TRIO is a Dbl family guanine nucleotide exchange factor (GEF) and an important regulator of neuronal development. Most truncating and missense variants affecting the Dbl homology domain of TRIO are associated with a neurodevelopmental disorder with microcephaly (MIM617061). Recently, de novo missense variants affecting the spectrin repeat region of TRIO were associated with a novel phenotype comprising severe developmental delay and macrocephaly (MIM618825). Here, we provide more evidence on this new TRIO-associated phenotype by reporting two severely affected probands with de novo missense variants in TRIO affecting the spectrin repeat region upstream of the typically affected GEF1 domain of the protein.

TRIO 是 Dbl 家族鸟嘌呤核苷酸交换因子 (GEF) 和神经元发育的重要调节剂。大多数影响TRIO的 Dbl 同源域的截断和错义变异与小头畸形的神经发育障碍 (MIM617061) 相关。最近，影响 TRIO 血影蛋白重复区的从头错义变体与包括严重发育迟缓和大头畸形 (MIM618825) 的新表型相关。在这里，我们通过报告两个严重受影响的先证者提供了更多关于这种新的TRIO相关表型的证据，这些先证者在TRIO 中具有从头错义变体，影响蛋白质通常受影响的 GEF1 结构域上游的血影蛋白重复区。