An atypical case of macrocephaly and severe intellectual disability associated with a missense variant in the guanine nucleotide exchange factor-1 domain of TRIO.

Background: Trio rho guanine nucleotide exchange factor (TRIO), encodes a guanine nucleotide exchange factor (GEF) that is critical for neurodevelopment and regulates Rho guanosine triphosphatase. It has been shown that missense variants in the GEF1 or GEF2 domains or loss-of-function variants in TRIO are associated with microcephaly while gain-of-function variants in the spectrin repeat domain result in macrocephaly. Rare cases of macrocephaly linked to missense variants in the GEF1 domain have been reported; however, clinical details remain limited.

Case Presentation: We describe the case of a Japanese boy with macrocephaly, severe intellectual disability, distinctive facial features, scoliosis, and growth hormone deficiency. Brain magnetic resonance imaging revealed a thin corpus callosum and pituitary hypoplasia. His occipitofrontal circumference was +2.5 standard deviations above the normal range, while his height and weight were below the average. He displayed many features characteristic of TRIO-related neurodevelopmental disorders caused by gain-of-function variants. However, trio-based exome sequencing identified a de novo missense variant (instead of gain-of-function variant) in the GEF1 domain of TRIO (NM_007118.4:c.4104T>A, p.(Asp1368Glu)).

Conclusions: This case expands the phenotypic spectrum of TRIO-related neurodevelopmental disorders, highlighting macrocephaly associated with a missense variant in the GEF1 domain. Further studies are required to clarify the functional effects of TRIO variants and their phenotypic consequences.