Bernard Bonaïti

TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance?

The Val30Met transthyretin familial amyloid polyneuropathy (TTR-V30M-FAP) is the most frequent familial amyloidosis, with autosomal dominant transmission. This severe disease shows important differences in age of onset and penetrance. Recently, a difference in penetrance according to the gender of the transmitting parent was elicited in different geographic areas with a higher penetrance in case of maternal transmission of the trait. In addition, differences in mitochondrial haplogroup distribution in early and late onset Swedish and French cases of TTR-V30M-FAP suggested that a polymorphism of mitochondrial DNA could be one underlying mechanism of the phenotypic variation. We further investigated this hypothesis by modeling the penetrance function with a parent-of-origin and/or a mitochondrial polymorphism effect in samples of Portuguese (n=33) and Swedish families (n=86) with TTR-V30M-FAP in which several individuals had been tested for mitochondrial haplogroups. Our analysis showed that a mitochondrial polymorphism effect was sufficient to explain the observed difference in penetrance according to gender of the transmitting parent in the Portuguese sample, whereas, in the Swedish sample, a clear residual parent-of-origin effect remained. This study further supported the role of a mitochondrial polymorphism effect that might induce a higher penetrance in case of maternal inheritance of the disease. In clinical practice, these results might help to better delineate the individual disease risk and have a significant impact on the management of both patients and carriers.

Parent-of-origin effect in transthyretin related amyloid polyneuropathy

Transthyretin (TTR) amyloid neuropathy is the most severe neuropathy of adulthood with autosomal dominant transmission [1]. Liver transplantation is the only therapeutic approach available, and can stabilize the disease when performed early in the course. Important differences in the disease expression, particularly regarding the age of onset and the penetrance, exist among countries. In a previous work [2], we found significant differences between Portuguese and French populations with cumulative risks of 18% by age 50 and 64% by age 70 years in French carriers, whereas this risk in Portuguese carriers was 80% by age 50 and 91% by age 70 years. Recently, Hellman et al. found that Swedish carriers seemed to be closer to French than to Portuguese carriers with an even lower risk of 11% by age 50 and 36% by age 70 years [3]. These results are consistent with the late age at onset, previously reported in the Swedish population [4]. The other remarkable finding of the study of Hellman et al. [3] is the marked differences of penetrance according to gender of the transmitting parent. Indeed, the risk of disease in carriers was significantly higher when the mutation was inherited from the mother than from the father. Differences of age of onset according to gender of the transmitting parent have also been mentioned in Portuguese families but such variation of penetrance has not been precisely analyzed in other populations [5]. We investigated this parent-of-origin effect in our samples of French and Portuguese families, using a modified version of the Proband’s phenotype exclusion likelihood (PEL) [6]. The PEL is a maximum likelihood method based on a survival analysis approach that estimates penetrance of mutation carriers by using genotypes and phenotypes of members of families ascertained through at least one affected individual. The phenotypes are the age of onset for affected members and the age at censoring for unaffected ones. For each family, the correction for ascertainment is performed by ignoring the phenotype of the Proband(s) who allowed the ascertainment of this family, and by duplicating a family if there are several Probands. To take into account the gender of the transmitting parent, the genotype of heterozygous carrier individuals was ordered according to the parent (father or mother) who transmitted the mutation, and the penetrances were estimated separately. In the 33 Portuguese families, the gender of the transmitting parent was known for 291 individuals: the mother in 153 and the father in 138 cases. Among the 48 French families, there were 435 individuals for whom the gender of the transmitting parent was known: for 216 individuals the transmitting parent was the mother, and for 219 individuals the transmitting parent was the father. Figure 1 shows the penetrance curves for French and Portuguese mutation carriers according to gender of the parent who transmitted the mutation. As in the Swedish families, the penetrance was found to be higher when the mutation was inherited from the mother than from the father and the difference was highly significant in the Portuguese families

Use of an animal model for genetic evaluation of the Lacaune dairy sheep

Abstract This paper presents the characteristics and the results of an analysis of the Lacaune dairy sheep with an animal model. The analysis involved 1 003 071 lactations of parity 1 to 7, exhibited from 1978 to 1989 by 340 541 Lacaune dairy ewes. After including useful pedigrees, 492 149 females and 8231 males were evaluated for milk yield. Fat and protein yields and contents, partially recorded since 1986, were also analysed. 27 groups were defined for unknown parents only, according to the sex and birth year of their progeny. Results were consistent with those obtained with the present evaluation system (IF2). For males, the correlations between expected breeding values ranged from 0.92 to 0.98, according to the traits and the distribution of the daughters between flocks. The estimated genetic trend for milk yield was found rather insensitive to the heritability value and reached about 0.18 genetic standard deviation per year, i.e. about two thirds of the phenotypic trend and 2.2% of the production level. Some indication is given about the gain in efficiency due to the animal model.

Estimating penetrance from multiple case families with predisposing mutations: Extension of the "genotype-restricted likelihood" (GRL) method

Some diseases are due to germline mutations in predisposing genes, such as cancer family syndromes. Precise estimation of the age-specific cumulative risk (penetrance) for mutation carriers is essential for defining prevention strategies. The genotype-restricted likelihood (GRL) method is aimed at estimating penetrance from multiple case families with such a mutation. In this paper, we proposed an extension of the GRL to account for multiple trait disease and to allow for a parent-of-origin effect. Using simulations of pedigrees, we studied the properties of this method and the effect of departures from underlying hypotheses, misspecification of disease incidence in the general population or misspecification of the index case, and penetrance heterogeneity. In contrast with the previous version of the GRL, accounting for multiple trait disease allowed unbiased estimation of penetrance. We also showed that accounting for a parent-of-origin effect allowed a powerful test for detecting this effect. We found that the GRL method was robust to misspecification of disease incidence in the population, but that misspecification of the index case induced a bias in some situations for which we proposed efficient corrections. When ignoring heterogeneity, the penetrance estimate was biased toward that of the highest risk individuals. A homogeneity test performed by stratifying the families according to the number of affected members was shown to have low power and seems useless for detecting such heterogeneity. These extensions are essential to better estimate the risk of diseases and to provide valid recommendations for the management of patients.

Nouveau système de score pour le diagnostic des prédispositions aux cancers du sein et de l’ovaire associées à BRCA1/2

Criteria have been proposed for genetic testing of breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. Using simulations, this study evaluates the efficiency (sensitivity, positive predictive value [PPV] and specificity) of the various criteria used in France. The efficiency of the criteria published in 1998, which are largely used, is not optimal. We show that some extensions of these criteria provide an increase in sensitivity with a low decrease in specificity and PPV. The study shows that scoring systems (Manchester, Eisinger) have similar efficiency that may be improved. In this aim, we propose a new scoring system that takes into account unaffected individuals and kinship coefficients between family members. This system increases sensitivity without affecting PPV and specificity. Finally, we propose a two-step procedure with a large screening by the physician for recommending genetic counselling, followed by a more stringent selection by the geneticist for prescribing genetic testing. This procedure would result in an increase of genetic counselling activity but would allow the identification of almost 80% of mutation carriers among affected individuals, with a mutation detection rate of 15% and a specificity of 88%.

A new scoring system in cancer genetics: application to criteria for BRCA1 and BRCA2 mutation screening

Background In hereditary forms of cancer due to mutations of genes such as BRCA1 and BRCA2, methods have been proposed to predict the presence of a mutation in a family. Methods Relying on carriage probability computation is the most predictive, but scores are a good proxy and avoid using computer software. An empirical method, the Manchester scoring system, has been elaborated for BRCA1 and BRCA2 mutation identification. We propose a general scoring system based on a transformation of the carriage probability. Up to an approximation, the transformed carriage probability becomes an additive score. We applied this new scoring system to the diagnosis of BRCA1-associated and BRCA2-associated breast–ovarian cancer predisposition. Using simulations, its performance was evaluated and compared with that of the Manchester scoring system and of the exact probability. Finally, the score system was used on a sample of 4563 families screened for BRCA1 and BRCA2 mutations. Results The performance of the new scoring system was superior to the Manchester scoring system, but the probability computation remained the most predictive. The better performance of the new scoring system was attributed to accounting for unaffected family members and for the degree of kinship of relatives with the proband. Conclusions The new scoring system has a theoretical basis and may be applied to any cancer family syndrome and, more generally, to any disease with monogenic subentities, in which the causal gene mutations have been identified. It will be easily modified when additional predictive factors are found.

Nouveau système de score pour le diagnostic des prédispositions aux cancers du sein et de l’ovaire associées à BRCA1/2A new scoring system for the diagnosis of BRCA1/2 associated breast-ovarian cancer predisposition

Criteria have been proposed for genetic testing of breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. Using simulations, this study evaluates the efficiency (sensitivity, positive predictive value [PPV] and specificity) of the various criteria used in France. The efficiency of the criteria published in 1998, which are largely used, is not optimal. We show that some extensions of these criteria provide an increase in sensitivity with a low decrease in specificity and PPV. The study shows that scoring systems (Manchester, Eisinger) have similar efficiency that may be improved. In this aim, we propose a new scoring system that takes into account unaffected individuals and kinship coefficients between family members. This system increases sensitivity without affecting PPV and specificity. Finally, we propose a two-step procedure with a large screening by the physician for recommending genetic counselling, followed by a more stringent selection by the geneticist for prescribing genetic testing. This procedure would result in an increase of genetic counselling activity but would allow the identification of almost 80% of mutation carriers among affected individuals, with a mutation detection rate of 15% and a specificity of 88%.

Nouveau système de scorepour le diagnostic des prédispositionsaux cancers du sein et de l’ovaire associéesà BRCA1/2

Criteria have been proposed for genetic testing of breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. Using simulations, this study evaluates the efficiency (sensitivity, positive predictive value [PPV] and specificity) of the various criteria used in France. The efficiency of the criteria published in 1998, which are largely used, is not optimal. We show that some extensions of these criteria provide an increase in sensitivity with a low decrease in specificity and PPV. The study shows that scoring systems (Manchester, Eisinger) have similar efficiency that may be improved. In this aim, we propose a new scoring system that takes into account unaffected individuals and kinship coefficients between family members. This system increases sensitivity without affecting PPV and specificity. Finally, we propose a two-step procedure with a large screening by the physician for recommending genetic counselling, followed by a more stringent selection by the geneticist for prescribing genetic testing. This procedure would result in an increase of genetic counselling activity but would allow the identification of almost 80% of mutation carriers among affected individuals, with a mutation detection rate of 15% and a specificity of 88%.