Autozygosity-driven genetic diagnosis in consanguineous families from Italy and the Greater Middle East
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ORIGINAL INVESTIGATION
Autozygosity‑driven genetic diagnosis in consanguineous families from Italy and the Greater Middle East Flavia Palombo1,2 · Claudio Graziano1 · Nadia Al Wardy3 · Nayereh Nouri4,5 · Caterina Marconi6 · Pamela Magini1 · Giulia Severi1 · Chiara La Morgia2,7 · Gaetano Cantalupo8,9 · Duccio Maria Cordelli6,10 · Simone Gangarossa11 · Mohammed Nasser Al Kindi3 · Mazin Al Khabouri3,12 · Mansoor Salehi4 · Elisa Giorgio13 · Alfredo Brusco13 · Francesco Pisani14 · Giovanni Romeo6 · Valerio Carelli2,7 · Tommaso Pippucci1 · Marco Seri1,6 Received: 26 November 2019 / Accepted: 25 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Autozygosity-driven exome analysis has been shown effective for identification of genes underlying recessive diseases especially in countries of the so-called Greater Middle East (GME), where high consanguinity unravels the phenotypic effects of recessive alleles and large family sizes facilitate homozygosity mapping. In Italy, as in most European countries, consanguinity is estimated low. Nonetheless, consanguineous Italian families are not uncommon in publications of genetic findings and are often key to new associations of genes with rare diseases. We collected 52 patients from 47 consanguineous families with suspected recessive diseases, 29 originated in GME countries and 18 of Italian descent. We performed autozygosity-driven exome analysis by detecting long runs of homozygosity (ROHs > 1.5 Mb) and by prioritizing candidate clinical variants within. We identified a pathogenic synonymous variant that had been previously missed in NARS2 and we increased an initial high diagnostic rate (47%) to 55% by matchmaking our candidate genes and including in the analysis shorter ROHs that may also happen to be autozygous. GME and Italian families contributed to diagnostic yield comparably. We found no significant difference either in the extension of the autozygous genome, or in the distribution of candidate clinical variants between GME and Italian families, while we showed that the average autozygous genome was larger and the mean number of candidate clinical variants was significantly higher (p = 0.003) in mutation-positive than in mutationnegative individuals, suggesting that these features influence the likelihood that the disease is autozygosity-related. We highlight the utility of autozygosity-driven genomic analysis also in countries and/or communities, where consanguinity is not widespread cultural tradition.
Introduction In genetics, consanguineous marriages are commonly defined as unions between individuals related as second cousins or closer, resulting in a pedigree-based coefficient of inbreeding (F) in their progeny ≥ 0.0156 (Bittles 2001). Individuals whose parents are so closely related are expected to have an increased proportion of their autosomal genome that is autozygous, where two identical haplotypes descend from a recent common ancestor; the closer the degree of Electronic supplementary material The online version of this article (
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