Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation disorders caused by paternal deficiency (PWS) or maternal deficiency (AS) of gene(s) in 15qll.2-ql3. We have constructed a 3.5 Mb yeast artificial chromosome (YAC) contig of the PWS/AS region and cosmid contigs of selected YACs at D15S13, SNRPN, S10, and S113. Cosmid clones have been used for fluorescence in situ hybridization (FISH) detection of deletions in PWS and AS patients. In addition, a total of 28 short tandem repeat polymorphisms (STRs) have been mapped to specific YACs in the contig, providing a highly informative set of markers for detection of deletion or uniparental disomy (UPD) in PWS and AS patients. Use of the 3 most informative markers in this region (S542, S128, and ASSCA-1) plus 3 markers distal on 15q (S123, S125, and S131) provide an efficient diagnostic strategy for UPD15.

A combination of FISH and STR analysis has identified small deletions in one sporadic and one familial case of PWS (family O). Both deletions involve all or part of the SNRPN gene but do not extend telomeric to PAR-5 or PAR-1, two novel transcripts expressed exclusively from the paternal chromosome. However, expression of SNRPN, PAR-5, and PAR-1 is lost in both cases, implying the presence of an imprinting control region near SNRPN. The smallest deletion in family O is estimated at approximately 30-40 kb in size and involves a newly identified CpG island at the 5′ end of SNRPN which is methylated on the maternal chromosome. This small deletion in two PWS affected siblings was present in the father and the paternal grandmother, both of whom were phenotypically normal.

When calculating the chance of monozygosis from the results of a blood group study in a twin-family, it is desirable to use the complete information that is presented by these results and not only part of it.

A calculation-method in which the complete genetic-information is used is presented.

The use of the formulas is demonstrated by calculating the probability of monozygosis in two examples.

The problem of the equilibrium stability of a phenotypic selection process, with a single pair of autosomal alleles, has been numerically studied, on the basis of previously established reproduction differential equations.

The evaluation of the sketches of the hands of 746 consanguineous persons of different ages and sexes as well as the examinations of 120 radiograms of the hands of non-related adults have shown the following results:

1) Relatives (Brothers and sisters, mothers and children, parents and children) resemble each other with regard to the respective finger-lengths and the proportions of these between right and left hand more than non-relatives do.

2) The respective finger-length is organized anatomically by the longitudinal variations of all elements of the second and forth rays and modified by the Carpalia and the longitudinal proportion of Radius and Ulna. We can regard the most extensive variations of growth at the second ray in men and at the forth ray in women. In the same manner the lateral differences between the right and the left hand can be explained for both sexes mainly by the longitudinal differences of the second rays.

3) In reference to these anatomical conditions a genetical hypothesis about a transmission of the relative finger-length is developped and its usefulnes for the diagnosis of paternity comes to discussion.

A total of 71 pairs of like-sexed dizygotic twins were studied, comparing within-pair differences for plasma total, free and esterified cholesterol, and triglyceride with the number of HLA haplotypes the twins had in common. If associations are present between HLA and the blood lipids studied, the twins with no haplotypes in common would be expected to have the largest within-pair mean square, those with two in common the smallest, and those with one in common an intermediate value. No significant differences were found comparing within-pair mean squares for the variables studied.

Con il 1956 si apre il V volume della nostra Rivista e si compiono cinque anni da quando abbiamo pubblicato il libro « Studio dei Gemelli ». Una vasta famiglia di autori, ed una più vasta di lettori, si è raccolta attorno ad « Acta Geneticae Medicae et Gemellologiae » la quale, unitamente al libro, ha valso a rinfocolare l'attesa e l'impegno attorno agli studi gemellari, ed a raccogliere un materiale di cospicuo interesse.

Per sottolineare questa circostanza riprendiamo il profilo storico della gemellologia che abbiamo tracciato in un capitolo di « Studio dei Gemelli » per integrarlo con alcuni dati recentemente acquisiti, non senza notare che, in genere, questo assunto non coincide con quello di aggiornare il lettore con i progressi della gemellologia, perchè altra cosa è l'apporto scientifico, a cui attende periodicamente la Rivista, ed altra cosa l'elaborazione storica del pensiero scientifico.

Quest'ultima richiede, fra l'altro, una certa prospettiva nel tempo, cioè una distanza che consenta di attribuire ad ogni apporto il valore che effettivamente e definitivamente gli compete per accordarlo con le linee di sviluppo del pensiero scientifico.

The clinical findings in a group of syndromes in which tapetoretinal degenerations are associated with systemic lipid disorders are described. This group includes abetalipoproteinemia (the syndrome of Bassen and Kornzweig), Refsum's syndrome, Neuronal Ceroid Lipofuscinosis, and Cockayne's syndrome. AII four are transmitted by single autosomal recessive genes. The pathological findings are discussed. If diagnosed early enough, abetalipoproteinemia should be treated by administration of vitamin A, and Refsum's syndrome by restriction of intake of phytanic acid and phytol.

Among the 85,976 children born at the «Istituto Ospitaliero Provinciale per la Maternità di Milano» from January 1st 1942 through December 31st 1962, 1185 newborn infants have

been observed with one or more congenital malformations, i. e. with a frequency of 13,8°/°°. Distribution of this material in a first period of six years and in three subsequent quinquennia, and comparison of the frequencies of the subjects with malformations observed in the various periods allow us to draw the following conclusions:

1) in the period 1942-1962, especially in the latest years, the total frequency of congenital malformations has not exhibited significant variations;

2) the frequency of harelip and/or cleft-palate, omphalocele, hypospadia, polydactily, hypodactily and syndactily appears rather uniform. The same applies, as a whole, to CNS malformations, though a certain heterogeneity has been found in the frequencies of rachischisis observed in the various periods;

3 ) as for mongoloid, dysmyelitic and club-foot subjects a significant heterogeneity of the frequencies observed in the various quinquennia has been demonstrated.

The statistical data on the malformation occurred in Italy from 1956 to 1958 have been examined. It has been seen that their number is almost constant (i. e. some 1,500 per year). The ratio of alive malformed to dead malformed is of 3:1, but the number of deaths by congenital malformations increases considerably during the first year of life, mostly due to inner organ malformations, non detectable at birth.

50% of the cases of harelip die during the first year of life. The most serious malformations are those concerning the central nervous system, while the most common ones, are those affecting the locomotive apparatus.

The number of malformations has not been influenced by the very insufficient diet during the four years of war, neither by the 1957 « asiatic influenza ». The malformation index, furthermore, appears almost constant in the time and in the various regions, showing the highest figure in Lucania and Friuli (3.05) and the lowest ones in Campania (0,89), Sicily and Liguria (1.21).

Our starting point was Franz Alexander's well-known hypothesis about the hypertensive personality. According to Alexander (1939), hypertensive patients are characterized by a neurotic conflict between passive dependent tendencies and over-compensatory, competitive, hostile impulses. Hypertensive patients seem to be anti-aggressive, submissive, polite, and reserved. At the same time, they show no direct neurotic symptoms such as anxiety, obsessive ideas, or conversion symptoms. Hypertension may be looked upon as a substitute for symptom neurosis. According to Alexander, hypertensive patients are unable to express freely aggressive impulses, and at the same time unable to repress or absorb the impulses through symptom formation. An accumulation of psychic energy takes place, which manifests itself in constant vasomotoric stimulation. In the long run, this development may be able to change the balance of the baroceptors and finally destroy the circulatory system.

A sample of MZ twins is particularly suitable for studying the influence of inhibited aggression on blood pressure. In addition to the methodological advantages of controlling the genetic and external environmental factors of childhood, one frequently finds a casting of roles with one of the twins dominant and aggressive, and the other as a submissive and timid partner.

A study of 30 families, belonging to a 290 individuals pedigree, showes that the epithelioma adenoides cysticum is genetically influenced by an autosamal dominant factor. But, owing to penetrance differences between sexes, apparently the disease is irregularly transmitted.

Weights of developing incisors in 10 pairs of twin fetuses have previously been related to ages in order to compare dental growth status (Stack, 1963). Ages (T0) at which weights (W) of mineralised portions of teeth of the temporary dentition become significant have been computed (Stack, 1968), using a Fortran program giving maximum likelihood estimates of the required parameters, based on the statistical model of Angleton and Pettus (1966).

Availability of the additional parameter T0 allows a reexamination of the previous data, now fortified by observations on incisors from five further pairs of twin fetuses. Estimates of ages were made from the relationship (T—T0) = k·W½, where values for upper and lower central incisors were 2.0 and 2.8 for k, 19.5 and 18.5 for T0, respectively. Less reliable estimates were obtained from the lateral incisors. These values were computed from observations on 40 dentitions from normal singleton fetuses. Ages were also estimated from tabulated body weights (Documenta Geigy).

α 1-at phenotypes and serum levels were studied in 100 Greek patients of pulmonary TBC by starch-gel electrophoresis and radial immunodiffusion. The mean value of α 1-at (315 ± 77) was significantly lower (p < 0.005) than in the control group. An attempt is made to explain this finding based on the α 1-at phenotypes distribution in the TBC patients.

In the beginning the dogma was that sex determination in man followed the Drosophila pattern in which XO is male, XXY female, and the Y chromosome has no direct influence on the determination of sex. On the grounds of specific anomalies with which they presented, females with Turner Syndrome were sex chromatin tested and found to be chromatin negative [1]. This result, confirmed in 1956 by the male frequency of red-green colour blindness in these subjects which indicated that they carried only one X chromosome in spite of their female phenotype, suggested that therefore they might be XO, and, so, hinted that sex determination in man might not follow the then accepted pattern [2]. In 1959 chromosome studies confirmed that XOs were female [3] and showed that subjects with the symmetrical XXY sex-chromosome anomaly were with Klinefelter syndrome [4]. In the same year, by showing that XOs were females also in mice [5] it became accepted that the Y chromosome was the determiner of the formation of the testis in the mammalian embryo, and so was the key element in primary sexual differentation. It would seem appropriate to call this formal model of chromosomal sex determination the Malandrium pattern [6].

In 1966 Jacobs and Ross [7], from work on males with Y chromosome deletions narrowed down the testis determining function of the Y chromosome to its short arm. Then, in 1975, Wachtel and collaborators [8] were the first to formulate a hypothesis on the sex determining gene, or, more precisely on the nature of its product. They suggested that this developmental role might be played by the H-Y antigen, a weak histocompatibility antigen which had been known to be involved in the rejection of male skin grafted onto otherwise histocompatible female mice. The idea had run into technical difficulties and a major problem was related to the significance that should be attached to the results of two different ways for demonstrating the antigen, namely the cell-mediated cytotoxicity test or the serological test. Efforts were made to keep the H-Y hypothesis alive, largely because there was a certain elegance about it [9, 10]. However eventually XX male mice, lacking H-Y by either test, spelt the end of the candidature of H-Y as the testis determining mechanism [11, 12].

A method for the estimation of genetic correlations based upon analysis of genetic marker phenotypes is presented. At a given marker locus, the probability of observing a pair of individuals with a specific combination of phenotypes can be expressed as a function of the gene frequencies at that locus and the genetic correlation (R) between that pair. The likelihood of obtaining a sample of n such pairs with their phenotypes at m marker loci can be expressed as a product of nm such functions. From the likelihood function, maximum likelihood estimates of R can be obtained, and hypotheses about R may be tested. A sample of Swedish twin families (61 dizygotic twin pairs, 268 husband-wife pairs, and 164 sib pairs) were analyzed by this method using information from 21 markers. It was found that for the twin pairs, R = 0.458, which was significantly different from the R calculated for sib pairs (R = 0.5 58) but not significantly different from the expected 0.5. For the husband-wife pairs, it was found that R = 0.086, which did differ significantly from the expected value of 0, indicating the presence of nonrandom mating in this population.

The biometrical genetical method of analysis of continuously varying human traits is described and shown to unify a number of common approaches to the analysis of twin data. The method, which is based on the analysis of variance, goes beyond alternative approaches by providing tests of basic assumptions and by investigating the possibility of assortative mating and dominant gene action.

Twins form an indispensable group for the application of the biometrical genetical method but the value of including other groups, often more easily collected, is demonstrated.

The techniques are illustrated through the reanalysis of data on the behavioural measures, neuroticism and intelligence quotient (I.Q.). For both measures fundamental assumptions are met. The results suggest the absence of dominant gene action for neuroticism, indicating an evolutionary history of stabilising selection, and directional dominance for high I.Q., indicating an evolutionary history of strong directional selection. Both these findings seem reasonable in view of psychological knowledge concerning the two measures.

In a series of 114 twin pregnancies followed in the course of 12 years (1961-1972) we noted the favourable effect of specialised preventive care. More exact diagnostics (ultrasound scanner) shifted the recovery of twins from the 35th to the 30th week of pregnancy. Due to the therapeutic and preventive bed rest and to the systematic use of orciprenalin, the duration of pregnancy has been prolonged from 36 to 38.5 weeks on the average. The perinatal mortality in twin deliveries decreased from 14.4 to 5%.

The Autors have begun a genetic research on the ovarian cancer. In this first part of the work:

1. it has been defined the group of the “ primary cases ” in which have been included 74 cases of solid carcinoma, 108 cases of cystic carcinoma and 93 cases of unclassified malignant tumor of the ovary.

2. it has been studied the age of appearance and the age incidence variation of the ovarian cancer, and it has been found that:

a) the mean age of appearance is 51,15 ± 0,64 years, but it lowers to 48,94 ± 0,68 years for the solid carcinoma and rises to 52,36 ± 0,90 years for the cystic carcinoma;

b) the period of the greatest frequency of the disease is between 40-60 years of age, followed by a sharp decrease over age 65;

3. it has been analysed the fertility of the patients, and it has ben recorded a decrease of the mean fertility up to 29% as compared to the general population;

4. it has been mentioned the importance of the hormonal factor as a problable condition for the development of the ovarian cancer, that nevertheless calls for other — likely idiotypic — factors.

Chromosomal evaluation was done in 62 patients affected with otosclerosis, clinically and surgically proven. Numerical and structural karyotype analysis of leucocyte and fibroblast cultures, showed normal results.

Cytogenetic findings published earlier by other authors in a small series of otosclerosis patients and where mosaicism in the D-group was detected, are contradicted.

The importance of the critical evaluation of the cytogenetic method used and of the necessity to investigate cytogenetically a large enough number of patients, before linking a clinical and phenotypical condition to cytogenetic finding, is stressed.