Balkan Journal of Medical Genetics

CLINICAL NEXT GENERATION SEQUENCING REVEALS AN H3F3A GENE AS A NEW POTENTIAL GENE CANDIDATE FOR MICROCEPHALY ASSOCIATED WITH SEVERE DEVELOPMENTAL DELAY, INTELLECTUAL DISABILITY AND GROWTH RETARDATION
Maver A1, Čuturilo G2,3, Ruml Stojanović J3, Peterlin B1,*
*Corresponding Author: Professor Borut Peterlin, Clinical Institute of Genomic Medicine, University Medical Center Ljubljana, Šlajmerjeva 4, 1000 Ljubljana, Slovenia. Tel: +38615401137. E-mail: borut.peterlin@kclj.si
page: 65

RESULTS

Exome analysis. Initially, we focused the search for causative variants in the proband to panels of genes, possibly associated with the clinical condition, including 1607 genes in an expanded developmental delay panel, 611 genes in an undiagnosed metabolic disorders panel and 155 genes in an intellectual disability panel. This initial search failed to reveal any causative variants. Subsequently, we performed the search for candidate de novo and biallelic variants in novel genes. This revealed the presence of a heterozygous de novo missense variant in the H3F3A gene (NM_002107.4: c.185T>G) detected in the proband and absent in the parents. This variant is predicted to result in a p.(Leu62Arg) amino acid substitution in the Histone H3 protein. The identified variant was absent in all populations of the gnomAD project and was also not detected in our in-house database of 3000 exomes. Furthermore, we observed a depletion of the overall rate of missense variants in the H3F3A gene in the gnomAD database, indicating an evolutionary constraint against missense variation in this gene, with only five missense variants in H3F3A observed in the gnomAD database populations (Z score for missense variant constraint in gnomAD dataset equaled 3.2). The identified variant affects a highly conserved leucine residue at position 62 of the Histone H3 protein and the GERP rejected substitution score indicated high conservation rate (GERP RS score 4.97) of the variant nucleotide position across species. The substitution of the aliphatic hydrophobic leucine residue with a positively charged hydrophilic arginine residue affects the polarity at position 62 and thus predicted to affect the physicochemical properties of the affected protein domain in the proximity of the DNA binding site. All the utilized tools for in silico prediction of the variant’s effect on protein function predict its damaging effect in consensus, including MutationTaster, SIFT, Polyphen2, MetaSVM, CADD and REVEL (Figure 2).

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