The PPP1R21 gene is located on chromosome 2p16.3 and encodes the Protein Phosphatase 1 Regulatory Subunit 21. PPP1R21 was first reported in relation to autosomal recessive neurodevelopmental disorder with hypotonia, facial dysmorphism and brain abnormalities (NEDHFBA) in 2018 Rehman et al. (PMID: 30520571). NEDHFBA is characterized by distinct facial dysmorphisms, intellectual disability, hypotonia, severe developmental delay and brain abnormalities. To date, 9 variants (including 3 nonsense, 5 frameshift and 1 splicing variants) have been reported in 9 probands in four publications and are included in this curation (PMID 29808498; 30520571; 32985083; 36692708). The mechanism of pathogenicity appears to be biallelic loss of function. Currently, there is limited experimental evidence to support the gene-disease association but other PP1 subunits have been linked to disease. In summary, there is strong evidence to support the relationship between PPP1R21 and autosomal recessive NEDHFBA. This classification is approved by the ClinGen Syndromic Disorders GCEP on the meeting date October 24, 2023 (SOP Version 9.0).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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