DCPS – Al-Raqad Syndrome

Al-Raqad syndrome is a rare autosomal recessive disorder caused by biallelic variants in DCPS, encoding a scavenger decapping enzyme essential for 3′–5′ mRNA decay. A total of three unrelated probands from consanguineous families have been reported, each harboring homozygous missense DCPS variants: c.724A>G (p.Arg242Gly) (PMID:30289615), c.260C>T (p.Thr87Met) (PMID:30289615), and c.918G>C (p.Glu306Asp) (PMID:32770650).

Affected individuals present with global developmental delay, intellectual disability, growth delay, craniofacial dysmorphism, skin dyschromia, neuromuscular defects, cerebellar and cerebral atrophy, and hypomyelination. One pedigree demonstrated segregation of the homozygous c.918G>C variant in affected offspring (PMID:32770650).

Experimental studies in human molecular genetics have shown that DCPS loss-of-function variants (splice site c.636+1G>A and missense c.947C>T (p.Thr316Met)) abolish decapping activity in vitro, underscoring a loss-of-function mechanism central to disease pathogenesis (PMID:25701870). Although these specific alleles differ from those in Al-Raqad syndrome, they confirm that impaired mRNA decapping underlies neurological phenotypes.

To date, no conflicting reports have been described, and the phenotype–genotype correlation is consistent across independent families. Additional evidence for variant pathogenicity (e.g., fibroblast enzymatic assays) remains to be published but exceeds current ClinGen scoring.

Key Take-home: Biallelic missense variants in DCPS cause a consistent autosomal recessive neurodevelopmental syndrome—Al-Raqad syndrome—supporting genetic testing and counseling for affected families.

References

• American journal of medical genetics. Part A • 2018 • An additional patient with a homozygous mutation in DCPS contributes to the delination of Al-Raqad syndrome. PMID:30289615
• American journal of medical genetics. Part A • 2020 • Leukoencephalopathy in Al-Raqad syndrome: Expanding the clinical and neuroimaging features caused by a biallelic novel missense variant in DCPS. PMID:32770650
• Human molecular genetics • 2015 • Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment. PMID:25701870

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