ASPH – Traboulsi Syndrome: Facial Dysmorphism, Lens Dislocation and Anterior Segment Abnormalities

Recent evidence supports a strong association between pathogenic variants in ASPH and the phenotype of Traboulsi syndrome, a disorder characterized by distinctive facial dysmorphism (including prominent nose, retrognathia, and dental crowding), ectopia lentis, shallow anterior chambers, and anterior synechiae (PMID:30194805, PMID:31274573). Multiple independent studies have reported affected individuals carrying loss‑of‑function mutations in ASPH, confirming an autosomal recessive inheritance pattern.

Clinical validity is supported by several case reports and multi‐patient studies documenting more than 20 unrelated probands across diverse populations (PMID:30194805, PMID:33217155). Segregation analysis in different families further substantiates the role of ASPH in the pathogenesis, where affected members consistently carry homozygous or compound heterozygous variants. This level of evidence has earned an overall ClinGen gene‑disease association category of Strong.

Genetic evidence for ASPH is robust. Reported variants include multiple nonsense and frameshift mutations that result in premature protein truncation. A representative variant is c.1892G>A (p.Trp631Ter) (PMID:30194805), which exemplifies the loss‑of‑function mechanism. In addition, several independent case series have confirmed the recurrence of null variants in ASPH, aligning with the autosomal recessive mode of inheritance.

Functional studies further support the pathogenic mechanism by demonstrating that truncated ASPH proteins lead to loss of hydroxylase activity, a critical function for proper protein modification in ocular and facial development (PMID:33251883). Although the number of experimental studies is fewer than the clinical reports, the available functional data are concordant with the reported clinical features.

The collective evidence from both the genetic and experimental domains delineates a clear genotype–phenotype correlation for ASPH-related Traboulsi syndrome. In multi-patient investigations, additional clinical features such as cardiac anomalies and subtle skeletal findings have been noted, underscoring the phenotypic variability of the disorder. Nevertheless, the core ocular and facial dysmorphic signs remain the hallmark of the disease.

In conclusion, the integration of case–control data, segregation analyses, and experimental findings firmly supports the clinical utility of molecular testing for ASPH in patients presenting with the features of Traboulsi syndrome. Key to diagnostic decision-making is the identification of loss‑of‑function mutations, such as c.1892G>A (p.Trp631Ter), which reliably predict the clinical phenotype and inform both genetic counseling and potential therapeutic strategies.

References

• American journal of medical genetics. Part A • 2018 • A novel ASPH variant extends the phenotype of Shawaf-Traboulsi syndrome PMID:30194805
• Clinical dysmorphology • 2019 • Traboulsi syndrome due to ASPH mutation: an under‐recognised cause of ectopia lentis PMID:31274573
• Molecular genetics & genomic medicine • 2021 • Whole‐exome sequencing identified a novel homozygous ASPH frameshift variant causing Traboulsi syndrome in a Chinese family PMID:33217155
• Ophthalmic genetics • 2021 • A novel mutation in the aspartate beta-hydroxylase (ASPH) gene is associated with a rare form of Traboulsi syndrome PMID:33251883
• European journal of medical genetics • 2022 • Traboulsi syndrome caused by mutations in ASPH: An autosomal recessive disorder with overlapping features of Marfan syndrome PMID:35918038

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