GNB5 – GNB5-related intellectual disability-cardiac arrhythmia syndrome

GNB5 (HGNC:4401) biallelic variants underlie an autosomal recessive intellectual disability-cardiac arrhythmia syndrome (MONDO:0014953). Affected infants present with early‐onset hypotonia, developmental delay, seizures and sinus bradycardia. The syndrome, also termed IDDCA, exhibits complete penetrance in homozygous or compound heterozygous carriers.

Four unrelated probands have been reported with consistent clinical features and parental segregation supporting pathogenicity: one homozygous frameshift c.136del (p.Glu46ArgfsTer12) in a patient-derived hiPSC line (PMID:31479876); one Chinese infant with compound heterozygous c.458G>A (p.Cys153Tyr) and c.1032C>A (p.Tyr344Ter) (PMID:32203251); one female with a homozygous missense c.920T>G (p.Leu307Arg) identified during overlapping 3-MCC deficiency evaluation (PMID:34573334); and one patient carrying c.514del (p.Ser172LeufsTer5) and hypomorphic c.628-6G>A with parental expression analyses (PMID:37994112). These biallelic variants segregate in parents with no additional affected relatives.

The variant spectrum includes two frameshift alleles (c.136del (p.Glu46ArgfsTer12), c.514del (p.Ser172LeufsTer5)), two nonsense/splice defects (c.1032C>A (p.Tyr344Ter), c.628-6G>A), and two deleterious missense changes (c.458G>A (p.Cys153Tyr), c.920T>G (p.Leu307Arg)). All variants were absent or extremely rare in population databases and predicted to disrupt the Gβ5 structure or expression.

Functional studies in patient‐derived and engineered human induced pluripotent stem cells recapitulate core features. HiPSC‐derived cardiomyocytes homozygous for the p.Ser123Leu (p.Ser123Leu) allele exhibit augmented IK,ACh density and pronounced bradycardia reversible by the IK,ACh blocker XEN-R0703 (PMID:31208990). Fibroblast assays of the p.Leu307Arg variant demonstrate abolished Gβ5–RGS complex formation and deficient dopamine receptor deactivation (PMID:34573334). These concordant cellular models support a loss‐of‐function mechanism.

No conflicting studies have refuted the association or identified dominant‐negative effects. All reported variants follow a recessive inheritance pattern with consistent genotype–phenotype correlation.

Integration of genetic and functional data yields a cohesive mechanistic narrative: pathogenic GNB5 variants cause haploinsufficiency of the Gβ5 subunit, impair GPCR signaling termination, and lead to early‐onset neurologic and cardiac manifestations. Key Take-home: GNB5 genetic testing should be considered in infants with intellectual disability, hypotonia and unexplained bradycardia to enable accurate diagnosis and therapeutic interventions.

References

• Stem cell research • 2019 • Generation of the induced human pluripotent stem cell lines CSSi009-A from a patient with a GNB5 pathogenic variant, and CSSi010-A from a CRISPR/Cas9 engineered GNB5 knock-out human cell line. PMID:31479876
• Journal of human genetics • 2020 • IDDCA syndrome in a Chinese infant due to GNB5 biallelic mutations. PMID:32203251
• Genes • 2021 • Extended Phenotyping and Functional Validation Facilitate Diagnosis of a Complex Patient Harboring Genetic Variants in MCCC1 and GNB5 Causing Overlapping Phenotypes. PMID:34573334
• Disease models & mechanisms • 2019 • Genetic variation in GNB5 causes bradycardia by augmenting the cholinergic response via increased acetylcholine-activated potassium current (IK,ACh). PMID:31208990
• Clinical genetics • 2024 • Inheritance of c.628-6G>A GNB5 hypomorphic allele uncovers another challenge in the pathogenic prediction of genomic variants. PMID:37994112

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