The RAD21 gene encodes a protein that localises to the centromere region of the chromosome. The protein forms a part of the cohesin complex which is required for the cohesion of sister chromatids after DNA replication, as well as for double strand break repair, DNA recombination and the apoptotic process. It is hence responsible for the negative regulation of the mitotic metaphase/anaphase transition and mitotic cell cycle G2/M transition.
The gene has been implicated in Cornelia de Lange Syndrome 4 (CDLS4), a highly variable multisystem disorder characterized by growth retardation, cognitive delay, upper limb anomalies and distinct facial dysmorphia.
The RAD21 gene is located on the long arm of chromosome 8. It spans a length of 28.9 kb of DNA and its coding sequence is spread across 14 exons. The gene encodes a 71.6 kDa protein product composed of 631 amino acids. While the gene is ubiquitously expressed in the human body, overexpression is seen in peripheral blood mononuclear cells and lymphocytes. Heterozygous mutations in the RAD21 gene have been linked to CDLS4. At least 8 mutations in the gene have been identified, including missense variants and a large deletion that results in the absence of the gene.
Monies et al. (2017) described the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, a 4-month-old male, presented with overgrowth, macrocephaly, speech delay, moderate to severe intellectual disability, stereotypic behaviors, ataxia, hypospadias, kidney malformation, renal tubulopathy, ptosis, anorectal malformation and AML. Using a multigene panel for dysmorphology/skeletal dysplasia, a heterozygous mutation (c.68G>A, p.W23X) was identified in exon 2 of the patient’s RAD21 gene, associated with CDLS4. Given the atypical presentation of the patient, this case helped in the phenotypic expansion of the disorder.
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