PENCALC: a program for penetrance estimation in autosomal dominant diseases

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 percent 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.

Inbreeding levels in Northeast Brazil: strategies for the prospecting of new genetic disorders

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 percent 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 percent to 32 percent, 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.

Population and mutation analysis of Y-STR loci in a sample from the city of São Paulo (Brazil)

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 percent. The haplotype diversity index was calculated as 98.83 percent. 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: clinical and biochemical findings in Brazilian patients

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).

Recurrence risks for isolated cases of nonsyndromic deafness

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.

Aconselhamento genetico da deficiencia auditiva / Genetic counseling for deafness

Baseando-se em dados por nos coletados e pesquisados na literatura nacional e internacional, fornecemos estimativas de incidencia de surdez infantil nao-sindromica, das frequencias de casos ambientais e geneticos e das frequencias relativas dos tipos de surdez monogenica hereditaria...

Experience with molecular and cytogenetic diagnosis of fragile X syndrome in Brazilian families

Realizamos análises citogenéticas e moleculares em 55 famílias com a mutaçäo 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-mutaçäo e nenhum apresentou o sítio frágil. Foram detectados 73 portadores da mutaçäo completa e 18 por cento eram mosaicos, ou seja, apresentavam também a pré-mutaçäo. Todos expressaram o sítio frágil em pelo menos um dos sistemas de induçäo utilizados. O tamanho da expansäo de trinucleotídeos CGG (delta) e a freqüência de manifestaçäo do sítio frágil apresentaram correlaçäo positiva. Entre as 153 mulheres normais, 85 eram portadoras da pré-mutaçäo e 15 da mutaçäo completa. A freqüência de expressäo do fra(X) foi zero ou extremamente baixa entre as pré-mutadas e essa freqüência näo diferiu da expressäo das näo portadoras da mutaçäo. Portanto a análise citogenética é ineficaz na determinaçäo de indivíduos pré-mutados, homens ou mulheres. Entre as 51 mulheres com a mutaçäo completa, 70 por cento manifestaram algum grau de comprometimento mental. Encontramos também correlaçäo entre o delta e a freqüência de expressäo do fra(X) nessas mulheres. Contudo, a detecçäo citogenética das mulheres com mutaçäo completa foi menos eficiente do que no caso dos homens, pois 14 por cento de falsos negativos foram observados. A análise de segregaçäo confirmou que o risco de prole afetada aumenta com o delta, e o risco médio de prole afetada para todas as heterozigotas foi de 30 por cento. Näo houve indicaçäo de desvio de segregaçäo nas famílias estudadas, pois o número de indivíduos que herdaram a mutaçäo näo diferiu do número daqueles que herdaram os alelos normais. Näo foi detectada nenhuma mutaçäo nova nas 55 genealogias investigadas.

Dermatoglyphic studies in rett syndrome

Foram analisadas as impressöes dermatoglíficas digitais e palmares de 12 pacientes com síndrome de Rett. Os resultados obtidos foram comparados com os de uma amostra de 144 mulheres normais. Diferenças significativas foram encontradas nas medidas do ângulo atd médio (mais alto nas pacientes) e nas freqüências de arcos e verticilos no 4- dedo: as mais altas e as segundas mais baixas nas pacientes

Estimativas de riscos de doença genética na prole de primos em primeiro grau / Estimates of risks for genetic disease in the offspring of first cousin couples

Estimam-se, por dois métodos diferentes, os riscos de afecçäo por doença autossômica recessiva na prole de näo-consangüíneos (cerca de 1%) e de primos em primeiro grau (12 ou 13%). Conclui-se que a reproduçäo de casais de primos em primeiro grau näo deve ser encorajada