Ataxia-hypogonadism-choroidal dystrophy syndrome

Summary

Ataxia-hypogonadism-choroidal dystrophy syndrome (MONDO:0008980) is a disease with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 1
• ClinVar variants: 47
• Phenotypes (HPO): 3

Clinical features

Signs & symptoms

Clinical features (HPO)

3 HPO clinical features (Orphanet curated; top 3 by frequency):

HPO ID	Term	Frequency
HP:0000044	Hypogonadotropic hypogonadism	Very frequent (80-99%)
HP:0001135	Chorioretinal dystrophy	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ataxia-hypogonadism-choroidal dystrophy syndrome
Mondo ID	MONDO:0008980
MeSH	C565850
OMIM	215470
Orphanet	1180
DOID	DOID:0111265
SNOMED CT	715984007
UMLS	C1859093
MedGen	347798
GARD	0000944
Is cancer (heuristic)	no

Also known as: ataxia - hypogonadism - choroidal dystrophy · BNHS · Boucher-Neuhauser syndrome · Boucher-Neuhchäuser syndrome · Boucher-Neuhäuser syndrome · chorioretinal dystrophy, spinocerebellar ataxia and hypogonadotropic hypogonadism · spinocerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy

Data availability: 47 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › hypogonadotropic hypogonadism › congenital hypogonadotropic hypogonadism › ataxia-hypogonadism-choroidal dystrophy syndrome

Related subtypes (24): brachytelephalangy-dysmorphism-Kallmann syndrome, hypogonadotropic hypogonadism 7 with or without anosmia, Prader-Willi syndrome, familial adrenal hypoplasia with absent pituitary luteinizing hormone, cerebellar ataxia-hypogonadism syndrome, CHARGE syndrome, Woodhouse-Sakati syndrome, Laurence-Moon syndrome, X-linked adrenal hypoplasia congenita, obesity due to prohormone convertase I deficiency, arhinia, choanal atresia, and microphthalmia, ANE syndrome, combined pituitary hormone deficiencies, genetic form, obesity due to congenital leptin deficiency, obesity due to leptin receptor gene deficiency, polyendocrine-polyneuropathy syndrome, hypogonadotropic hypogonadism-frontoparietal alopecia syndrome, hypogonadotropic hypogonadism-retinitis pigmentosa syndrome, Kallmann syndrome-heart disease syndrome, isolated congenital hypogonadotropic hypogonadism, Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, Prader-Willi-like syndrome, Martsolf syndrome 1

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

47 retrieved; paginated sample, class counts are floors:

13 benign, 10 pathogenic, 7 uncertain significance, 6 conflicting classifications of pathogenicity, 5 likely pathogenic, 4 pathogenic/likely pathogenic, 1 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
430849	NM_006702.4(PNPLA6):c.[3242G>T];[3390G>C]		Pathogenic	no assertion criteria provided
101039	NM_001166114.2(PNPLA6):c.3143C>T (p.Thr1048Ile)	PNPLA6	Pathogenic	criteria provided, single submitter
101040	NM_001166114.2(PNPLA6):c.2185-1G>C	PNPLA6	Pathogenic	no assertion criteria provided
101041	NM_001166114.2(PNPLA6):c.3298G>A (p.Val1100Met)	PNPLA6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
101042	NM_001166114.2(PNPLA6):c.3167T>C (p.Phe1056Ser)	PNPLA6	Pathogenic	no assertion criteria provided
1027474	NM_001166114.2(PNPLA6):c.4051C>T (p.Arg1351Ter)	PNPLA6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1195875	NM_001166114.2(PNPLA6):c.3104C>T (p.Ser1035Leu)	PNPLA6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143933	NM_001166114.2(PNPLA6):c.1705G>T (p.Gly569Trp)	PNPLA6	Pathogenic	no assertion criteria provided
156538	NM_001166114.2(PNPLA6):c.1243dup (p.Asp415fs)	PNPLA6	Pathogenic	no assertion criteria provided
183693	NM_001166114.2(PNPLA6):c.3266G>A (p.Arg1089Gln)	PNPLA6	Pathogenic	criteria provided, multiple submitters, no conflicts
374055	NM_001166114.2(PNPLA6):c.4045C>T (p.Arg1349Trp)	PNPLA6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6605	NM_001166114.2(PNPLA6):c.3148A>G (p.Met1050Val)	PNPLA6	Pathogenic	no assertion criteria provided
6607	NM_001166114.2(PNPLA6):c.3058_3061dup (p.Arg1021fs)	PNPLA6	Pathogenic	criteria provided, multiple submitters, no conflicts
872466	NM_001166114.2(PNPLA6):c.316-2A>T	PNPLA6	Pathogenic	criteria provided, multiple submitters, no conflicts
1027449	NM_001166114.2(PNPLA6):c.2237A>C (p.Gln746Pro)	PNPLA6	Likely pathogenic	criteria provided, single submitter
1027450	NM_001166114.2(PNPLA6):c.3358C>T (p.His1120Tyr)	PNPLA6	Likely pathogenic	criteria provided, single submitter
1027451	NM_001166114.2(PNPLA6):c.2993A>G (p.Asp998Gly)	PNPLA6	Likely pathogenic	criteria provided, single submitter
156539	NM_001166114.2(PNPLA6):c.3409C>T (p.Arg1137Cys)	PNPLA6	Likely pathogenic	criteria provided, single submitter
4531194	NM_001166114.2(PNPLA6):c.1914G>A (p.Trp638Ter)	PNPLA6	Likely pathogenic	criteria provided, single submitter
1027473	NM_001166114.2(PNPLA6):c.3335C>T (p.Pro1112Leu)	PNPLA6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
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
409994	NM_001166114.2(PNPLA6):c.4003C>T (p.Pro1335Ser)	PNPLA6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807470	NM_001166114.2(PNPLA6):c.1853C>T (p.Ala618Val)	PNPLA6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1333223	NM_001166114.2(PNPLA6):c.833C>G (p.Ala278Gly)	PNPLA6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333230	NM_001166114.2(PNPLA6):c.3832A>G (p.Ser1278Gly)	PNPLA6	Uncertain significance	criteria provided, single submitter
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
330515	NM_001166114.2(PNPLA6):c.452G>A (p.Arg151Gln)	PNPLA6	Uncertain significance	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	Definitive	Autosomal recessive	retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism 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.