PPP1R21 – Neurodevelopmental Disorder with Hypotonia, Facial Dysmorphism, and Brain Abnormalities

PPP1R21 encodes a co-factor of protein phosphatase 1 critical for cell division, glycogen metabolism, protein synthesis, and muscle contractility. Biallelic PPP1R21 variants cause an autosomal recessive neurodevelopmental disorder with pediatric onset, hypotonia, facial dysmorphism, and variable brain anomalies (MONDO:0859165).

Genetic evidence arises from a cohort of 9 unrelated individuals with autosomal recessive intellectual disability syndrome and multisystem involvement (PMID:32985083) and a single patient harboring a homozygous splice-site variant c.748-3A>G presenting with severe developmental delay and muscle weakness (PMID:36692708). In total, 10 probands have been reported with biallelic PPP1R21 variants inherited recessively.

Reported alleles include a nonsense variant c.193C>T (p.Arg65Ter) and a splice-site substitution c.748-3A>G. Both variants segregate with disease in affected sibships and are absent or very rare in population databases, supporting loss of function as the pathogenic mechanism.

No additional affected relatives beyond the probands have been documented; parental carriers are asymptomatic, consistent with full penetrance in homozygous or compound heterozygous states.

Functional studies in patient-derived fibroblasts reveal impaired vesicular transport, endolysosomal trafficking defects, and profound activation of the ubiquitin–proteasome system with protein aggregates and altered cytoskeletal architecture, concordant with clinical severity and suggesting disrupted proteostasis and autophagy pathways (PMID:36692708).

Together, the genetic and experimental data support a loss-of-function mechanism of PPP1R21 in neurodevelopment, fulfilling strong gene–disease validity. Key take-home: PPP1R21 genetic testing is recommended for pediatric patients presenting with autosomal recessive hypotonia, facial dysmorphism, and neurodevelopmental delay to enable accurate diagnosis and management.

References

• American Journal of Medical Genetics Part A • 2020 • PPP1R21-related syndromic intellectual disability: Report of an adult patient and review. PMID:32985083
• Molecular Neurobiology • 2023 • A Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle Weakness Leads to Activated Proteasome Function. PMID:36692708

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