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キーワード:
autosomal recessive disorders, exome homozygosity, genomics of consanguinity, homozygosity index
要旨:
Purpose: Classical studies of consanguinity have taken advantage of the relationship between the gene frequency for a rare autosomal recessive disorder (q) and the proportion of offspring of consanguineous couples who are affected with the same disorder. The Swedish geneticist Gunnar Dahlberg provided the first theoretical formulation of the inverse correlation between q and the increase in frequency of consanguineous marriages among parents of affected children with respect to marriages of the same degree in the general population. Today it is possible to develop a new approach for estimating q using mutation analysis of affected offspring of consanguineous couples. The rationale of this new approach is based on the possibility that the child born of consanguineous parents carries the same mutation in double copy (true homozygosity) or alternatively carries two different mutations in the same gene (compound heterozygosity). In the latter case the two mutations must have been inherited through two different ancestors of the consanguineous parents (in this case the two mutated alleles are not ‘identical by descent’).
Patients and methods: Data from the offspring of consanguineous marriages affected with different autosomal recessive disorders were collected by different molecular diagnostic laboratories in Mediterranean countries and in particular in Arab countries, where the frequencies of consanguineous marriages is high, show the validity of this approach.
Results: The proportion of compound heterozygotes among children affected with a given autosomal recessive disorder, born of consanguineous parents, can be taken as an indirect indicator of the frequency of the same disorder in the general population. Identification of the responsible gene (and mutations) is the necessary condition to apply this method.
Conclusion: The following paper from our group relevant for the present review is being published: Alessandro Gialluisi, Tommaso Pippucci, Yair Anikster, Ugur Ozbek, Myrna Medlej-Hashim, Andre Megarbane and Giovanni Romeo: Estimating the allele frequency of autosomal recessive disorders through mutational records and consanguinity: the homozygosity index (HI) annals of human genetics (in press; acceptance date 1 November 2011) In addition, our experimental data show that the causative mutation for a rare autosomal recessive disorder can be identified by whole exome sequencing of only two affected children of first cousins parents, as described in the following recent paper: Pippucci T, Benelli M, Magi A, Martelli PL, Magini P, Torricelli F, Casadio R, Seri M, Romeo G EX-HOM (EXome HOMozygosity): A Proof of Principle. Hum Hered 2011; 72:45-53.
