RAD21 – Cornelia de Lange syndrome

Cornelia de Lange syndrome (CdLS) type 4 is a clinically heterogeneous developmental disorder characterized by distinctive facial features, growth retardation, intellectual disability, limb anomalies, and various organ system involvement. RAD21, encoding a core component of the cohesin ring that bridges SMC1A and SMC3, has been implicated in a milder CdLS phenotype with autosomal dominant inheritance and incomplete penetrance. Pathogenic RAD21 variants account for a small proportion of CdLS cases, expanding the genetic heterogeneity beyond the more frequently mutated NIPBL, SMC1A, and SMC3 genes.

Initial case reports identified a novel heterozygous single‐base deletion, c.704delG (p.Ser235IlefsTer19), segregating in a mild CdLS proband and three unaffected relatives, suggesting variable expressivity ([PMID:27882533]). Subsequent exome sequencing in a 15-month-old patient revealed a de novo RAD21 variant, c.1774_1776del (p.Gln592del), which led to classic CdLS type 4 features and disrupted the RAD21–SMC1A interface on structural modeling ([PMID:30125677]). A larger cohort study described 49 individuals from 33 unrelated families harboring 24 intragenic RAD21 sequence variants and seven unique microdeletions, confirming the association of RAD21 LoF and in-frame variants with an attenuated CdLS phenotype ([PMID:32193685]).

The variant spectrum in RAD21‐related CdLS is dominated by loss-of-function alleles—frameshift, nonsense, and splice site changes—along with occasional in-frame deletions such as p.Gln592del. No recurrent founder alleles have been reported, and microdeletions spanning exons 9–14 establish haploinsufficiency as a mechanism. These variants arise de novo in the majority of index cases, with rare familial transmission displaying reduced penetrance.

Functional and structural studies support a haploinsufficiency model: in silico structural modeling of p.Gln592del predicts loss of critical contacts between RAD21 and SMC1A, destabilizing the cohesin ring ([PMID:30125677]). Molecular dynamic simulations of additional RAD21 variants further corroborate perturbation of cohesin assembly and retention on chromatin, aligning with the attenuated but persistent developmental features seen in patients ([PMID:32193685]).

Some RAD21 variant carriers remain clinically unaffected or exhibit subthreshold features, highlighting incomplete penetrance and the potential for underdiagnosis. No studies have convincingly refuted the gene–disease link, but variable expressivity necessitates careful phenotyping and family counseling.

In summary, heterozygous RAD21 variants cause an autosomal dominant, incompletely penetrant form of CdLS (type 4) through haploinsufficiency and disruption of the RAD21–SMC1A interface. Recognition of this association informs molecular diagnosis, genetic counseling, and management of affected individuals. A targeted RAD21 analysis should be considered in patients with CdLS‐like features, particularly when NIPBL, SMC1A, and SMC3 tests are negative. Key take-home: RAD21 LoF and in-frame variants define a milder CdLS subtype with variable penetrance, underscoring the importance of comprehensive genetic testing for accurate diagnosis.

References

• Human genetics • 2020 • Delineation of phenotypes and genotypes related to cohesin structural protein RAD21 PMID:32193685
• European journal of medical genetics • 2019 • A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 - Review of the literature PMID:30125677
• Clinical genetics • 2017 • A novel RAD21 variant associated with intrafamilial phenotypic variation in Cornelia de Lange syndrome - review of the literature PMID:27882533

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