Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
The AP1S2 gene encodes the sigma1B subunit of the clathrin-associated adaptor protein complex 1 (AP1S2). Hemizygous loss-of-function variants in AP1S2 cause Fried syndrome (Fried syndrome), an X-linked recessive neurodevelopmental disorder. Affected males typically present with intellectual disability, hypotonia, delayed speech and language development (HP:0000750), aggressive behavior (HP:0000718), and progressive cerebral calcifications (HP:0002514). Additional features include elevated cerebrospinal fluid protein and variable autistic traits. Female heterozygotes are usually unaffected or have milder features. The prevalence remains unknown owing to rarity, but increasing case reports have refined the phenotype.
In 2008, five XLMR families including the original Fried syndrome pedigree were reported with AP1S2 nonsense and splice-site variants segregating in affected males (PMID:18428203). In this cohort, four patients across two unrelated families exhibited early-onset hypotonia, developmental delay, aggressive behavior, and progressive basal ganglia calcifications. A recurrent nonsense variant c.154C>T (p.Arg52Ter) was identified and shown to segregate with disease. Cerebrospinal fluid analysis revealed elevated protein levels in affected individuals, supporting central nervous system involvement. CT scanning demonstrated onset and progression of brain calcifications during childhood. These findings established the initial link between AP1S2 LoF alleles and Fried syndrome.
Subsequently, a Chinese four-generation pedigree with seven affected males harboring a splice acceptor mutation c.1-1G>C confirmed X-linked recessive inheritance and intrafamilial variability in intellectual disability severity (PMID:30714330). This study summarized clinical data from 59 patients with AP1S2 mutations, reinforcing that loss-of-function alleles underlie a broad neurodevelopmental spectrum. Patients with splice-site defects more frequently developed seizures, whereas those with nonsense variants showed higher rates of microcephaly. A Thai family study described six affected males with severe-to-profound intellectual impairment and a leaky splice variant c.1-2A>G yielding two aberrant transcripts (PMID:38682877). Progressive limb spasticity and coarse facial evolution further delineated the phenotype. Together, these series expand the genetic and phenotypic spectrum of AP1S2-related Fried syndrome.
To date, all pathogenic AP1S2 variants reported in Fried syndrome are loss-of-function, including nonsense (e.g., c.154C>T (p.Arg52Ter)), splice-site (c.1-1G>C, c.1-2A>G), and frameshift alleles. A total of 11 distinct pathogenic alleles have been described across more than ten families. Recurrent null variants have not been observed and no founder effects have been established. No missense variants have been definitively associated, underscoring haploinsufficiency as the primary mechanism. Carrier frequency is not known but is expected to be very low given rarity. Genetic testing should include sequencing and deletion/duplication analysis for comprehensive LoF variant detection.
Functional assessment using AP-1 complex models demonstrated that sigma subunits are essential for adaptor complex stability, and AP1S2 deficiency leads to reduced AP-2 complex stability (PMID:18428203). Fibroblast studies from patients showed no major disruption of AP-1 complex stability or localization, suggesting redundancy in peripheral tissues. Neuropathological evaluation of affected fetal brain revealed no gross macroscopic defects but supports a brain-specific trafficking defect. These data indicate that loss of sigma1B impairs intracellular protein traffic in neuronal cells, leading to the clinical phenotype. The mechanism is consistent with haploinsufficiency rather than a dominant-negative effect. No animal models have been reported to date.
Collectively, strong genetic and experimental evidence supports a definitive X-linked recessive association between AP1S2 LoF variants and Fried syndrome. Segregation in multiple pedigrees, identification of 59 affected individuals, and consistent clinical features provide high clinical validity. Functional studies corroborate a loss-of-function mechanism manifesting as a brain-specific trafficking defect. No conflicting evidence has been reported. Additional case reports have broadened the phenotypic spectrum but exceed ClinGen scoring scope. Key take-home: AP1S2 loss-of-function testing is clinically actionable for males with unexplained intellectual disability and basal ganglia calcifications.
Gene–Disease AssociationStrong59 patients across >10 families; segregation in four multigenerational pedigrees; concordant loss-of-function mechanism Genetic EvidenceStrong11 distinct LoF alleles in 59 affected males from >10 families; confirmed X-linked recessive segregation in three pedigrees Functional EvidenceModerateAP-1 complex stability assays and patient cell studies support a brain-specific loss-of-function defect |