Genotype-phenotype variability in TRMT10A deficiency: divergent developmental outcomes associated with biallelic loss-of-function variants.

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.