Abstract Besides reviewing the unusual case of sex-ratio in the lemming and presenting alternative analyses of general models in which the shift in the usual sex-ratio 1:1 is determined by autosomal or sex-linked mutant alleles, three novel models are presented, in which the shift on the progeny sex-ratio depends on the number of copies of a mutant allele present in the parental pair. The analysis of these models with additive effects shows that: 1) autosomal mutations that alter the usual sex-ratio are eliminated from the population; 2) mutations occurring on the X chromosome lead to an evolutionary stable 1:1 sex-ratio only if the mutation favors the production of males; when the mutant allele favors the production of females, however, females will prevail in the population, with a frequency dependent impact on δ (the deviation from the usual 0.5 proportion) ; for most of the range of possible values of δ the stable but extraordinary sex-ratio will vary from 1 male : 1 female to 1 male : 3 females or 1 male : 2 females approximately depending whether the mutant allele is randomly inactivated or not.

Ectrodactyly – ectodermal dysplasia and cleft lip/palate (EEC) syndrome (OMIM 604292) is a rare disorder determined by mutations in the TP63 gene. Most cases of EEC syndrome are associated to mutations in the DNA binding domain (DBD) region of the p63 protein. Here we report on a three-generation Brazilian family with three individuals (mother, son and grandfather) affected by EEC syndrome, determined by a novel mutation c.1037C > G (p.Ala346Gly). The disorder in this family exhibits a broad spectrum of phenotypes: two individuals were personally examined, one presenting the complete constellation of EEC syndrome manifestations and the other presenting an intermediate phenotype; the third affected, a deceased individual not examined personally and referred to by his daughter, exhibited only the split-hand/foot malformation (SHFM). Our findings contribute to elucidate the complex phenotype-genotype correlations in EEC syndrome and other related TP63-mutation syndromes. The possibility of the mutation c.1037C > G being related both to acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome and SHFM is also raised by the findings here reported.

Observations by Dobzhansky's group in the 1940s suggesting that the presence of recessive genotypes could account for lower larval developmental rates in Drosophila melanogaster were not confirmed at the time and all subsequent investigations on this subject focused on the analysis of ecological models based on competition among pre-adult individuals. However, a paper published in this journal in 1991 eventually confirmed the finding made by Dobzhansky and his co-workers. In this report, we provide a theoretical analysis of the population genetic effects of a delay in the rate of larval development produced by such a genetic mechanism.

Accurate estimates of the penetrance rate of autosomal dominant conditions are important, among other issues, for optimizing recurrence risks in genetic counseling. The present work on penetrance rate estimation from pedigree data considers the following situations: 1) estimation of the penetrance rate K (brief review of the method); 2) construction of exact credible intervals for K estimates; 3) specificity and heterogeneity issues; 4) penetrance rate estimates obtained through molecular testing of families; 5) lack of information about the phenotype of the pedigree generator; 6) genealogies containing grouped parent-offspring information; 7) ascertainment issues responsible for the inflation of K estimates.

A new autosomal recessive genetic condition, the SPOAN syndrome (an acronym for spastic paraplegia, optic atrophy and neuropathy syndrome), was recently discovered in an isolated region of the State of Rio Grande do Norte in Northeast Brazil, in a population that was identified by the IBGE (Brazilian Institute of Geography and Statistics) as belonging to the Brazilian communities with the highest rates of "deficiencies" (Neri, 2003), a term used to describe diseases, malformations, and handicaps in general. This prompted us to conduct a study of consanguinity levels in five of its municipal districts by directly interviewing their inhabitants. Information on 7,639 couples (corresponding to about 40% of the whole population of the studied districts) was obtained. The research disclosed the existence of very high frequencies of consanguineous marriages, which varied from about 9% to 32%, suggesting the presence of a direct association between genetic diseases such as the SPOAN syndrome, genetic drift and inbreeding levels. This fact calls for the introduction of educational programs for the local populations, as well as for further studies aiming to identify and characterize other genetic conditions. Epidemiological strategies developed to collect inbreeding data, with the collaboration of health systems available in the region, might be very successful in the prospecting of genetic disorders.

We present a computer program developed for estimating penetrance rates in autosomal dominant diseases by means of family kinship and phenotype information contained within the pedigrees. The program also determines the exact 95% credibility interval for the penetrance estimate. Both executable (PenCalc for Windows) and web versions (PenCalcWeb) of the software are available. The web version enables further calculations, such as heterozygosity probabilities and assessment of offspring risks for all individuals in the pedigrees. Both programs can be accessed and down-loaded freely at the home-page address http://www.ib.usp.br/~otto/software.htm.

The haplotypes of seven Y-chromosome STR loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, and DYS393) were determined in a sample of 634 healthy Brazilian males (190 adult individuals and 222 father-son pairs). The 412 adults were unrelated, and the 222 father-son pairs had their biological relationship confirmed using autosomal STRs (LR > 10,000). Among the 412 adults, a total of 264 different 7-loci haplotypes were identified, 210 of which were unique. The most frequent haplotype was detected in 31 instances, occurring with a frequency of 7.52%. The haplotype diversity index was calculated as 98.83%. Upon transmission of the 1,554 alleles, in 222 father-son pairs, six mutations were observed, with an average overall rate of 3.86 x 10-3 per locus. A haplotype with a duplicated DYS389I locus, and another with duplicated DYS389I, DYS389II, and DYS439 loci were detected in both fathers and their respective sons.

Smith-Lemli-Opitz syndrome (SLOS) or RSH syndrome comprises multiple congenital anomalies and mental retardation. The underlying defect is a deficiency in the activity of delta7-sterol reductase, which decreases cholesterol and increases 7-dehydrocholesterol (7-DHC) levels. Our aim was to identify and evaluate the frequency of SLOS manifestations in a group of Brazilian patients. Based on our own data and those reported previously, we present a simple method that allows the estimation of probabilities favoring the diagnosis of SLOS. We evaluated 30 patients clinically and determined their plasma levels of cholesterol and 7-dehydrocholesterol. In 11 patients, the diagnosis was confirmed by ultraviolet spectrophotometry (UV). Of 19 patients with normal laboratory results, 17 showed a high probability favoring the diagnosis of SLOS. The most significant signs and symptoms observed in over 2/3 of the biochemically confirmed cases were mental retardation (10/11), delayed neuropsychomotor development (10/11), syndactyly of 2nd/3rd toes (10/11), and craniofacial anomalies including microcephaly (11/11), incompletely rotated ears (8/11), palpebral ptosis (10/11), anteverted nostrils (10/11), and micrognathia (9/11). Genital anomalies were found in all male patients (6/6).

We describe two different novel mutations in the PAX3 gene, detected in two families with cases of Waardenburg syndrome type I (WSI). The missense mutation detected in one family involved a single substitution in exon 2 (c.142 G > T) and was present both in the affected individual and in his clinically normal father. The mutation found in the second family consisted of a deletion of 13 bases, c.764-776del(TTACCCTGACATT), in exon 5.

We present, in this paper, general formulae developed so as to permit the calculation of the recurrence risks for isolated cases of nonsyndromic deafness in the offspring of nonconsanguineous and consanguineous couples. We included, in all analyzed situations, the following factors: (a) a generic degree of parental consanguinity; (b) a variable proportion of environmental (non-genetic) cases of the defect, so that the formulae can be easily applied to populations with any epidemiological profile; (c) a variable number of normal sibs of the propositus. Besides presenting the logic and the detailed derivation of all original formulae, we present tables for immediate use, with the numerical values of the recurrence risks as a function of the variables mentioned above.

Realizamos análises citogenéticas e moleculares em 55 famílias com a mutação da síndrome do cromossomo X frágil, loco FMR-1 (318 indivíduos e 15 amostras de vilosidade coriônica). Foram estudados 129 indivíduos do sexo masculino, 75 com retardo mental e 54 normais. Entre os 54 normais, 11 eram portadores da pré-mutação e nenhum apresentou o sítio frágil. Foram detectados 73 portadores da mutação completa e 18% eram mosaicos, ou seja, apresentavam também a pré-mutação. Todos expressaram o sítio frágil em pelo menos um dos sistemas de indução utilizados. O tamanho da expansão de trinucleotídeos CGG (<FONT FACE="Symbol">D</FONT>) e a freqüência de manifestação do sítio frágil apresentaram correlação positiva. Entre as 153 mulheres normais, 85 eram portadoras da pré-mutação e 15 da mutação completa. A freqüência de expressão do fra(X) foi zero ou extremamente baixa entre as pré-mutadas e essa freqüência não diferiu da expressão das não portadoras da mutação. Portanto, a análise citogenética é ineficaz na detecção de indivíduos pré-mutados, homens ou mulheres. Entre as 51 mulheres com a mutação completa, 70% manifestaram algum grau de comprometimento mental. Encontramos também correlação entre o <FONT FACE="Symbol">D</FONT> e a freqüência de expressão do fra(X) nessas mulheres. Contudo, a detecção citogenética das mulheres com mutação completa foi menos eficiente do que no caso dos homens, pois 14% de falsos negativos foram observados. A análise de segregação confirmou que o risco de prole afeta- da aumenta com o <FONT FACE="Symbol">D</FONT>, e o risco médio de prole afetada para todas as heterozigotas foi de 30%. Não houve indicação de desvio de segregação nas famílias estudadas, pois o número de indivíduos que herdaram a mutação não diferiu do número daqueles que herdaram os alelos normais. Não foi detectada nenhuma mutação nova nas 55 genealogias investigadas

We report on the cytogenetic and DNA analysis of 55 families with the fragile X (FMR-1 locus) mutation (318 individuals and 15 chorionic villi samples). A total of 129 males were investigated, 54 mentally normal and 75 presenting mental retardation. Among the 54 normal males, 11 had the premutation, and none expressed the fragile site. The full mutation was detected in 73 retarded males, and 14 (18%) presented a premutation along with the full mutation (mosaics). All of them manifested the fragile site. The frequencies of fragile site expression correlated positively with the sizes of the expansion of the CGG repeats (<FONT FACE="Symbol">D</FONT>). Among 153 normal females, 85 were found to be heterozygous for the premutation and 15 had the full mutation. In the premutated females the fragile site was not observed or it occurred at frequencies that did not differ from those observed in 53 noncarriers. Cytogenetic analysis was thus ineffective for the diagnosis of premutated males or females. Among the 51 heterozygotes for the full mutation, 36 (70%) had some degree of mental impairment. As in males, a positive correlation was detected between the frequencies of fragile site manifestation and the size of the expansion. However, the cytogenetic test was less effective for the detection of fully mutated females, than in the case of males, since 14% false negative results were found among females. Segregation analysis confirmed that the risk of mental retardation in the offspring of heterozygotes increases with the length of <FONT FACE="Symbol">D</FONT>. The average observed frequency of mental retardation in the offspring of all heterozygotes was 30%. There was no indication of meiotic drive occurring in female carriers, since the number of individuals who inherited the mutation did not differ from the number of those inheriting the normal allele. No new mutations were detected in the 55 genealogies studied here.

Os autores apresentam os resultados de levantamentos seccionais sobre a prevalência e a morbidade da esquistossomose mansônica no Estado de Alagoas. Os inquéritos foram feitos em oito localidades, urbanas e rurais. A prevalência da esquistossomose e de outras helmintoses intestinais foi muito elevada. As formas hepato-esplênicas variaram de 1 a 3%.

Cross-section studies on prevalence and morbidity of schistosomiasis are presented for the State of Alagoas, as part of a long term. project which is being carried out in Northeartern Brasil. The survey was made in 8 localities, including rural and urban areas. Prevalence of schistosomiasis and other helminthic infections were very high. Percentage of hepato-splenic forms varied from 1 to 3.