body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency

Summary

body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency (MONDO:0012570) is a disease caused by GGCX (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GGCX (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 17
• Phenotypes (HPO): 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0000973	Cutis laxa	Very frequent (80-99%)
HP:0001582	Redundant skin	Very frequent (80-99%)
HP:0001928	Abnormality of coagulation	Very frequent (80-99%)
HP:0200034	Papule	Very frequent (80-99%)
HP:0001102	Angioid streaks of the fundus	Frequent (30-79%)
HP:0001892	Abnormal bleeding	Frequent (30-79%)
HP:0002621	Atherosclerosis	Frequent (30-79%)
HP:0004944	Dilatation of the cerebral artery	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency
Mondo ID	MONDO:0012570
MeSH	C563654
OMIM	610842
Orphanet	91135
SNOMED CT	717941005
UMLS	C1835813
MedGen	332067
GARD	0016796
Is cancer (heuristic)	no

Also known as: pseudoxanthoma elasticum-like syndrome · PXE-like syndrome

Data availability: 17 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary skin disorder › body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency

Related subtypes (113): alopecia, isolated, reticulate pigment disorder, dyschromatosis universalis hereditaria, psoriasis, porokeratosis, hereditary papulotranslucent acrokeratoderma, acrokeratosis verruciformis, Tietz syndrome, familial primary localized cutaneous amyloidosis, isolated anhidrosis with normal sweat glands, aplasia cutis congenita, blue rubber bleb nevus, Darier disease, dermatosis papulosa nigra, autosomal dominant vibratory urticaria, absence of fingerprints-congenital milia syndrome, pilomatrixoma, spinocerebellar ataxia type 34, isolated congenital adermatoglyphia, isolated hyperchlorhidrosis, hyperkeratosis-hyperpigmentation syndrome, hyperpigmentation with or without hypopigmentation, familial progressive, lichen sclerosus et atrophicus, lichen planus, familial, monilethrix, hereditary mucoepithelial dysplasia, schwannomatosis, nevus, epidermal, familial multiple nevi flammei, linear nevus sebaceous syndrome, progressive osseous heteroplasia, Hailey-Hailey disease, piebaldism, familial pityriasis rubra pilaris, scalp defects-postaxial polydactyly syndrome, seborrheic keratosis, Sneddon syndrome, sebocystomatosis, stiff skin syndrome, familial multiple discoid fibromas, urticaria, aquagenic, urticaria, familial localized heat, vasculitis, lymphocytic, nodular, VPS13A-related neurodegenerative disease, acrogeria, anhidrosis, familial generalized, with abnormal or absent sweat glands, deafness, congenital, with total albinism, epidermodysplasia verruciformis, combined immunodeficiency with skin granulomas, lipoid proteinosis, neurocutaneous melanocytosis, neutrophil actin dysfunction, albinism-hearing loss syndrome, X-linked reticulate pigmentary disorder, CHILD syndrome, linear skin defects with multiple congenital anomalies, dermatitis herpetiformis, familial, keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome, H syndrome, hydroa vacciniforme, familial, poikiloderma with neutropenia, acne, infundibulocystic basal cell carcinoma, Becker nevus syndrome, generalized basaloid follicular hamartoma syndrome, sweet syndrome, MEDNIK syndrome, seborrhea-like dermatitis with psoriasiform elements, DK1-congenital disorder of glycosylation, Legius syndrome, CLOVES syndrome, encephalocraniocutaneous lipomatosis, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, hereditary sclerosing poikiloderma with tendon and pulmonary involvement, cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis, skin creases, congenital symmetric circumferential, 2, nevus comedonicus syndrome, severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome, chronic mucocutaneous candidiasis, segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome, hereditary mucosal leukokeratosis, inherited ichthyosis, hereditary photodermatosis, Cowden disease, juvenile hyaline fibromatosis, osteopathia striata-pigmentary dermopathy-white forelock syndrome, syndromic oculocutaneous albinism, phakomatosis pigmentokeratotica, neonatal inflammatory skin and bowel disease, lamellar ichthyosis, PENS syndrome, familial multiple fibrofolliculoma, autosomal recessive cutis laxa type 2A, familial chilblain lupus, familial keratoacanthoma, keratosis pilaris atrophicans, Cobb syndrome, oculocutaneous albinism, hereditary palmoplantar keratoderma, inherited epidermolysis bullosa, ectodermal dysplasia syndrome, subcutaneous panniculitis-like T-cell lymphoma, hereditary angioedema, hereditary lipodystrophy, X-linked chondrodysplasia punctata 2, multiple benign circumferential skin creases on limbs 1, lentigo, familial acne inversa, familial acanthosis nigricans, large congenital melanocytic nevus, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome, inflammatory poikiloderma with hair abnormalities and acral keratoses

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

17 retrieved; paginated sample, class counts are floors:

9 pathogenic, 3 uncertain significance, 3 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1470010	NM_000821.7(GGCX):c.469T>C (p.Trp157Arg)	GGCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16199	NM_000821.7(GGCX):c.896T>C (p.Phe299Ser)	GGCX	Pathogenic	no assertion criteria provided
16200	NM_000821.7(GGCX):c.1672G>A (p.Gly558Arg)	GGCX	Pathogenic	no assertion criteria provided
16201	NM_000821.7(GGCX):c.1478G>C (p.Trp493Ser)	GGCX	Pathogenic	no assertion criteria provided
16202	NM_000821.7(GGCX):c.1120C>T (p.Gln374Ter)	GGCX	Pathogenic	no assertion criteria provided
16203	G537Y	GGCX	Pathogenic	no assertion criteria provided
16204	NM_000821.7(GGCX):c.1426C>T (p.Arg476Cys)	GGCX	Pathogenic	no assertion criteria provided
16205	NM_000821.7(GGCX):c.1427G>A (p.Arg476His)	GGCX	Pathogenic	no assertion criteria provided
16206	NM_000821.7(GGCX):c.763G>A (p.Val255Met)	GGCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3023945	NM_000821.7(GGCX):c.938_939del (p.Pro313fs)	GGCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
995971	NM_000821.7(GGCX):c.1538G>A (p.Arg513Lys)	GGCX	Pathogenic	criteria provided, single submitter
995973	NM_000821.7(GGCX):c.1609G>T (p.Gly537Ter)	GGCX	Pathogenic	criteria provided, single submitter
3779694	NM_000821.7(GGCX):c.610C>T (p.Arg204Cys)	GGCX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
337260	NM_000821.7(GGCX):c.1906C>A (p.Pro636Thr)	GGCX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031664	NM_000821.7(GGCX):c.2084+5G>A	GGCX	Uncertain significance	criteria provided, multiple submitters, no conflicts
16196	NM_000821.7(GGCX):c.899C>T (p.Ser300Phe)	GGCX	Uncertain significance	criteria provided, single submitter
988875	NM_000821.7(GGCX):c.1217G>A (p.Arg406His)	GGCX	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GGCX	Definitive	Autosomal recessive	vitamin K-dependent clotting factors, combined deficiency of, type 1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GGCX	Orphanet:436274	Pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa
GGCX	Orphanet:91135	Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency
GGCX	Orphanet:98434	Hereditary combined deficiency of vitamin K-dependent clotting factors

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GGCX	HGNC:4247	ENSG00000115486	P38435	Vitamin K-dependent gamma-carboxylase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GGCX	Vitamin K-dependent gamma-carboxylase	Mediates the vitamin K-dependent carboxylation of glutamate residues to calcium-binding gamma-carboxyglutamate (Gla) residues with the concomitant epoxidation of vitamin K hydroquinone to vitamin K epoxide.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GGCX	Enzyme (other)	yes	4.1.1.90	VKG_COase, HTTM-like, RmlC_Cupin_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
liver	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GGCX	283	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GGCX	1,117

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GGCX	P38435	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective gamma-carboxylation of F9	1	5710.0×	4e-04	GGCX
Gamma-carboxylation of protein precursors	1	1142.0×	9e-04	GGCX

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of bone development	1	8426.0×	0.001	GGCX
negative regulation of testosterone biosynthetic process	1	4213.0×	0.001	GGCX
negative regulation of neurotransmitter secretion	1	2407.4×	0.001	GGCX
vitamin K metabolic process	1	2106.5×	0.001	GGCX
type B pancreatic cell proliferation	1	887.0×	0.002	GGCX
protein modification process	1	244.2×	0.007	GGCX
blood coagulation	1	173.7×	0.007	GGCX
cellular response to insulin stimulus	1	170.2×	0.007	GGCX
protein maturation	1	163.6×	0.007	GGCX
glucose homeostasis	1	130.6×	0.008	GGCX

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GGCX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GGCX	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GGCX	4.1.1.90	peptidyl-glutamate 4-carboxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	GGCX
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GGCX	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.