| domain | finding | suggested ontology term(s)/identifier(s) | evidence strength/limitations |
|---|---|---|---|
| Disease entity | KRT74-related pure hair-nail ectodermal dysplasia; autosomal recessive hair/nail ectodermal dysplasia caused by biallelic KRT74 variation; reported as PHNED/ectodermal dysplasia hair and nail type | OMIM: 614929; MONDO: candidate requiring ontology validation; synonym candidates: pure hair and nail ectodermal dysplasia, ectodermal dysplasia hair/nail type, KRT74-related PHNED | Strong for existence of a distinct KRT74-associated entity, but evidence is limited to n=4 affected siblings from one consanguineous Pakistani family (pqac-00000002, pqac-00000003, pqac-00000005) |
| Causal gene/protein | KRT74 encodes keratin-74, a type II keratin involved in hair/nail epithelial appendages | KRT74; candidate HGNC/NCBI identifiers require ontology validation; protein: Keratin-74 | Strong gene-disease association within the single family; broader literature supports KRT74 as a hair keratin, but disease-specific evidence remains sparse (pqac-00000004, pqac-00000005, pqac-00000008) |
| Inheritance | Autosomal recessive segregation with unaffected heterozygous parents/siblings and homozygous affected siblings | HP:0000007 Autosomal recessive inheritance | Strong segregation evidence in one pedigree only; penetrance beyond this family is unknown (pqac-00000001, pqac-00000003) |
| Pathogenic variant | Homozygous NM_175053:c.821T>C, p.Phe274Ser in KRT74; missense in coil 1B domain; rs147962513 reported | HGVS: NM_175053:c.821T>C; p.Phe274Ser; dbSNP: rs147962513; ACMG class: candidate pathogenic/likely pathogenic requiring current database re-validation | Strong family-level causal evidence plus conservation and IHC support; formal contemporary ACMG/ClinVar status was not established here and should be rechecked (pqac-00000000, pqac-00000003, pqac-00000004) |
| Onset | Hair and nail abnormalities present since birth; congenital onset | HP:0003577 Congenital onset; candidate HPO term requiring validation if more specific onset term desired | Strong within reported family; no longitudinal natural history cohorts (pqac-00000002, pqac-00000003, pqac-00000004) |
| Hair phenotype | Congenital hypotrichosis with sparse, brittle, shaggy scalp hair; involvement of eyebrows and eyelashes | HP:0001006 Hypotrichosis; candidate HPO terms requiring validation: sparse scalp hair, brittle hair, abnormal eyebrow hair, sparse eyelashes | Strong descriptive evidence in n=4; exact standardized HPO mapping for “shaggy” hair and eyebrow/eyelash involvement should be ontology-validated (pqac-00000001, pqac-00000002, pqac-00000003) |
| Nail phenotype | Spoon-shaped dystrophic nails with onychodystrophy, distal onycholysis, and mild micronychia | HP:0012203 Onycholysis; HP:0001813 Micronychia; candidate HPO terms requiring validation: spoon-shaped nails, nail dystrophy/onychodystrophy | Strong descriptive evidence in n=4; some nail morphology terms need validation against current HPO nomenclature (pqac-00000001, pqac-00000002, pqac-00000003) |
| Negative ectodermal/systemic findings | Otherwise healthy; no skin abnormalities; dentition and sweating reported as normal | Candidate HPO negatives requiring validation: normal skin morphology, normal dentition, normal sweating | Useful for differential diagnosis, but negative findings are only from the single family report and were not deeply phenotyped by standardized instruments (pqac-00000002, pqac-00000003) |
| Primary anatomy | Hair follicle and nail unit are the principal affected structures | UBERON candidate terms requiring validation: hair follicle, nail unit, scalp hair, eyebrow, eyelash | Strong clinicopathologic concordance; disease appears appendage-restricted in available evidence (pqac-00000002, pqac-00000003, pqac-00000005) |
| Tissue/cell localization | Keratin-74 expression demonstrated in hair follicle inner root sheath and in nail matrix, nail bed, and hyponychium | UBERON/CL candidates requiring validation: hair follicle inner root sheath, nail matrix, nail bed, hyponychium; CL candidate: hair follicle keratinocyte | Strong localization evidence by immunohistochemistry, including mouse distal digit/nail tissues and normal human hair follicles; cell ontology mapping needs validation (pqac-00000000, pqac-00000001, pqac-00000004) |
| Molecular function/pathway | Conserved Phe274 in coil 1B domain is predicted to be required for keratin long-range dimerization and intermediate filament stability; disease mechanism consistent with keratinization/intermediate filament defect | GO candidate terms requiring validation: intermediate filament organization, keratin filament, keratinization, structural constituent of cytoskeleton | Moderate mechanistic strength: supported by domain/conservation analysis and loss of staining, but no direct biochemical filament-assembly assay in patient cells was reported (pqac-00000000, pqac-00000004, pqac-00000006) |
| Functional consequence | Affected hair follicles/epidermis stained negative for keratin-74, supporting loss of function/protein degradation | GO candidate: loss of protein expression requiring validation | Moderate evidence from IHC; absence of signal supports loss of function but does not fully resolve whether degradation, failed translation, or epitope loss predominates (pqac-00000000, pqac-00000004, pqac-00000007) |
| Population data | Variant reported as extremely rare; present heterozygously at very low frequency in older population resources and not observed homozygously | Population resource annotation candidates requiring re-validation in current gnomAD/dbSNP | Weak-to-moderate because frequency estimates cited are from older EVS/dbSNP-era resources; modern population frequency should be rechecked (pqac-00000000, pqac-00000003, pqac-00000007) |
| Differential diagnosis | Distinguish from KRT85-related PHNED, HOXC13-related PHNED, and dominant KRT74-associated woolly hair/hypotrichosis without nail disease | OMIM candidates requiring validation for differential entities; HPO pattern: hair+nail ectodermal dysplasia versus isolated woolly hair/hypotrichosis | Strong conceptual differential, but comparative phenotypic granularity is limited by few cases and literature availability (pqac-00000000, pqac-00000005, pqac-00000006) |
| Evidence scope | Human evidence base consists of one published family with four affected full siblings; no dedicated clinical trial, biomarker study, or natural history cohort identified | Evidence annotation candidate: single-family case series | Critical limitation for all downstream assertions; ontology entry should flag very low case count and need for replication (pqac-00000001, pqac-00000002, pqac-00000003) |


*Table: This table summarizes ontology-ready disease, phenotype, anatomy, and mechanism annotations for KRT74-related pure hair-nail ectodermal dysplasia. It emphasizes the narrow evidence base: four affected individuals from a single family, with several ontology IDs marked as candidates requiring validation.*