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. 2019 Dec 21;22(2):65-68.
doi: 10.2478/bjmg-2019-0028. eCollection 2019 Dec.

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

A Maver  1 , G Čuturilo  2   3 , Stojanović J Ruml  3 , B Peterlin  1
Affiliations

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

A Maver et al. Balkan J Med Genet. .

Abstract

Microcephaly is characterized by significant clinical and genetic heterogeneity, therefore reaching the genetic diagnosis remains challenging in this group of disorders. We describe a case of a girl with secondary microcephaly, associated with severe developmental delay, intellectual disability, growth retardation and dysmorphic features. For purposes of clinical genetic diagnostic testing, we performed trio whole exome sequencing in the proband and unaffected parents. We found a heterozygous de novo missense variant in the H3F3A gene in the proband (NM_ 002107.4: c.185T>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 (H3.3) and is predicted to affect the physicochemical properties of the affected protein. Mouse models, which demonstrated involvement of H3.3 protein in the control of neuronal- and glial-specific gene expression patterns that control synaptic connectivity and behavioral plasticity. Additionally, we also identified similar cases reported in the ClinVar database. These arguments support the possible pathogenic role of the reported genetic variant and thus suggest a novel molecular mechanism for this syndromic form of microcephaly.

Keywords: Growth delay; H3F3A gene; Microcephaly; Severe developmental delay; intellectual disability.

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Figures

Figure 1
Figure 1
Facial features of the patient with a heterozygous de novo H3F3A gene variant p.(Leu62Arg) include wide and depressed nasal bridge, hypertelorism, hypotonic face and poorly formed, posteriorly set ears.
Figure 2
Figure 2
The identified H3F3A gene variant affects a highly evolutionary conserved leucine at amino acid position 62 in the Histone H3 protein, which is invariant in all the surveyed species (according to Multiz alignments). Figure was generated using the University of CA Santa Cruz (UCSC) genome browser (https://genome.ucsc.edu/)
See this image and copyright information in PMC

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