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GAPO syndrome (MONDO:0009263) is a rare autosomal recessive disorder characterized by growth retardation, alopecia, pseudo-anodontia and progressive optic atrophy. Bi-allelic pathogenic variants in ANTXR1 (HGNC:21014) have been established as the genetic cause since the initial discovery of homozygous nonsense and splice mutations in four ethnically unrelated individuals (PMID:23602711). Core clinical features, including eruption failure (pseudo-anodontia), progressive visual loss, and characteristic craniofacial findings, are highly penetrant in affected individuals.
Inheritance is autosomal recessive, with at least 22 unrelated probands reported across seven studies harboring homozygous or compound heterozygous truncating, frameshift, splice-site, and missense variants (PMID:23602711; PMID:25045128; PMID:30575274). Segregation of disease-causing alleles has been confirmed in 11 consanguineous and non-consanguineous families, consistent with full co-segregation of recessive ANTXR1 mutations and phenotype (PMID:27587992; PMID:38691016). No unaffected individuals have been reported to be homozygous for these variants.
The variant spectrum includes at least 8 predicted loss-of-function alleles (nonsense: c.262C>T (p.Arg88Ter); c.505C>T (p.Arg169Ter); frameshift: c.1220_1221insT (p.Ala408CysfsTer2); splice-site: c.1435-12A>G) and multiple missense changes (e.g., c.1150G>A (p.Gly384Ser); c.410A>T (p.Gln137Leu)). Recurrent founder alleles have not been clearly defined, and carrier frequency remains extremely low, consistent with <35 total cases worldwide.
ANTXR1 loss-of-function leads to defective extracellular matrix regulation. Antxr1-knockout mice recapitulate the human phenotype, exhibiting growth retardation and extracellular matrix accumulation in dermal and ocular tissues, supporting haploinsufficiency as the mechanism of pathogenicity (PMID:23602711). In vitro studies demonstrate that disease-associated nonsense and frameshift mutations abolish receptor expression and disrupt matrix-binding activity, concordant with the connective tissue abnormalities observed clinically.
No robust conflicting evidence has been reported; all published ANTXR1 variants in GAPO patients are deleterious and segregate appropriately. While TGFBI variants have been observed in GAPO patients with glaucoma, these do not weaken the core ANTXR1–GAPO association but suggest potential modifier effects in ocular phenotypes (PMID:38577561).
In summary, genetic and experimental data uniformly support a strong gene-disease relationship between ANTXR1 and GAPO syndrome. The autosomal recessive inheritance, high penetrance of loss-of-function alleles, robust segregation, and faithful animal models provide definitive clinical validity. ANTXR1 sequencing should be considered in patients presenting with the cardinal GAPO features, enabling accurate diagnosis, genetic counseling, and potential future targeted therapies.
Gene–Disease AssociationStrong22 probands in multiple consanguineous and unrelated families; segregation across 11 pedigrees; functional concordance Genetic EvidenceStrong22 probands with homozygous or compound heterozygous truncating and missense variants in ANTXR1 across ≥7 families, reaching genetic evidence cap Functional EvidenceModerateANTXR1-null mice recapitulate extracellular matrix defects and GAPO features; cellular studies confirm loss-of-function |