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 download article in pdf format
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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.
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