| Domain | Finding | Suggested ontology identifiers/terms | Evidence/notes |
|---|---|---|---|
| Disease identity | Peters plus syndrome is a rare syndromic Peters anomaly / congenital disorder of glycosylation caused by biallelic B3GLCT variants | MONDO:0009856; suggested term: autosomal recessive congenital disorder of glycosylation; suggested term: syndromic anterior segment dysgenesis | Open Targets links Peters plus syndrome specifically to **B3GLCT**; literature distinguishes PPS from isolated Peters anomaly and Peters-plus-like syndrome (pqac-00000000, pqac-00000002, pqac-00000003) |
| Synonyms / nomenclature | Historical/alternative gene name overlap may appear in records | suggested terms requiring validation: Peters'-plus syndrome; Peters plus; B3GALTL-related Peters plus syndrome; B3GLCT-related Peters plus syndrome | Sources note former gene symbol **B3GALTL** and current **B3GLCT**; curation should normalize both (pqac-00000002, pqac-00000005) |
| Etiology | Primary cause is germline biallelic loss of function in **B3GLCT** | suggested term: germline autosomal recessive inheritance; HGNC gene symbol: B3GLCT | Human genetic evidence is strong and disease-level, not EHR-derived; recurrent splice and truncating variants reported (pqac-00000000, pqac-00000002, pqac-00000004) |
| Key variant class | Recurrent canonical splice variant and other truncating alleles are important pathogenic classes | suggested variant terms: c.660+1G>A (rs80338851); c.755delC (p.Thr252fs) requiring nomenclature validation | c.660+1G>A is repeatedly cited as previously known PPS allele; 2019 report adds novel frameshift c.755delC (pqac-00000002) |
| Core ocular phenotype | Peters anomaly / anterior segment dysgenesis with congenital corneal opacity | HP:0000659 Corneal opacity; suggested HPO term requiring validation: Peters anomaly; suggested HPO term: Anterior segment dysgenesis | Core defining feature of PPS; congenital onset (pqac-00000002, pqac-00000003) |
| Ocular adhesion phenotype | Iridocorneal and/or lenticulocorneal adhesions may accompany corneal opacity | suggested HPO terms requiring ontology validation: iridocorneal adhesions; corneolenticular adhesions | Well-described within Peters anomaly spectrum; use as phenotype mapping after validation (pqac-00000003, pqac-00000012) |
| Ocular lens phenotype | Congenital cataract can occur within Peters anomaly spectrum and PPS differential workup | HP:0000519 Cataract | Cataract is especially relevant in PA2 and syndromic differential diagnosis; not every PPS case has cataract (pqac-00000003, pqac-00000006) |
| Ocular complication | Secondary glaucoma is a major vision-threatening complication | HP:0000501 Glaucoma | PA-spectrum review cited glaucoma in 30-70% of PA patients; this should not be over-interpreted as PPS-specific frequency (pqac-00000003) |
| Craniofacial phenotype | Cleft lip with/without cleft palate and characteristic facial dysmorphism | HP:0000204 Cleft upper lip; HP:0000175 Cleft palate | Clinical diagnosis commonly includes cleft lip/palate and facial changes (pqac-00000001, pqac-00000005) |
| Growth / skeletal phenotype | Short stature, short limbs, brachydactyly are characteristic systemic findings | HP:0004322 Short stature; HP:0001156 Brachydactyly; suggested HPO term: rhizomelia/short limbs requiring validation | PPS is distinguished from isolated PA by systemic skeletal/growth findings (pqac-00000001, pqac-00000003, pqac-00000005) |
| Neurodevelopmental phenotype | Developmental delay / intellectual disability of variable severity | HP:0001263 Global developmental delay; HP:0001249 Intellectual disability | Often described as variable psychomotor delay/mental retardation in older literature; harmonize to current HPO usage (pqac-00000001) |
| Auditory phenotype | Hearing loss can occur, sometimes linked to congenital ear malformations | HP:0000365 Hearing impairment | Conductive hearing loss noted in syndrome descriptions and case reports (pqac-00000001) |
| Cardiac phenotype | Congenital heart defects are variably reported | HP:0001627 Abnormality of the cardiovascular system morphology; suggested HPO term: congenital heart defect requiring validation | One review-oriented source states cardiac malformations in ~33% of reported cases, but this estimate derives from small literature and should be treated cautiously (pqac-00000001) |
| Additional organ involvement | Brain/CNS, urogenital, and other multisystem anomalies may occur in severe cases | suggested HPO terms requiring validation: hydrocephalus; agenesis of corpus callosum; urogenital abnormality | Prenatal and case literature suggest broader malformation spectrum; evidence is case-based and variable (pqac-00000004) |
| Molecular mechanism | B3GLCT is an ER-localized beta-1,3-glucosyltransferase that adds glucose to O-fucosylated TSRs, producing Glcβ1-3Fuc | GO:0005783 endoplasmic reticulum; suggested GO term: protein O-linked glycosylation; suggested GO term: O-fucose glycan extension on thrombospondin type-1 repeat | Vasudevan et al. provide direct mechanistic evidence for ER localization and TSR disaccharide formation (pqac-00000005) |
| Upstream partner | POFUT2 adds the initial O-fucose to properly folded TSRs upstream of B3GLCT | suggested term requiring validation: POFUT2-mediated protein O-fucosylation of TSR domains | PPS mechanism is part of a two-step POFUT2→B3GLCT pathway (pqac-00000005) |
| Protein homeostasis mechanism | PPS mutations disrupt a noncanonical ER quality-control system for properly folded TSR-containing proteins | GO:0006457 protein folding; suggested GO term: endoplasmic reticulum protein quality control; suggested GO term: regulation of protein secretion | Mechanistic hallmark from Current Biology 2015; downstream effect is impaired folding/ER exit/secretion for susceptible TSR proteins (pqac-00000002, pqac-00000005) |
| Candidate affected protein classes | TSR-containing extracellular proteins are likely downstream effectors | suggested terms requiring validation: thrombospondin-1; thrombospondin-2; ADAMTS family; ADAMTSL family; properdin | Human/cell biochemical evidence supports defective glycosylation of TSR-bearing proteins; exact causal contributors to each PPS feature remain incompletely mapped (pqac-00000005) |
| Cell types | Relevant developmental cell populations likely include corneal endothelium, neural crest derivatives, and chondrocytes | CL:0000114 endothelial cell; suggested CL term: corneal endothelial cell; CL:0000000 cell? / suggested CL term: neural crest cell; CL:0000138 chondrocyte | Numeric CL IDs should be validated before loading except for generic chondrocyte/endothelial mappings; literature supports neural crest and connective/skeletal involvement conceptually (pqac-00000003) |
| Anatomical structures | Primary affected sites include cornea, anterior chamber, iris, lens, palate, limb skeleton, brain, and heart | UBERON:0000964 cornea; UBERON:0001769 iris; UBERON:0001773 lens; UBERON:0001836 anterior chamber of eyeball; UBERON:0001703 palate; UBERON:0000922 embryo? / suggested term: limb skeleton; UBERON:0000955 brain; UBERON:0000948 heart | Use validated UBERON mappings for local database ingestion; eye and multisystem anatomy are well supported clinically (pqac-00000001, pqac-00000003, pqac-00000005) |
| Inheritance / population | Inheritance is autosomal recessive; robust PPS-specific prevalence/incidence not found | suggested term: autosomal recessive inheritance | Do not substitute Peters anomaly prevalence (2.2-3.1 per 100,000 births) for PPS prevalence; PPS remains ultra-rare (pqac-00000002, pqac-00000011) |
| Diagnostics | Diagnostic workflow combines ophthalmic exam with molecular confirmation of biallelic B3GLCT variants | NCIT:C47891 Ophthalmic Examination; NCIT:C84351 Whole Exome Sequencing; suggested NCIT term: gene panel testing; suggested NCIT term: Sanger sequencing confirmation | WES/WGS/panel testing are standard modern approaches in PA-spectrum diagnosis; PPS confirmation is genotype-driven (pqac-00000002, pqac-00000003, pqac-00000012) |
| Differential diagnosis | Distinguish from isolated Peters anomaly and Peters-plus-like syndrome; other PA genes are relevant | suggested disease/gene terms: PAX6, PITX2, PITX3, FOXE3, FOXC1, CYP1B1, SOX2, PXDN, COL4A1, CDH2, PEX2, ZFHX4 | PPLS denotes PPS-like phenotype without B3GLCT variants; isolated/syndromic PA is genetically heterogeneous (pqac-00000003, pqac-00000007, pqac-00000012) |
| Treatment / management | Care is supportive and multidisciplinary; ocular monitoring, amblyopia prevention, glaucoma surveillance, selective surgery, cleft and hearing management | NCIT:C157740 Supportive Care; suggested NCIT terms: penetrating keratoplasty; Boston keratoprosthesis implantation; cleft palate repair; hearing aid therapy; physical therapy; dental care | No disease-modifying therapy found; management is phenotype-directed and risk-benefit sensitive (pqac-00000001, pqac-00000009) |
| Prevention | Main preventive options are genetic counseling, reproductive testing, and prenatal/preimplantation diagnosis in at-risk families | NCIT:C15240 Genetic Counseling; suggested NCIT terms: prenatal molecular diagnosis; carrier screening; preimplantation genetic testing | Prevention is familial/reproductive rather than environmental; parental exome sequencing has been used to establish recurrence risk in lethal/prenatal AR disease settings including B3GLCT diagnoses (pqac-00000001, pqac-00000004) |
| Research / recent developments | Recent work mainly refines PA-spectrum genetics rather than PPS-specific therapy | suggested terms: comprehensive genomic analysis; rare disease registry; molecular diagnosis | 2022-2024 literature highlights expanded PA genes, WES/WGS use, and childhood glaucoma registry context; no PPS interventional trials identified (pqac-00000009, pqac-00000012) |
| Evidence gaps | No validated environmental or infectious cause, protective factor, biomarker panel, targeted therapy, pharmacogenomic rule, omics diagnostic signature, or natural animal disease established | suggested terms: evidence gap; no data | Also no robust PPS-specific survival statistics, QoL instruments, or confirmed whole-animal PPS model were found in retrieved evidence; clinical trial search found no relevant interventional PPS trial (pqac-00000005, pqac-00000006, pqac-00000007) |


*Table: This table summarizes database-ready disease findings, ontology mappings, and evidence notes for Peters plus syndrome. It emphasizes confirmed identifiers and mechanisms while flagging terms and evidence gaps that require ontology or literature validation.*