med Genet: first published as 10.1136/jmg.14.5.316 on 1 October 1977. Downloaded from Monogenic disorders 319 is 1P7 per 1000 and adding rarer conditions would drotic ectodermal dysplasia, X-linked aqueduct total about 2-5 per 1000 for presently known re- stenosis, and X-linked amelogenesis imperfecta. cessives. Others will be discovered. Recently for There are many other X-linked conditions some of example homozygotes for antitrypsin deficiency, which also perhaps have a frequency of 0-01 per 1000. with a birth frequency of about 0 7 per 1000, have These include Aldrich syndrome, Fabry's disease, been shown to have a high risk of developing severe Borjeson syndrome, , nephrogenic pulmonary emphysema in early adult life and might , chronic granulomatous disease, have been included in Table 1. , Lowe's syndrome, Menkes Stevenson's estimate for Northern Ireland was 2 1 syndrome, Type II mucopolysaccharidosis, the per 1000 and Trimble and Doughty's for British Becker type ofX-linked muscular dystrophy, Norrie's Columbia 1 1 per 1000. disease, oral-facial-digital syndrome, Pelizaeus- Merzbacher syndrome, X-linked retinitis pigmentosa, X-linked conditions and testicular feminisation syndrome. There is no indication that heterozygote advantage X-linked conditions are intermediate between domi- plays any part in maintaining the frequency of any of nant and recessive conditions in the information they these X-linked conditions and as with dominants provide on radiation effects. Where reproductive their frequency probablyreflects directly the mutation fitness is zero and there is no selective advantage of rate and the reproductive fitness of affected males. the heterozygous woman, and for equal mutation Heterozygote advantage against malaria is probably rates in the two sexes, the proportion of males important in the case of G6PD deficiency, but this is affected is 3 times the mutation rate and of these a uncommon in Britain. third are affected as a result of fresh mutation. Only The total frequency of X-linked conditions in the latter would be immediately increased by an Table 3 is about 0 5 per 1000 male births and the increase in the mutation rate and it would take total frequency of all X-linked conditions presently several generations for the full effect ofa simultaneous known of the order of 0-8 per 1000, that is about 0 4 increase in female heterozygotes to be reflected in the per 1000 births of both sexes. Both Stevenson's and birth of affected sons. Trimble and Doughty's estimates were also 0 4. copyright. Table 3 Estimate ofbirthfrequency in males ofmore Conclusion common X-linked conditions in European derived populations per 1000 livebirths The total birth frequencies ofpresently known serious Locomotor system and moderately serious dominant conditions as Muscle dystrophy-Duchenne 0-2 estimated from ad hoc surveys in British and allied Blood clotting

Haemophilia, classical 0.1 populations is about 7-0 for dominants, 2-5 for re- http://jmg.bmj.com/ Skin cessives, and 0 4 for X-linked conditions, i.e. a total Ichthyosis 0 1 Mental retardation ofabout 10 per 1000 livebirths, which is similar to that Non-specific X-linked 0 1 obtained by Stevenson (1959) and about 10 times (Estimates mainly from Stevenson and Kerr, 1967) more than that obtained by Trimble and Doughty (1974). Table 3 summarises the findings of ad hoc surveys of X-linked conditions with birth frequencies of 0 1 References on September 25, 2021 by guest. Protected or more per 1000 births. Several surveys are available of Duchenne type X-linked muscular dystrophy Beighton, P. (1970). The Ehlers-Danlos Syndrome. Heinemann, giving similar results to the Oxford survey of London. Blyth, H., and Ockenden, B. (1971). Polycystic disease of Stevenson and Kerr (1967). This is also the case with kidneys and liver presenting in childhood. Journal of classical haemophilia. 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