TRMT10A缺陷的基因型-表型变异性：与双等位基因功能丧失变异相关的不同发育结局

文献信息

中文摘要

背景： TRMT10A的功能丧失变异已知会导致一种罕见的常染色体隐性遗传病，主要特征为小头畸形、身材矮小和糖代谢受损。然而，表型变异的程度以及影响临床异质性的因素仍知之甚少。方法：在此，我们描述了两名携带TRMT10A不同双等位基因功能丧失变异的个体，他们表现出不同的发育表型。结果：第一名患者是一名34岁男性，携带纯合早期移码变异，表现为认知功能保留以及此前未报道的多系统特征，包括男性不育、高度近视、双侧感音神经性听力损失和法洛四联症。相比之下，第二名患者是一名3岁男孩，携带涉及外显子6-7的纯合缺失，表现出早发性发育迟缓、癫痫、先天性心脏病和新生儿低血糖。转录本水平分析支持了这两种变异对TRMT10A转录本的预测效应。结论：这些发现提示TRMT10A功能丧失变异相关的表型变异性。值得注意的是，在成年患者中发现的移码变异此前曾被报道与更典型的神经发育表型相关，而我们的患者表现出认知功能保留。这一观察支持可变表现度，并提示其他因素可能促成临床异质性。

英文摘要

Loss-of-function variants in TRMT10A are known to cause a rare autosomal recessive disorder primarily characterized by microcephaly, short stature, and impaired glucose metabolism. However, the extent of phenotypic variability and the factors influencing clinical heterogeneity remain poorly understood. Here, we describe two individuals harboring distinct biallelic loss-of-function variants in TRMT10A who exhibited divergent developmental phenotypes. The first patient, a 34-year-old man with a homozygous early frameshift variant, presented with preserved cognitive function and previously unreported multisystem features, including male infertility, high-grade myopia, bilateral sensorineural hearing loss, and tetralogy of Fallot. In contrast, the second patient, a 3-year-old boy with a homozygous deletion involving exons 6-7, demonstrated early-onset developmental delay, epilepsy, congenital heart disease, and neonatal hypoglycemia. Transcript-level analyses supported the predicted effects of both variants on TRMT10A transcripts. These findings suggest phenotypic variability associated with TRMT10A loss-of-function variants. Notably, the frameshift variant identified in the adult patient has previously been reported in association with a more typical neurodevelopmental phenotype, whereas our patient exhibited preserved cognitive function. This observation supports variable expressivity and suggests that additional factors may contribute to clinical heterogeneity.