UBAP2L – Neurodevelopmental Disorder with Impaired Language, Behavioral Abnormalities, and Dysmorphic Facies

This summary reviews the evidence for the association between UBAP2L and neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies. Multiple lines of evidence, including case reports and multi‐patient studies, support a strong relationship between heterozygous loss‑of‑function variants in UBAP2L and the neurodevelopmental disorder phenotype (PMID:39720179). The disorder is rare but consistently presents with intellectual disability, seizures, abnormal facial features, and delayed speech, highlighting its distinct clinical presentation.

Genetic evidence comes from the identification of 12 de novo loss‑of‑function variants in unrelated probands, supplemented by a familial report where a novel heterozygous frameshift variant was found in two affected individuals within a single Chinese family (PMID:39720179). Segregation analysis in the familial study further supports autosomal dominant inheritance, with the affected mother transmitting the variant to her proband, strengthening the evidence for a pathogenic role of UBAP2L variants in disease.

The variant c.2453_2454del (p.Tyr818TrpfsTer3) exemplifies the mutation spectrum observed in UBAP2L deficiency. This frameshift variant, meeting HGVS criteria with a complete coding change and proper three‑letter amino acid codes, illustrates the pathogenic mechanism whereby loss‑of‑function drives the clinical phenotype. The genetic evidence is bolstered by the recurrence of deleterious variants that disrupt UBAP2L function and have been consistently identified in multiple cases (PMID:39720179).

Functional assessment studies further demonstrate that UBAP2L plays a key role in stress granule formation, a process essential for normal cellular response to stress. Disruption of this function helps explain the abnormal cellular processes underlying the neurodevelopmental phenotype. Experimental assays in patient‐derived models have shown concordant results, with stress granule formation significantly impaired in the presence of UBAP2L loss‑of‑function alleles (PMID:39720179).

Integrating the genetic and functional lines of evidence, the association between UBAP2L and neurodevelopmental disorder is well supported. The combination of multiple de novo loss‑of‑function variants, documented familial segregation, and biologically plausible experimental data indicates a strong gene‑disease relationship. The evidence exceeds typical scoring thresholds and confirms that the pathogenicity is mediated by a haploinsufficiency mechanism.

Key take‑home: The robust genetic and functional evidence for UBAP2L variants, including the recurrent c.2453_2454del (p.Tyr818TrpfsTer3), supports their use in diagnostic decision‑making, commercial assay design, and future research publication.

References

• Frontiers in genetics • 2024 • Whole-exome sequencing identified a novel heterozygous variant in UBAP2L in a Chinese family with neurodevelopmental disorder characterized by impaired language, behavioral abnormalities, and dysmorphic facies PMID:39720179

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