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            <title xml:lang="en">Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature</title>
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              <persName>
                <forename type="first">Gabriella</forename>
                <surname>Gazdagh</surname>
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                <forename type="first">David</forename>
                <surname>Hunt</surname>
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              <idno type="halauthorid">1014645-0</idno>
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            <author role="aut">
              <persName>
                <forename type="first">Anna Maria Cueto</forename>
                <surname>Gonzalez</surname>
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              <idno type="halauthorid">2928097-0</idno>
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            <author role="aut">
              <persName>
                <forename type="first">Monserrat Pons</forename>
                <surname>Rodriguez</surname>
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              <persName>
                <forename type="first">Ayeshah</forename>
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              <date type="whenSubmitted">2023-10-19 12:36:09</date>
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            <idno type="stamp" n="CNRS">CNRS - Centre national de la recherche scientifique</idno>
            <idno type="stamp" n="UNIV-LYON1">Université Claude Bernard - Lyon I</idno>
            <idno type="stamp" n="CRBM">Centre de recherches de biochimie macromoléculaire</idno>
            <idno type="stamp" n="UNIV-MONTPELLIER">Université de Montpellier</idno>
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                <title xml:lang="en">Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature</title>
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                  <persName>
                    <forename type="first">Gabriella</forename>
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                    <forename type="first">Elena Sukarova</forename>
                    <surname>Angelovska</surname>
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                    <forename type="first">Catherine</forename>
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                  <persName>
                    <forename type="first">Philip</forename>
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                    <forename type="first">Anke</forename>
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                    <forename type="first">Leena</forename>
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                <author role="aut">
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                    <forename type="first">Diana</forename>
                    <surname>Baralle</surname>
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                <idno type="issn">1552-4825</idno>
                <idno type="eissn">1552-4833</idno>
                <title level="j">American Journal of Medical Genetics Part A</title>
                <imprint>
                  <publisher>Wiley</publisher>
                  <biblScope unit="volume">191</biblScope>
                  <biblScope unit="issue">7</biblScope>
                  <biblScope unit="pp">1722-1740</biblScope>
                  <date type="datePub">2023</date>
                  <date type="dateEpub">2023-03-29</date>
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              <idno type="doi">10.1002/ajmg.a.63194</idno>
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              <language ident="en">English</language>
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              <keywords scheme="author">
                <term xml:lang="en">microcephaly</term>
                <term xml:lang="en">phenotype</term>
                <term xml:lang="en">spectrin</term>
                <term xml:lang="en">TRIO gene</term>
                <term xml:lang="en">macrocephaly</term>
                <term xml:lang="en">GEFD</term>
              </keywords>
              <classCode scheme="halDomain" n="sdv.gen.gh">Life Sciences [q-bio]/Genetics/Human genetics</classCode>
              <classCode scheme="halDomain" n="sdv.bdd.eo">Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis</classCode>
              <classCode scheme="halDomain" n="sdv.neu.nb">Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology</classCode>
              <classCode scheme="halTypology" n="ART">Journal articles</classCode>
              <classCode scheme="halOldTypology" n="ART">Journal articles</classCode>
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            <abstract xml:lang="en">
              <p>The TRIO gene encodes a rho guanine exchange factor, the function of which is to exchange GDP to GTP, and hence to activate Rho GTPases, and has been described to impact neurodevelopment. Specific genotype‐to‐phenotype correlations have been established previously describing striking differentiating features seen in variants located in specific domains of the TRIO gene that are associated with opposite effects on RAC1 activity. Currently, 32 cases with a TRIO gene alteration have been published in the medical literature. Here, we report an additional 25, previously unreported individuals who possess heterozygous TRIO variants and we review the literature. In addition, functional studies were performed on the c.4394A &gt; G (N1465S) and c.6244‐2A &gt; G TRIO variants to provide evidence for their pathogenicity. Variants reported by the current study include missense variants, truncating nonsense variants, and an intragenic deletion. Clinical features were previously described and included developmental delay, learning difficulties, microcephaly, macrocephaly, seizures, behavioral issues (aggression, stereotypies), skeletal problems including short, tapering fingers and scoliosis, dental problems (overcrowding/delayed eruption), and variable facial features. Here, we report clinical features that have not been described previously, including specific structural brain malformations such as abnormalities of the corpus callosum and ventriculomegaly, additional psychological and dental issues along with a more recognizable facial gestalt linked to the specific domains of the TRIO gene and the effect of the variant upon the function of the encoded protein. This current study further strengthens the genotype‐to‐phenotype correlation that was previously established and extends the range of phenotypes to include structural brain abnormalities, additional skeletal, dental, and psychiatric issues.</p>
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              <addrLine>University Hospital Southampton NHS Foundation TrustTremona RoadSouthamptonHampshireSO16 6YD</addrLine>
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