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

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.