Submission Details

SYNCRIP encodes a nuclear ribonucleoprotein implicated in mRNA processing mechanisms. SYNCRIP was first reported in relation to autosomal dominant SYNCRIP-related neurodevelopmental disorder in 2021 (Gillentine et al., PMID: 33874999). The disorder is characterized by developmental delay, intellectual disability, speech and language delay, behavioral abnormalities including autism spectrum disorder, brain imaging abnormalities, hypotonia, seizures, and dysmorphic facial features (PMID: 3387499, doi.org/10.1016/j.rare.2024.100052). Other less frequent features include eye abnormalities, hand and feet abnormalities, skeletal abnormalities, growth delay, and genitourinary abnormalities.

Sixteen variants (frameshift and nonsense) that have been reported in 17 probands in four publications (PMIDs: 23020937, 27479843, 33874999, 34157790) are included in this curation. Variants were de novo in all instances in which parental DNA was available. Of note, 7 variants occurred in the penultimate or last exon and are expected to escape nonsense-mediated RNA decay; however, at least one nonsense variant in the last exon was shown to result in nonsense mediated decay as opposed to truncation (doi.org/10.1016/j.rare.2024.100052). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. De novo missense variants in SYNCRIP have also been reported in individuals with autism or other neurodevelopmental disorders (PMIDs: 30504930, 33057194, 33874999, 34157790). However, given the absence of functional evidence of pathogenicity, these variants were not scored. SYNCRIP is significantly constrained for loss-of-function variants (pLI = 1, LOEUF = 0.25, gnomAD v4.1.0) and missense variants (Z = 4.85). The mechanism of pathogenicity appears to be loss of function (PMIDs: 33874999, 39776340).

This gene-disease relationship is also supported by biochemical function, protein interaction, and a mouse model showing that loss of Syncrip causes abnormal neocortical development and memory impairments (PMID: 39776340). SYNCRIP (also known as HNRNPQ) belongs to the heterogeneous nuclear ribonucleoprotein (HNRNP) gene family; several genes of this family (including HNRNPC, HNRNPD, HNRNPH1, HNRNPH2, HNRNPK, HNRNPR, and HNRNPU) have been recently implicated in neurodevelopmental disorders with overlapping clinical features.

In summary, there is definitive evidence supporting the relationship between SYNCRIP and autosomal dominant SYNCRIP-related neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 1, 2025 (SOP Version 11).