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Background <p>Trio Rho guanine nucleotide exchange factor (TRIO) encodes the guanine nucleotide exchange factor (GEF) for RHOA and RAC1 GTPases, which plays a critical role in neurodevelopment. Pathogenic variants in the <i>TRIO</i> gene are predominantly associated with two autosomal dominant neurodevelopmental disorders: intellectual developmental disorder 44 with microcephaly (MRD44) and intellectual developmental disorder 63 with macrocephaly (MRD63). However, the genotype–phenotype correlation of <i>TRIO</i>-related disorders and the impacts of <i>TRIO</i> variants on early-life disease progression remain unclear.</p> Methods <p>In this study, we recruited a male infant with developmental delay and macrocephaly and chronologically detailed his growth from birth. Whole-exome sequencing was performed to identify genetic variants; three-dimensional protein modeling was employed to assess the pathogenicity of these variants, and previously reported <i>TRIO</i> variants were summarized.</p> Result <p>We identified a novel <i>TRIO</i> missense variant (NM_007118.4: c.7738&#xa0;A &gt; T, p.I2580F; chr5:14492781&#xa0;A &gt; T/hg19) in the patient, and the variant was positioned in the second Src homology 3 (SH3) domain. Bioinformatic and three-dimensional protein modeling evidence all support the p.I2580F variant as likely pathogenic. Additionally, we systematically collated and summarized previously reported <i>TRIO</i> gene variants.</p> Conclusion <p>Our findings broaden the variant landscape of <i>TRIO</i>, establish a correlation between macrocephaly and <i>TRIO</i> variants within the second SH3 domain, provide the first detailed growth chart for a patient with <i>TRIO</i>-associated macrocephaly, and deepen our understanding of developmental impairments attributed to <i>TRIO</i> variants.</p>

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Identification and growth features of developmental delay with macrocephaly caused by a novel TRIO variant affecting the second SH3 domain

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Si-Yuan Zhang,
  • Jie-Yuan Jin,
  • Lei Zeng,
  • Rui-Chao Niu,
  • Xia Wang

摘要

Background

Trio Rho guanine nucleotide exchange factor (TRIO) encodes the guanine nucleotide exchange factor (GEF) for RHOA and RAC1 GTPases, which plays a critical role in neurodevelopment. Pathogenic variants in the TRIO gene are predominantly associated with two autosomal dominant neurodevelopmental disorders: intellectual developmental disorder 44 with microcephaly (MRD44) and intellectual developmental disorder 63 with macrocephaly (MRD63). However, the genotype–phenotype correlation of TRIO-related disorders and the impacts of TRIO variants on early-life disease progression remain unclear.

Methods

In this study, we recruited a male infant with developmental delay and macrocephaly and chronologically detailed his growth from birth. Whole-exome sequencing was performed to identify genetic variants; three-dimensional protein modeling was employed to assess the pathogenicity of these variants, and previously reported TRIO variants were summarized.

Result

We identified a novel TRIO missense variant (NM_007118.4: c.7738 A > T, p.I2580F; chr5:14492781 A > T/hg19) in the patient, and the variant was positioned in the second Src homology 3 (SH3) domain. Bioinformatic and three-dimensional protein modeling evidence all support the p.I2580F variant as likely pathogenic. Additionally, we systematically collated and summarized previously reported TRIO gene variants.

Conclusion

Our findings broaden the variant landscape of TRIO, establish a correlation between macrocephaly and TRIO variants within the second SH3 domain, provide the first detailed growth chart for a patient with TRIO-associated macrocephaly, and deepen our understanding of developmental impairments attributed to TRIO variants.