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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

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, gro...

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Autores principales: Maver, A, Čuturilo, G, Ruml, Stojanović J, Peterlin, B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Sciendo 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956640/
https://www.ncbi.nlm.nih.gov/pubmed/31942419
http://dx.doi.org/10.2478/bjmg-2019-0028
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author Maver, A
Čuturilo, G
Ruml, Stojanović J
Peterlin, B
author_facet Maver, A
Čuturilo, G
Ruml, Stojanović J
Peterlin, B
author_sort Maver, A
collection PubMed
description 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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spelling pubmed-69566402020-01-15 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, A Čuturilo, G Ruml, Stojanović J Peterlin, B Balkan J Med Genet Case Report 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. Sciendo 2019-12-21 /pmc/articles/PMC6956640/ /pubmed/31942419 http://dx.doi.org/10.2478/bjmg-2019-0028 Text en © 2019 Maver A, Čuturilo G, Ruml Stojanović J, Peterlin B, published by Sciendo https://creativecommons.org/licenses/by-nc-nd/3.0/This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
spellingShingle Case Report
Maver, A
Čuturilo, G
Ruml, Stojanović J
Peterlin, B
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956640/
https://www.ncbi.nlm.nih.gov/pubmed/31942419
http://dx.doi.org/10.2478/bjmg-2019-0028
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