A novel hemizygous nonsense variant in PPP1R3F is associated with intellectual disability and autismNew gene variant linked to autism and intellectual disability

BackgroundPPP1R3F deficiency syndrome is an extremely rare, recently identified X-linked recessive neurodevelopmental disorder. It is caused by hemizygous variants in the PPP1R3F gene, which encodes a glycogen-targeting subunit of the brain-specific protein phosphatase 1 (PP1). Dysfunction of PPP1R3F disrupts glycogen metabolism in astrocytes, leading to insufficient energy supply to synapses during critical periods of brain development and subsequently causing neurodevelopmental abnormalities. Only a small number of cases of PPP1R3F deficiency syndrome have been reported to date, which significantly limits our comprehensive understanding of the clinical features of the disease and the relationship between genetic variants and clinical manifestations in patients.MethodsWhole-exome sequencing (WES) was performed on a Chinese male presenting with intellectual disability (ID), developmental delay (DD), and autism spectrum disorder (ASD). Sanger sequencing was then used to identify and determine the origins of the variant. We evaluated the pathogenicity of the identified variant following the established ACMG/AMP guidelines. Additionally, we conducted a thorough review of previously reported cases to summarize the variants and clinical features of PPP1R3F deficiency syndrome.ResultsWe identified a novel hemizygous nonsense variant [NM_033215.5: c.907C>T, p.(Gln303*)] in the PPP1R3F gene in the proband, which was inherited from his mother. The patient we described here exhibited clinical phenotypes similar to those associated with PPP1R3F gene variants but lacked other reported multisystem manifestations, such as epilepsy, brain abnormalities, and dysmorphic features. An analysis of the 15 variants and their associated phenotypes in 15 patients from both the current and previous studies demonstrates that PPP1R3F gene variants can lead to a variety of phenotypic deficits, and a clear genotype–phenotype correlation has not yet been established. Despite the high variability in some clinical manifestations, the core phenotypic features of PPP1R3F variants include varying degrees of ID, DD, speech delay, dysmorphic facial features, and ASD.ConclusionOur findings support DD, ID, ASD, and speech impairment as core features of PPP1R3F deficiency syndrome, while also highlighting the extensive clinical variability. This study further expanded the genetic and phenotypic spectrum associated with PPP1R3F deficiency syndrome.