Jul 2026· Molecular Syndromology· pp. 1-10· 0 citations
Medicine
TL;DR
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, and a definitive causal relationship between the THUMPD1 variant and the skeletal phenotype cannot be established.
Abstract
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.
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Coffin-Siris syndrome type 4 (CSS4; OMIM 614609) is a rare autosomal dominant disorder caused by variants in SMARCA4, encoding the BRG1 ATPase subunit of the BAF chromatin-remodeling complex. Although classically characterized by intellectual disability, distinctive facial features, and fifth digit hypoplasia, the phenotypic spectrum is broad and includes autism spectrum disorder (ASD) without typical somatic features. We report a 3-year-old Chinese girl with global developmental delay, ASD features, characteristic facial features, and a documented normal ophthalmologic examination in whom whole-exome sequencing identified a novel heterozygous
de novo
frameshift duplication, c.4767dup (p.Ser1590Ilefs*39), in SMARCA4 (NM_003072), classified as Pathogenic (PVS1+PM2_Supporting + PM6). Notably, she lacked fifth digit hypoplasia and had no structural ocular anomalies on detailed ophthalmologic evaluation. A systematic review of the literature identified 39 genetically confirmed SMARCA4-related CSS4 cases; combined with our patient, 40 cases were analyzed. Intellectual disability was universal (100%), ASD manifestations occurred in 42.5%, and fifth digit hypoplasia was present in only 55.0%. Truncating variants (37.5% of the cohort) showed descriptive trends toward higher prevalence of fifth digit hypoplasia and ocular abnormalities than missense variants, though these differences did not reach statistical significance. Our proband, despite carrying a truncating variant, presented without classic digital anomalies or ocular involvement, underscoring that even loss-of-function alleles can produce atypical CSS4 phenotypes. For children with developmental delay, ASD, and distinctive facial features—regardless of the presence of classic digital anomalies—genetic testing for SWI/SNF complex genes should be considered. Given current limited evidence, carriers of truncating variants should be counseled regarding potential tumor predisposition, and individualized surveillance strategies may be considered pending further data.
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