Cerebellar ataxia-hypogonadism syndrome

Summary

Cerebellar ataxia-hypogonadism syndrome (MONDO:0008935) is a disease caused by RNF216 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: RNF216 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 34
• Phenotypes (HPO): 20
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000044	Hypogonadotropic hypogonadism	Very frequent (80-99%)
HP:0000135	Hypogonadism	Very frequent (80-99%)
HP:0000144	Decreased fertility	Very frequent (80-99%)
HP:0000512	Abnormal electroretinogram	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0000771	Gynecomastia	Very frequent (80-99%)
HP:0000864	Abnormality of the hypothalamus-pituitary axis	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0007703	Abnormality of retinal pigmentation	Very frequent (80-99%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0004374	Hemiplegia/hemiparesis	Frequent (30-79%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0000751	Personality changes	Occasional (5-29%)
HP:0002558	Supernumerary nipple	Occasional (5-29%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebellar ataxia-hypogonadism syndrome
Mondo ID	MONDO:0008935
MeSH	C565870
OMIM	212840
Orphanet	1173
DOID	DOID:0111587
UMLS	C1859305
MedGen	349137
GARD	0003314
Is cancer (heuristic)	no

Also known as: cerebellar ataxia - hypogonadism · GDHS · Gordon Holmes syndrome · Gordon-Holmes syndrome · luteinizing hormone releasing hormone, deficiency of with ataxia · luteinizing hormone-releasing hormone deficiency with ataxia

Data availability: 34 ClinVar variants · 6 GenCC gene-disease records · 4 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

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

Subtypes (1): cerebellar ataxia and hypergonadotropic hypogonadism

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

34 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 11 pathogenic, 3 conflicting classifications of pathogenicity, 2 likely pathogenic, 2 pathogenic/likely pathogenic, 1 not provided, 1 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1343797	NM_207111.4(RNF216):c.2149C>T (p.Arg717Cys)	RNF216	Pathogenic	criteria provided, single submitter
1804037	NM_207111.4(RNF216):c.991C>T (p.Gln331Ter)	RNF216	Pathogenic	criteria provided, single submitter
199654	NM_207111.4(RNF216):c.1367G>A (p.Gly456Glu)	RNF216	Pathogenic	no assertion criteria provided
199655	NM_207111.4(RNF216):c.904C>T (p.Gln302Ter)	RNF216	Pathogenic	no assertion criteria provided
2444427	NM_207111.4(RNF216):c.986G>A (p.Trp329Ter)	RNF216	Pathogenic	criteria provided, single submitter
3778778	NM_207111.4(RNF216):c.1224+2C>T	RNF216	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4532074	NM_207111.4(RNF216):c.1731_1732del (p.Glu578fs)	RNF216	Pathogenic	criteria provided, single submitter
50912	NM_207111.4(RNF216):c.2251C>T (p.Arg751Cys)	RNF216	Pathogenic	no assertion criteria provided
50913	NM_207111.4(RNF216):c.1791T>A (p.Cys597Ter)	RNF216	Pathogenic	no assertion criteria provided
50914	NM_207111.4(RNF216):c.615_616del (p.Glu205fs)	RNF216	Pathogenic	no assertion criteria provided
587594	NM_207111.4(RNF216):c.202-1G>C	RNF216	Pathogenic	criteria provided, single submitter
813323	GRCh37/hg19 7p22.1(chr7:5692044-5692141)	RNF216	Pathogenic	criteria provided, single submitter
841220	NM_207111.4(RNF216):c.687G>A (p.Trp229Ter)	RNF216	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027514	NM_207111.4(RNF216):c.2061+3A>G	RNF216	Likely pathogenic	criteria provided, single submitter
1027515	NM_207111.4(RNF216):c.1849A>G (p.Met617Val)	RNF216	Likely pathogenic	criteria provided, single submitter
372471	NM_001166114.2(PNPLA6):c.3518G>A (p.Arg1173Gln)	PNPLA6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1407791	NM_207111.4(RNF216):c.1717C>T (p.Arg573Cys)	RNF216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2154874	NM_207111.4(RNF216):c.83G>A (p.Arg28Gln)	RNF216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3068594	NM_001166114.2(PNPLA6):c.1655A>C (p.Gln552Pro)	PNPLA6	Uncertain significance	criteria provided, single submitter
1397588	NM_207111.4(RNF216):c.2374G>A (p.Asp792Asn)	RNF216	Uncertain significance	criteria provided, multiple submitters, no conflicts
1676236	NM_207111.4(RNF216):c.108C>G (p.Asp36Glu)	RNF216	Uncertain significance	criteria provided, single submitter
1676240	NM_207111.4(RNF216):c.1172G>C (p.Arg391Thr)	RNF216	Uncertain significance	criteria provided, single submitter
1696861	NM_207111.4(RNF216):c.2375A>C (p.Asp792Ala)	RNF216	Uncertain significance	no assertion criteria provided
1696862	NM_207111.4(RNF216):c.2044A>C (p.Asn682His)	RNF216	Uncertain significance	no assertion criteria provided
199656	NM_207111.4(RNF216):c.1616A>G (p.Tyr539Cys)	RNF216	Uncertain significance	criteria provided, single submitter
2435449	NM_207111.4(RNF216):c.54C>G (p.Cys18Trp)	RNF216	Uncertain significance	criteria provided, single submitter
2435450	NM_207111.4(RNF216):c.1del (p.Met1fs)	RNF216	Uncertain significance	criteria provided, single submitter
2435451	NM_207111.4(RNF216):c.1644G>C (p.Glu548Asp)	RNF216	Uncertain significance	criteria provided, single submitter
3341367	NM_207111.4(RNF216):c.1904C>T (p.Pro635Leu)	RNF216	Uncertain significance	criteria provided, single submitter
800990	NM_207111.4(RNF216):c.2663T>A (p.Val888Glu)	RNF216	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 6 · 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
RNF216	Strong	Autosomal recessive	cerebellar ataxia-hypogonadism syndrome	5

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
RNF216	Orphanet:1173	Cerebellar ataxia-hypogonadism syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PNPLA6	HGNC:16268	ENSG00000032444	Q8IY17	Patatin-like phospholipase domain-containing protein 6	gencc,clinvar
RNF216	HGNC:21698	ENSG00000011275	Q9NWF9	E3 ubiquitin-protein ligase RNF216	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).
RNF216	E3 ubiquitin-protein ligase RNF216	E3 ubiquitin ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their ubiquitination.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PNPLA6	Other/Unknown	no		cNMP-bd_dom, LysoPLipase_patatin_CS, PNPLA_dom
RNF216	Transcription factor	no		IBR_dom, Znf_RING/FYVE/PHD, TRIAD_supradom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
metanephros cortex	1
upper lobe of left lung	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	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
RNF216	278	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PNPLA6	2,676
RNF216	1,268

Intra-cohort edges

A	B	Sources
PNPLA6	RNF216	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RNF216	Q9NWF9	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PNPLA6	Q8IY17	69.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (2 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 2 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	815.7×	0.006	PNPLA6
Negative regulators of DDX58/IFIH1 signaling	1	163.1×	0.013	RNF216
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	126.9×	0.013	RNF216
Innate Immune System	1	12.8×	0.096	RNF216
Immune System	1	6.5×	0.148	RNF216

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of interferon-beta production	1	1685.2×	0.004	RNF216
regulation of defense response to virus by host	1	1053.2×	0.004	RNF216
glycerophospholipid catabolic process	1	526.6×	0.005	PNPLA6
phosphatidylcholine metabolic process	1	401.2×	0.005	PNPLA6
negative regulation of type I interferon production	1	247.8×	0.006	RNF216
protein K48-linked ubiquitination	1	84.3×	0.016	RNF216
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.043	RNF216
apoptotic process	1	14.3×	0.068	RNF216

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
RNF216	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: 2; 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	2	PNPLA6, RNF216

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PNPLA6	1	—
RNF216	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford