Natural human knockouts and Mendelian disorders: deep phenotyping in Italian isolates

Natural human knockouts and Mendelian disorders: deep phenotyping in Italian isolates

Whole genome sequencing (WGS) allows the identification of human knockouts (HKOs), individuals in whom loss of function (LoF) variants disrupt both alleles of a given gene. HKOs are a valuable model for understanding the consequences of genes function loss. Naturally occurring biallelic LoF variants...

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Bibliographic Details
Published in:European journal of human genetics : EJHG Vol. 29; no. 8; pp. 1272 - 1281
Main Authors: Spedicati, Beatrice, Cocca, Massimiliano, Palmisano, Roberto, Faletra, Flavio, Barbieri, Caterina, Francescatto, Margherita, Mezzavilla, Massimo, Morgan, Anna, Pelliccione, Giulia, Gasparini, Paolo, Girotto, Giorgia
Format: Journal Article
Language:English
Published: England Nature Publishing Group 01-08-2021
Springer International Publishing
Subjects:
Ablation
Childrens health
Diepoxybutane
Fanconi syndrome
Gene Frequency
Genes
Genetic Diseases, Inborn - genetics
Genetic disorders
Genomes
Humans
Italy
Loss of Function Mutation
Maternal & child health
Phenotypes
Phenotyping
Population - genetics
Reproductive Isolation
Rhodopsin kinase
Whole genome sequencing
Whole Genome Sequencing - statistics & numerical data
Italy
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Summary:Whole genome sequencing (WGS) allows the identification of human knockouts (HKOs), individuals in whom loss of function (LoF) variants disrupt both alleles of a given gene. HKOs are a valuable model for understanding the consequences of genes function loss. Naturally occurring biallelic LoF variants tend to be significantly enriched in "genetic isolates," making these populations specifically suited for HKO studies. In this work, a meticulous WGS data analysis combined with an in-depth phenotypic assessment of 947 individuals from three Italian genetic isolates led to the identification of ten biallelic LoF variants in ten OMIM genes associated with known autosomal recessive diseases. Notably, only a minority of the identified HKOs (C7, F12, and GPR68 genes) displayed the expected phenotype. For most of the genes, instead, (ACADSB, FANCL, GRK1, LGI4, MPO, PGAM2, and RP1L1), the carriers showed none or few of the signs and symptoms typically associated with the related diseases. Of particular interest is a case presenting with a FANCL biallelic LoF variant and a positive diepoxybutane test but lacking a full Fanconi anemia phenotypic spectrum. Identifying KO subjects displaying expected phenotypes suggests that the lack of correct genetic diagnoses may lead to inappropriate and delayed treatment. In contrast, the presence of HKOs with phenotypes deviating from the expected patterns underlines how LoF variants may be responsible for broader phenotypic spectra. Overall, these results highlight the importance of in-depth phenotypical characterization to understand the role of LoF variants and the advantage of studying these variants in genetic isolates.
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ISSN:1018-4813
1476-5438
DOI:10.1038/s41431-021-00850-9