Trichomegaly-retina pigmentary degeneration-dwarfism syndrome

Summary

Trichomegaly-retina pigmentary degeneration-dwarfism syndrome (MONDO:0010152) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 31
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000546	Retinal degeneration	Very frequent (80-99%)
HP:0000135	Hypogonadism	Frequent (30-79%)
HP:0000527	Long eyelashes	Frequent (30-79%)
HP:0000580	Pigmentary retinopathy	Frequent (30-79%)
HP:0000821	Hypothyroidism	Frequent (30-79%)
HP:0000824	Decreased response to growth hormone stimulation test	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001518	Small for gestational age	Frequent (30-79%)
HP:0001596	Alopecia	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0003265	Neonatal hyperbilirubinemia	Frequent (30-79%)
HP:0008070	Sparse hair	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000054	Micropenis	Occasional (5-29%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	trichomegaly-retina pigmentary degeneration-dwarfism syndrome
Mondo ID	MONDO:0010152
MeSH	C536554
OMIM	275400
Orphanet	3363
DOID	DOID:0111271
SNOMED CT	719944006
UMLS	C1848745
MedGen	338532
GARD	0005266
Is cancer (heuristic)	no

Also known as: eyelashes, long with intellectual disability · eyelashes, long, with mental retardation · long eyelashes-intellectual disability syndrome · Oliver McFarlane syndrome · Oliver-McFarlane syndrome · OMCS · trichomegaly with intellectual disability, dwarfism and pigmentary degeneration of retina · trichomegaly with mental retardation, dwarfism, and pigmentary Degeneration of retina

Data availability: 31 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › ectodermal dysplasia syndrome › trichomegaly-retina pigmentary degeneration-dwarfism syndrome

Related subtypes (119): ADULT syndrome, autosomal dominant palmoplantar keratoderma and congenital alopecia, ameloonychohypohidrotic syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, anonychia with flexural pigmentation, Böök syndrome, blepharocheilodontic syndrome, Stern-Lubinsky-Durrie syndrome, dermatopathia pigmentosa reticularis, dermo-odonto dysplasia, Rapp-Hodgkin syndrome, Clouston syndrome, ectodermal dysplasia, trichoodontoonychial type, gingival fibromatosis-hypertrichosis syndrome, hypertrichosis cubiti-short stature syndrome, Johnson neuroectodermal syndrome, Marshall syndrome, Naegeli-Franceschetti-Jadassohn syndrome, oculodentodigital dysplasia, Cronkhite-Canada syndrome, scalp-ear-nipple syndrome, tooth and nail syndrome, tricho-dento-osseous syndrome, tricho-retino-dento-digital syndrome, acrofacial dysostosis, Weyers type, Ackerman syndrome, alopecia - contractures - dwarfism - intellectual disability syndrome, AREDYLD syndrome, Barber-Say syndrome, oculoosteocutaneous syndrome, cataract-hypertrichosis-intellectual disability syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, cerebellar ataxia-ectodermal dysplasia syndrome, cranioectodermal dysplasia, conductive deafness-ptosis-skeletal anomalies syndrome, dermatoosteolysis, Kirghizian type, Dubowitz syndrome, ectodermal dysplasia-sensorineural deafness syndrome, ectodermal dysplasia-intellectual disability-central nervous system malformation syndrome, hypohidrotic ectodermal dysplasia-hypothyroidism-ciliary dyskinesia syndrome, cleft lip/palate-ectodermal dysplasia syndrome, EEM syndrome, Ellis-van Creveld syndrome, amelocerebrohypohidrotic syndrome, GAPO syndrome, ichthyosis-alopecia-eclabion-ectropion-intellectual disability syndrome, Leukomelanoderma-infantilism-intellectual disability-hypodontia-hypotrichosis syndrome, Dahlberg-Borer-Newcomer syndrome, cartilage-hair hypoplasia, oculotrichodysplasia, pilodental dysplasia-refractive errors syndrome, Bartsocas-Papas syndrome 1, ectodermal dysplasia-blindness syndrome, Schinzel-Giedion syndrome, Teebi-Shaltout syndrome, taurodontia-absent teeth-sparse hair syndrome, odontotrichomelic syndrome, trichoodontoonychial dysplasia, CHIME syndrome, anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome, Ito hypomelanosis, contractures-ectodermal dysplasia-cleft lip/palate syndrome, incontinentia pigmenti, Toriello-Lacassie-Droste syndrome, odontomicronychial dysplasia, ectodermal dysplasia with natal teeth, Turnpenny type, hidrotic ectodermal dysplasia, Christianson-Fourie type, trichodental syndrome, congenital hypotrichosis with juvenile macular dystrophy, tricho-oculo-dermo-vertebral syndrome, odonto-tricho-ungual-digito-palmar syndrome, Fried’s tooth and nail syndrome, limb-mammary syndrome, epidermolysis bullosa simplex due to plakophilin deficiency, arrhythmogenic cardiomyopathy with wooly hair and keratoderma, Curly hair - acral keratoderma - caries syndrome, hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome, Lelis syndrome, Fontaine progeroid syndrome, ectodermal dysplasia-syndactyly syndrome, ectodermal dysplasia 5, hair/nail type, nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome, ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, cardiofaciocutaneous syndrome, choroidal atrophy-alopecia syndrome, dyskeratosis congenita, hidrotic ectodermal dysplasia, Halal type, hypertrichosis lanuginosa congenita, hypohidrotic ectodermal dysplasia, odonto-onycho dysplasia-alopecia syndrome, pili torti-onychodysplasia syndrome, chondroectodermal dysplasia with night blindness, trichorhinophalangeal syndrome, trichothiodystrophy, trichodermodysplasia-dental alterations syndrome, autosomal dominant trichoodontoonychodysplasia-syndactyly, focal facial dermal dysplasia, KID syndrome, pure hair and nail ectodermal dysplasia, circumscribed palmoplantar hypokeratosis, trichodysplasia-amelogenesis imperfecta syndrome, dermotrichic syndrome, alves Castelo dos Santos syndrome, Brunoni syndrome, ectodermal dysplasia Bartalos type, ectodermal dysplasia margarita type, ectodermal dysplasia alopecia preaxial polydactyly, ectodermal dysplasia arthrogryposis diabetes mellitus, ectodermal dysplasia blindness, ectodermal dysplasia neurosensory deafness, ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, ectodermal dysplasia 15, hypohidrotic/hair type, linear hypopigmentation and craniofacial asymmetry with acral, ocular and brain anomalies, jones hersh yusk syndrome, ectodermal dysplasia 13, hair/tooth type, arthrogryposis-ectodermal dysplasia-other anomalies syndrome, ectodermal dysplasia WNT10A related, CTSC-related disorder, ectodermal dysplasia 17 with or without limb malformations

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

31 retrieved; paginated sample, class counts are floors:

13 benign, 5 uncertain significance, 4 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 2 pathogenic, 1 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
101041	NM_001166114.2(PNPLA6):c.3298G>A (p.Val1100Met)	PNPLA6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027474	NM_001166114.2(PNPLA6):c.4051C>T (p.Arg1351Ter)	PNPLA6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183693	NM_001166114.2(PNPLA6):c.3266G>A (p.Arg1089Gln)	PNPLA6	Pathogenic	criteria provided, multiple submitters, no conflicts
6607	NM_001166114.2(PNPLA6):c.3058_3061dup (p.Arg1021fs)	PNPLA6	Pathogenic	criteria provided, multiple submitters, no conflicts
183692	NM_001166114.2(PNPLA6):c.3496G>A (p.Gly1166Ser)	PNPLA6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531194	NM_001166114.2(PNPLA6):c.1914G>A (p.Trp638Ter)	PNPLA6	Likely pathogenic	criteria provided, single submitter
846399	NM_001166114.2(PNPLA6):c.3614T>C (p.Val1205Ala)	PNPLA6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073450	NM_001166114.2(PNPLA6):c.4046G>A (p.Arg1349Gln)	PNPLA6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372471	NM_001166114.2(PNPLA6):c.3518G>A (p.Arg1173Gln)	PNPLA6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
409993	NM_001166114.2(PNPLA6):c.3355G>A (p.Gly1119Arg)	PNPLA6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
586350	NM_001166114.2(PNPLA6):c.1228G>A (p.Val410Ile)	PNPLA6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1679717	NM_001166114.2(PNPLA6):c.29C>G (p.Thr10Arg)	PNPLA6	Uncertain significance	criteria provided, single submitter
240694	NM_001166114.2(PNPLA6):c.3095G>C (p.Ser1032Thr)	PNPLA6	Uncertain significance	criteria provided, multiple submitters, no conflicts
547855	NM_001166114.2(PNPLA6):c.1492G>A (p.Ala498Thr)	PNPLA6	Uncertain significance	criteria provided, multiple submitters, no conflicts
567501	NM_001166114.2(PNPLA6):c.1430C>T (p.Ser477Leu)	PNPLA6	Uncertain significance	criteria provided, multiple submitters, no conflicts
936254	NM_001166114.2(PNPLA6):c.555G>T (p.Arg185=)	PNPLA6	Uncertain significance	criteria provided, single submitter
1221245	NM_001166114.2(PNPLA6):c.2634+38G>C	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts
1221947	NM_001166114.2(PNPLA6):c.2634+39T>C	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts
1234311	NM_001166114.2(PNPLA6):c.2465+41C>G	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts
1258779	NM_001166114.2(PNPLA6):c.3699+41C>T	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts
1265729	NM_001166114.2(PNPLA6):c.3398-36G>A	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts
1268471	NM_001166114.2(PNPLA6):c.3280+38C>T	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts
1295442	NM_001166114.2(PNPLA6):c.2260+24G>A	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts
240703	NM_001166114.2(PNPLA6):c.181G>C (p.Val61Leu)	PNPLA6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
330520	NM_001166114.2(PNPLA6):c.1253-6C>T	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts
330522	NM_001166114.2(PNPLA6):c.1362+8T>C	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts
380864	NM_001166114.2(PNPLA6):c.2635-19A>C	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts
380865	NM_001166114.2(PNPLA6):c.2818-19A>G	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts
429198	NM_001166114.2(PNPLA6):c.3913+23del	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts
667948	NM_001166114.2(PNPLA6):c.3699+42G>A	PNPLA6	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 5 · 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
PNPLA6	Supportive	Autosomal recessive	trichomegaly-retina pigmentary degeneration-dwarfism syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PNPLA6	Orphanet:1173	Cerebellar ataxia-hypogonadism syndrome
PNPLA6	Orphanet:1180	Ataxia-hypogonadism-choroidal dystrophy syndrome
PNPLA6	Orphanet:139480	Autosomal recessive spastic paraplegia type 39
PNPLA6	Orphanet:2377	Laurence-Moon syndrome
PNPLA6	Orphanet:3363	Trichomegaly-retina pigmentary degeneration-dwarfism syndrome

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
PNPLA6	HGNC:16268	ENSG00000032444	Q8IY17	Patatin-like phospholipase domain-containing protein 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PNPLA6	Patatin-like phospholipase domain-containing protein 6	Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PNPLA6	Other/Unknown	no		cNMP-bd_dom, LysoPLipase_patatin_CS, PNPLA_dom

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
granulocyte	1
metanephros cortex	1
upper lobe of left lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PNPLA6	276	ubiquitous	marker	granulocyte, metanephros cortex, upper lobe of left lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PNPLA6	2,676

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PNPLA6	Q8IY17	69.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Glycerophospholipid catabolism	1	1631.4×	6e-04	PNPLA6

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
glycerophospholipid catabolic process	1	1053.2×	0.001	PNPLA6
phosphatidylcholine metabolic process	1	802.5×	0.001	PNPLA6

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
PNPLA6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PNPLA6	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PNPLA6

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)
PNPLA6	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.