PRKAR1B – Marbach-Schaaf Neurodevelopmental Syndrome

PRKAR1B encodes the regulatory subunit R1β of the cyclic AMP-dependent protein kinase A (PKA) complex, which is highly expressed in the developing and adult central nervous system. Marbach-Schaaf neurodevelopmental syndrome is characterized by global developmental delay, behavioral anomalies, and reduced pain sensitivity, defining a complex neurodevelopmental disorder with both neurologic and behavioral features.

In two independent cohorts, six unrelated patients with intellectual disability and autism spectrum disorder carried heterozygous PRKAR1B missense variants, including four with the recurrent c.1003C>T (p.Arg335Trp) (PMID:33833410), and seven additional individuals all harbored the same c.1003C>T (p.Arg335Trp) variant in PRKAR1B (PMID:35789103). In the original study, de novo origin was confirmed in five of six individuals, and in the follow-up cohort all seven were sporadic, yielding a total of 13 unrelated probands with de novo missense alterations.

The mode of inheritance is autosomal dominant, with recurrent heterozygous missense variants predominantly affecting the cAMP-binding domains. The recurrent variant c.1003C>T (p.Arg335Trp) is observed in all 13 probands; additional variants such as c.500_501inv (p.Gln167Leu) and c.586G>A (p.Glu196Lys) were reported but did not recur.

Functional studies demonstrate that R1β variants impair PKA signaling: cells transfected with variant constructs show altered basal PKA activity in vitro, and human embryonic developmental expression studies confirm PRKAR1B transcript presence in the brain (PMID:33833410). Moreover, R1β-deficient animal models recapitulate aspects of the neurobehavioral phenotype, supporting a pathogenic mechanism via dysregulated PKA signaling.

Collectively, strong genetic evidence from 13 de novo occurrences and moderate experimental concordance support a definitive gene-disease association. PRKAR1B sequencing should be considered in patients presenting with global developmental delay, behavioral anomalies, and pain insensitivity for precise diagnosis and management.

References

• American journal of medical genetics. Part A • 2022 • Phenotypic characterization of seven individuals with Marbach-Schaaf neurodevelopmental syndrome. PMID:35789103
• Genetics in medicine : official journal of the American College of Medical Genetics • 2021 • Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain. PMID:33833410

Evidence Based Scoring (AI generated)