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. 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. 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.

中文翻译：

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TRIO中新的功能丧失变异与神经发育障碍有关：病例报告

TRIO中的破坏性变异已与人类中度至重度神经发育障碍相关。尽管最近的工作已经描述了错义变异对所产生的表型的位置影响，但与功能丧失变异相关的临床范围尚未完全确定。我们报告了TRIO中具有新型功能丧失变异的两个先证者。患者1出现严重的神经发育障碍和大头畸形。TRIO变体是从他受影响的母亲那里继承的。患者2表现为中度发育迟缓，小头畸形和角质发育不全，伴有遗传性未知的移码变体。我们描述了两名患者神经发育障碍，大/小头畸形和角质发育不全的两名患者。两名患者都有功能丧失的变异体，帮助进一步表征这些类型的变体如何影响与TRIO相关的表型谱。我们还介绍了TRIO中一个破坏性变异的常染色体显性遗传的第三例报道病例。