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
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DISCUSSION

We report the H3F3A gene as a new candidate gene, associated with microcephaly, severe global developmental delay and intellectual disability. Additionally, prenatal and postnatal growth retardation, structural abnormalities of central nervous system and dysmorphological features were present in the reported patient. The H3F3A gene, together with the H3F3B gene, codes the replacement histone H3.3. The H3.3-containing nucleosomes remain highly dynamic and are involved in the control of neuronal- and glial-specific gene expression patterns throughout life, which are required to support synaptic connectivity and behavioral plasticity [14]. H3.3 knock down resulted in decreased numbers of dendritic spines on pyramidal cells and global reduction of both excitatory and inhibitory synapses in the mouse model [14]. Disruption of the H3F3A gene in transgenic mice resulted in stunted growth and neuromuscular deficits [15]. Somatic mutations in the H3F3 gene were reported in pediatric glioblastoma [16] and in giant cell tumors of the bone [17]. Furthermore, it was recently suggested that the pathogenic mechanism of germline histone mutations is distinct from that of the published cancer-associated somatic histone mutations, and may converge on control of cell proliferation [18]. In our patient, we identified a heterozygous de novo missense variant in the H3F3A gene (NM_002107.4: c.185 T>G), which is absent from the gnomAD and from the Slovenian Genome databases. The identified variant affects a highly conserved leucine residue at position 62 of the Histone H3 protein and is predicted to affect the physicochemical properties of the affected protein domain. Further evidence for the potential role of the H3F3A gene in neurodevelopment is also based on the ClinVar reports of two patients with likely pathogenic heterozygous missense mutations in the H3F3A gene, c.377A>G (p.Gln 126Arg), who both demonstrated a neurological phenotype including hypotonia, global developmental delay, intellectual disability, visual impairment and dysmorphic features (ClinVar accession: VCV000520774.1) [13]. The limitation of our case report is lack of functional studies and lack of additional patients with mutations in the H3F3A gene and the suggested phenotype. Nevertheless, we provide evidence on a potentially new mechanism involving histones in the regulation of gene expression in the brain as the cause of a syndromic microcephaly. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Funding. This study was supported by the funding of Slovenian Research agency projects J3-8205 and J3-9280 and the framework programme P3-0326.

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