THUMPD1-Related Neurodevelopmental Disorder: A Novel Homozygous Loss-of-Function Variant with an Unusual Skeletal Phenotype - A Case Report.

INTRODUCTION: Genes involved in tRNA modification are critical contributors to a broad range of human neurodevelopmental disorders, reflecting the essential role of RNA modifications in brain development and function. The THUMPD1 gene plays a key role in tRNA modification, and biallelic loss-of-function variants in this gene are known to cause Neurodevelopmental Disorder with Speech Delay and Variable Ocular Anomalies (NEDSOA), an autosomal-recessive condition. CASE PRESENTATION: We report two sisters harboring a novel homozygous frameshift variant in THUMPD1(NM_017736.5):c.311del;p.(Gly104ValfsTer9), who presented with global developmental delay, severe speech impairment, and ocular anomalies. One affected individual also exhibited severe unilateral skeletal abnormalities on the left hand, including aplasia of the middle and distal phalanges of the fourth finger and the middle phalanx of the fifth finger. To our knowledge, this skeletal feature has not previously been reported in a patient with THUMPD1-related neurodevelopmental disorder. CONCLUSION: Although this skeletal anomaly contributes to the clinical description of the present family, the presence of the finding in only 1 of the 2 affected siblings, both of whom carry the same homozygous variant, limits the strength of the genotype-phenotype association. Therefore, a definitive causal relationship between the THUMPD1 variant and the skeletal phenotype cannot be established, and confirmation in additional individuals will be required.