4 - 6% of the liveboms are affected with some form of congenital disease (Warkany, 1971; Trimble & Doughty, 1974). Accordingly, in The Netherlands each year 8000 - 12.000 children are born with a more or less severe handi­cap. In some cases morphological and/or functional abnormalities are apparent shortly after birth, as is the case in anencephaly, meningomyelocele, conge­nital heart defects, several chromosomal aberrations and inborn errors of meta­bolism. In other congenital diseases the onset of clinical manifestations occurs in early or late childhood and some sex-chromosomal aberrations will not be detected before puberty.

Finally, a number of these diseases is not manifest before adulthood, like Huntington's chorea and a number of variants of inherited metabolic disorders. The three main categories of congenital diseases are:

1 . Chromosomal aberrations, with an incidence of 1 : 200 liveborns (Jacobs et al., 1974); about 1000 patients per year in The Netherlands.

2. Gene mutations, resulting in metabolic diseases, incidence 1 : 100 live­borns and accordingly 2000 patients per year.

3. Disturbances during embryonic development, 2 - 4 : 100 liveborns, and 4000 - 8000 patients per year.

Most numerical chromosomal aberrations are caused by nondisjunctions during gametogenesis or during the first divisions of the fertilized ovum. The most frequent examples are trisomy 21 (Down's syndrome), Klinefelter's syndrome (47 XXY), Turner's syndrome (45 XO) and 47 XYY. In some of these syn­dromes the risk of non-disjunction increases with maternal age, as in trisomy 21 . This has an incidence of 1 : 3000 newborns from mothers younger than 30 years; the incidence rises to 1 :280 in mothers of 35-39 years and to 1 : 40 in mothers older than 45 years. A minority of chromosomal disorders is caused by structural abnormalities of the chromosomes, like translocations, inversions, etc. Part of these are inherited from one of the parents, who is a phenotypic-

ally normal carrier of the balanced form of the rearrangement. The risk for affected offspring in carriers of balanced translocations is dependent on the type of translocation and the sex of the carrier-parent and may vary from 10-100%.

In McKusick's catalogue (1971) nearly 2000 different gene mutations of Men-delian inheritance are listed. Many of these result in metabolic disorders, but only in 10% of these the exact nature of the biochemical defect has been characterised (Stanbury et al., 1972). In about 50 severe inborn errors of me­tabolism the enzymatic defect or the storage of a specific metabolite can be demonstrated in in vitro cultured skin fibroblasts from the patient (for reviews: see Milunsky et al., 1970; Milunsky and Littlefield, 1972). If the genetic trait shows recessive inheritance, both parents are heterozygous carriers and asymptomatic; the (recurrence) risk for an affected child is 25%. A son of a mother, who is heterozygous for an X-linked disease, has a chance of 50% to be affected. Most of these genetic metabolic diseases are relatively infrequent (varying from about 1 : 1500 to 1 : 100.000), but as a total group they are twice as frequent as chromosomal aberrations.

The major category of congenital diseases are the disturbances in embryonic development which may be the result of environmental and/or genetic factors. The most common types are congenital heart defects (+ 1 : 100 live borns), neural tube defects (+ 1 : 500), cleft lip and/or palate, club foot and seve­ral hundred other congenital deformities. The risk for such an anomaly in­creases in some types after the birth of an affected child; in other types this is possibly not the case.

The knowledge about the etiology is very incomplete in most cases of conge­nital disease. As a result causal prevention is nearly impossible, except for the avoidance of well-known teratogenic factors like ionizing radiation, cer­tain viral infections and certain toxic drugs. Therapeutic methods are not a-vailable for chromosomal aberrations and most of the inherited metabolic di-

seases. Improved surgical techniques contributed to the management of many congenital malformations like cleft lip and palate, cardiac malformations, skeletal deformities, etc.

Genetic counseling and prenatal diagnosis of congenital diseases Many of the congenital diseases from the three categories are associated with severe physical and/or mental abnormalities and most patients require intensive medical and psychosocial care, often during several decades. Besides the pro­blems caused by a handicapped life, parents - and sometimes patients - are confronted with the fear of recurrence of the disease in their future offspring. The organization of genetic advice required in these situations received in­creasing attention during the last decade. An increasing number of couples, having a (distant) relative affected with some type of congenital disease, also ask for such an advice about their own risks and the methods for prevention. Genetic counseling will primarily be based upon the availability of a precise diagnosis and on information about the mode of inheritance of the disease in­volved. The physician giving genetic counseling should have sufficient know­ledge of the principles of genetics, embryonic development, recent diagnostic methods for congenital diseases and of therapeutic and preventive means. He needs time to explain the risks (which may vary from negligeable to 100%) and to help the counselees to reach a decision which is appropiate in their individual situation. These decisions are often very difficult, since they may involve the acceptance of a high risk of another affected child or the deci­sion to refrain from reproduction. In other cases artificial insemination, adop­tion, or abortion may be considered.

The interpretation of the risk-figures and the decision reached by the coun­selees will be determined by many factors, like the composition of their fa­mily, their age, the severity of the disease involved, their psychological tolerance and the opinions and attitudes in the society.

The development of methods enabling prenatal diagnosis of a number of con­genital diseases offers new perspectives to many couples at risk. The first re­ports of succesfull analyses of the fetal karyotype in cultured amniotic fluid cells were published nearly 10 years ago (Steele & Breg, 1966; Jacobson & Barter, 1967). The first genetic metabolic disorders were detected soon after­wards by biochemical assays of amniotic fluid supernatant and cultured amnio­tic fluid cells (Nadler, 1968; Fujimoto et al., 1968). During the last five years more and more experience has been gained with transabdominal amnio­centesis in the 14th - 16th week of pregnancy, the subsequent in vitro culti­vation of fetal cells from the amniotic fluid and the karyotyping and biochemi­cal analysis of these cells.An increasing number of parents at risk for a chromoso­mal aberration or a genetic metabolic disorder asked for prenatal diagnosis and several centers described the results on their first series of hundreds of cases (Nadler, 1972; Milunsky & Atkins, 1974; Philip et al., 1974; Hsu & Hirsch-horn, 1974; Golbus et al., 1974; Wahlstr8m et al., 1974; Niermeijer et al. 1975). It appears, that amniocentesis in early pregnancy is a relatively safe procedure and that the analytical results are very reliable.

It may be of great advantage for parents at risk to have certainty about the status of the fetus. Prenatal diagnosis will show in many cases that the fetus is not affected by the disease tested for and the parents can be reassured. On the detection of a fetal abnormality the parents may ask for interruption of the pregnancy, thus preventing the birth of a severely affected child. The possibilities for prenatal detection were recently extended by the finding of Brock & Sutcliffe (1972) that closure defects of the neural tube (anencepha-ly and meningomyelocele) are detectable in early pregnancy by elevated con­centrations of alpha-fetoprotein in the amniotic fluid supernatant.