Variants in Candidate Genes for Phenotype Heterogeneity in Patients with the 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with a broad and heterogeneous phenotype, even though most of the deletions present similar sizes, involving ∼3 Mb of DNA. In a relatively large population of a Brazilian 22q11.2DS cohort (60 patients), we investigated genetic variant...

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Published in:Genetics Research 2024, Vol.2024, p.5549592-9
Main Authors: Nunes, Natalia, Carvalho Nunes, Beatriz, Zamariolli, Malú, Cordeiro de Queiroz Soares, Diogo, Caires dos Santos, Leonardo, Gollo Dantas, Anelisa, Ayres Meloni, Vera, Iole Belangero, Sintia, Gil-Da-Silva-Lopes, Vera Lúcia, Ae Kim, Chong, Melaragno, Maria Isabel
Format: Article
Language:English
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Congenital diseases
Deep learning
Deletion
Gene sequencing
Genes
Genetic diversity
Genetic variance
Genomes
Genotype & phenotype
Heterogeneity
Immunology
Kinases
Next-generation sequencing
Nucleotides
Phenotypes
Proteins
Schizophrenia
Statistical power
Whole genome sequencing
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Summary:22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with a broad and heterogeneous phenotype, even though most of the deletions present similar sizes, involving ∼3 Mb of DNA. In a relatively large population of a Brazilian 22q11.2DS cohort (60 patients), we investigated genetic variants that could act as genetic modifiers and contribute to the phenotypic heterogeneity, using a targeted NGS (Next Generation Sequencing) with a specific Ion AmpliSeq panel to sequence nine candidate genes (CRKL, MAPK1, HIRA, TANGO2, PI4KA, HDAC1, ZDHHC8, ZFPM2, and JAM3), mapped in and outside the 22q11.2 hemizygous deleted region. In silico prediction was performed, and the whole-genome sequencing annotation analysis package (WGSA) was used to predict the possible pathogenic effect of single nucleotide variants (SNVs). For the in silico prediction of the indels, we used the genomic variants filtered by a deep learning model in NGS (GARFIELD-NGS). We identified six variants, 4 SNVs and 2 indels, in MAPK1, JAM3, and ZFPM2 genes with possibly synergistic deleterious effects in the context of the 22q11.2 deletion. Our results provide the opportunity for the discovery of the co-occurrence of genetic variants with 22q11.2 deletions, which may influence the patients´ phenotype.
ISSN:1469-5073
0016-6723
1469-5073
DOI:10.1155/2024/5549592