Novel loss-of-function variants in TRIO are associated with neurodevelopmental disorder: case report

Abstract

Background: Damaging variants in TRIO have been associated with moderate to severe neurodevelopmental disorders in humans. While recent work has delineated the positional effect of missense variation on the resulting phenotype, the clinical spectrum associated with loss-of-function variation has yet to be fully defined.

Case presentation: We report on two probands with novel loss-of-function variants in TRIO. Patient 1 presents with a severe neurodevelopmental disorder and macrocephaly. The TRIO variant is inherited from his affected mother. Patient 2 presents with moderate developmental delays, microcephaly, and cutis aplasia with a frameshift variant of unknown inheritance.

Conclusions: We describe two patients with neurodevelopmental disorder, macro/microcephaly, and cutis aplasia in one patient. Both patients have loss-of-function variants, helping to further characterize how these types of variants affect the phenotypic spectrum associated with TRIO. We also present the third reported case of autosomal dominant inheritance of a damaging variant in TRIO.

Keywords: Autism; Cutis aplasia; Macrocephaly; Microcephaly; TRIO gene.

Fig. 1

Variants associated with neurodevelopment disorder in TRIO. Schematic of protein domains of human TRIO (NM_NM_007118.3). Variants discussed in this report are in black. Variants associated with microcephaly are in blue; microcephaly-associated frameshift/nonsense variants span the gene, while microcephaly-associated missense variants cluster in the GEF1 domain. Macrocephaly-associated missense variants cluster in the Spectrin repeats domain. With the exception of current patient 1 described here, all frameshift/nonsense variants have to date been associated with microcephaly

Fig. 2

Characteristics of patients described with novel loss-of-function variants in TRIO. a Photograph of patient 1 displaying macrocephaly, broad forehead, deep set eyes, broad nasal root, hanging columella and short philtrum. b Pedigree for patient 1. c. Pedigree for patient 2