Genetic epidemiology of rare autosomal recessive disorders and genome researchadmin
Genetic epidemiology of rare autosomal recessive disorders and genome research
Giovanni Romeo M.D.
European School of Genetic Medicine (www.eurogene.org)
Understanding the medical genetics needs of any inbred community requires the knowledge of a few basic concepts of genetic epidemiology. I will start from the theoretical foundations which predict the frequency of alleles associated with rare autosomal recessive (RAR) disorders and are based on the study of children of consanguineous marriages, as established in the pre-molecular era by the Swedish geneticst Dahlberg. He first noticed in 1943 that the proportion of consanguineous parents of children affected with any RAR disorder is inversely proportional to the frequency of the mutated gene in the general population (q). In Italy it was possible to calculate q for PKU, Friedreich ataxia and CF even before the cloning of the respective genes using the “Vatican Archive” of consanguineous marriages, created 50 years ago by Cavalli-Sforza and coworkers, which documents the variations in time and space of consanguineous marriages in the general population broken down for the different Italian regions and provinces for five years periods during almost 400 years (1600–1964).
The probability that a child of consanguineous parents carries two copies of the same allele identical by descent (IBD) is called autozygosity (=homozygosity by IBD). Then if one knows precisely the frequency of consanguineous marriages in the general population (C) for any given time period and population subgroup (e.g. from the Vatican Archive) and the proportion of consanguineous parents of children affected with a given RAR disorder (C’) in the same population, q can be accurately calculated following Dahlberg’s approach.
Today a more efficient epidemiological approach based no longer on demographic data but on molecular data (defined Homozygosity Index: HI) makes it possible to estimate q for a RAR disorder if one knows the mutational spectrum, the proportion of truly homozygous patients determined by mutation analysis and the inbreeding coefficient estimate (F) in a small sample of affected individuals. This result was achieved for PKU and Mediterranean Fever in Lebanon and Turkey, for Wilson disease in Sardinia and more recently for Congenital Adrenal Hyperplasia ( CAH) in mainland Italy and Sardinia (Gialluisi et al. Clin. Genetics, 93, 223-227, 2018).
In conclusion these epidemiological studies based on consanguinity have originated an interesting strategy useful for planning public health policies regarding the prevention of RAR disorders in the genomic era. First of all, the inbreeding coefficient (F) can be calculated using genomic data (like SNP data) which make the HI approach easier and more precise. Moreover causative mutations associated with RAR disorders lie in Regions of Homozygosity (ROH) and can be identified more easily in consanguineous families, as done for example by Whole Exome Analysis in the case of the MYO15A frameshift duplication which represents the major cause of Genetic Hearing Loss (GHL) in Oman (Pippucci et al. J. Human Genetics, 62: 259–264 (2017) doi:10.1038/jhg.2016.120).