PDS5A and Cornelia de Lange syndrome

PDS5A is a cohesin regulatory factor whose altered dosage has recently been implicated in Cornelia de Lange syndrome (CdLS), a multisystem developmental disorder characterized by growth delay, congenital heart anomalies, cleft palate, and renal agenesis (PMID:19412548).

Recent clinical exome sequencing studies have identified an inherited variant in PDS5A in 1 affected individual (PMID:30158690), highlighting its potential involvement in the CdLS spectrum. The detected variant, c.2275G>T (p.Glu759Ter), is a protein-truncating event that supports a loss‑of‑function mechanism.

Complementary evidence from animal models reinforces the clinical findings. Pds5A‑deficient mice exhibit key phenotypes of CdLS, including growth retardation, abnormal heart morphology, and cleft palate (PMID:19412548). These experimental models underscore that proper gene dosage of Pds5A is critical for normal mammalian development.

The genetic evidence is further supported by a variant spectrum consistent with a haploinsufficiency mechanism. The observed protein‑truncating change, c.2275G>T (p.Glu759Ter), in the affected proband aligns with phenotypes typically seen in CdLS and suggests that even a single deleterious allele can disrupt cohesin function (PMID:30158690).

Functional studies demonstrate that reduced PDS5A activity compromises cohesin regulation, leading to developmental anomalies in murine models. Experiments reveal that decreased dosage adversely affects cardiac, renal, and craniofacial formation, lending strong support to the dosage sensitivity hypothesis in the pathogenesis of CdLS (PMID:19412548).

Although the number of human cases is limited, the convergent evidence from both clinical exome data and animal models provides a coherent picture. There is minimal conflicting evidence, and the data collectively affirm the role of PDS5A alterations in driving disease-relevant mechanisms.

In summary, integrated genetic and functional evidence supports a strong association between PDS5A and Cornelia de Lange syndrome. Key take‑home: The identification of variants such as c.2275G>T (p.Glu759Ter) in PDS5A confirms its clinical utility as a diagnostic marker and highlights a dosage sensitive mechanism that underpins CdLS pathogenesis.

References

• PloS One • 2009 • Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies PMID:19412548
• Genetics in Medicine • 2019 • Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies PMID:30158690

Evidence Based Scoring (AI generated)