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 mutation-negative 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.

已证明，自动合子性驱动的外显子组分析可有效鉴定隐性疾病的潜在基因，尤其是在所谓的大中东地区（GME），在这些国家中，高血缘性揭示了隐性等位基因的表型效应，大家族成员有助于纯合子作图。与大多数欧洲国家一样，意大利的血缘关系估计很低。尽管如此，近亲的意大利家庭在遗传发现的出版物中并不少见，并且经常是新的基因与稀有疾病联系的关键。我们收集了来自47个近亲血统的疑似隐性疾病的52例患者，其中29例来自GME国家和18例意大利裔。我们通过检测长期的纯合性（ROHs> 1.5 Mb）并通过确定优先级来进行自动纯合性驱动的外显子组分析候选临床变异。我们鉴定出先前在NARS2中遗漏的病原体同义词变体，并且通过匹配我们的候选基因并在分析中包括较短的ROH（也可能是纯合子），将初始高诊断率（47％）提高到55％。GME和意大利家庭对诊断产量的贡献相当。我们发现，无论是在纯合子基因组的延伸方面，还是在GME和义大利族之间的候选临床变体的分布方面都没有显着差异，而我们却发现平均的纯合子基因组更大，而候选临床变体的平均数量也明显更高（p = 0.003）的突变阳性者比突变阴性的个体，表明这些特征影响疾病与自噬相关的可能性。我们还强调了自噬性驱动的基因组分析在那些血缘关系不广泛的文化传统中的国家和/或社区中的效用。