Aland island eye disease

Summary

Aland island eye disease (MONDO:0010371) is a disease caused by CACNA1F (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CACNA1F (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 29
• Phenotypes (HPO): 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0000483	Astigmatism	Very frequent (80-99%)
HP:0000512	Abnormal electroretinogram	Very frequent (80-99%)
HP:0000545	Myopia	Very frequent (80-99%)
HP:0000551	Color vision defect	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0007663	Reduced visual acuity	Very frequent (80-99%)
HP:0007750	Hypoplasia of the fovea	Very frequent (80-99%)
HP:0007894	Hypopigmentation of the fundus	Very frequent (80-99%)
HP:0030513	Difficulty adjusting from light to dark	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Aland island eye disease
Mondo ID	MONDO:0010371
MeSH	C562664
OMIM	300600
Orphanet	178333
DOID	DOID:0050630
SNOMED CT	266455006
UMLS	C0268505
MedGen	120643
GARD	0010574
Is cancer (heuristic)	no

Also known as: AIED · Aland island eye disease · Forsius Eriksson type ocular albinism · Forsius-Eriksson syndrome · FORSIUS-Eriksson type ocular albinism · Forsius-Eriksson type ocular albinism

Data availability: 29 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › Aland island eye disease

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

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

29 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 6 pathogenic, 4 benign/likely benign, 4 likely pathogenic, 3 conflicting classifications of pathogenicity, 2 benign, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031513	NM_001256789.3(CACNA1F):c.4260+2del	CACNA1F	Pathogenic	criteria provided, multiple submitters, no conflicts
11621	NM_001256789.3(CACNA1F):c.3598-133_3709-76del	CACNA1F	Pathogenic	no assertion criteria provided
195237	NM_001256789.3(CACNA1F):c.244C>T (p.Arg82Ter)	CACNA1F	Pathogenic	criteria provided, multiple submitters, no conflicts
265464	NM_001256789.3(CACNA1F):c.1840C>T (p.Arg614Ter)	CACNA1F	Pathogenic	criteria provided, multiple submitters, no conflicts
285396	NM_001256789.3(CACNA1F):c.2543+1G>A	CACNA1F	Pathogenic	criteria provided, multiple submitters, no conflicts
425497	NM_001256789.3(CACNA1F):c.3236+1G>A	CACNA1F	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4721480	NM_001256789.3(CACNA1F):c.1438del (p.Ala480fs)	CACNA1F	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172621	NM_000292.3(PHKA2):c.3295_3296dup (p.Ile1100fs)	PHKA2	Pathogenic	criteria provided, single submitter
1333936	NM_001256789.3(CACNA1F):c.4190_4191del (p.Glu1397fs)	CACNA1F	Likely pathogenic	criteria provided, single submitter
2582767	NM_001256789.3(CACNA1F):c.3708+2T>C	CACNA1F	Likely pathogenic	no assertion criteria provided
2671737	NM_001256789.3(CACNA1F):c.4186_4187insCCCTA (p.Gly1396fs)	CACNA1F	Likely pathogenic	criteria provided, single submitter
3897718	NM_001256789.3(CACNA1F):c.1019_1025del	CACNA1F	Likely pathogenic	criteria provided, single submitter
636004	NM_145200.5(CABP4):c.773A>T (p.Asn258Ile)	CABP4	Conflicting classifications of pathogenicity	no assertion criteria provided
1347248	NM_001256789.3(CACNA1F):c.5504G>A (p.Arg1835Gln)	CACNA1F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
988786	NM_001256789.3(CACNA1F):c.245G>A (p.Arg82Gln)	CACNA1F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1509434	NM_001256789.3(CACNA1F):c.4862G>C (p.Arg1621Pro)	CACNA1F	Uncertain significance	criteria provided, multiple submitters, no conflicts
3370342	NM_001256789.3(CACNA1F):c.2969G>A (p.Gly990Glu)	CACNA1F	Uncertain significance	criteria provided, single submitter
3775414	NM_001256789.3(CACNA1F):c.3313TTC[1] (p.Phe1106del)	CACNA1F	Uncertain significance	criteria provided, single submitter
587564	NM_001256789.3(CACNA1F):c.1108G>A (p.Val370Ile)	CACNA1F	Uncertain significance	criteria provided, multiple submitters, no conflicts
636157	NM_001256789.3(CACNA1F):c.4363T>C (p.Trp1455Arg)	CACNA1F	Uncertain significance	no assertion criteria provided
812250	NM_001256789.3(CACNA1F):c.1276+34G>A	CACNA1F	Uncertain significance	criteria provided, multiple submitters, no conflicts
598318	NM_015404.4(WHRN):c.1850C>T (p.Ser617Leu)	WHRN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1192562	NM_001256789.3(CACNA1F):c.3037-30G>A	CACNA1F	Benign	criteria provided, single submitter
1192563	NM_001256789.3(CACNA1F):c.2928+5C>T	CACNA1F	Benign	criteria provided, single submitter
1192564	NM_001256789.3(CACNA1F):c.2334+123G>C	CACNA1F	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
166778	NM_001256789.3(CACNA1F):c.2673+3G>A	CACNA1F	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
208890	NM_001256789.3(CACNA1F):c.1535G>A (p.Arg512His)	CACNA1F	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
283388	NM_001256789.3(CACNA1F):c.2204A>C (p.Asn735Thr)	CACNA1F	Likely benign	criteria provided, multiple submitters, no conflicts
445846	NM_001256789.3(CACNA1F):c.3439-18C>T	CACNA1F	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 8 · 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
CACNA1F	Definitive	X-linked	Aland island eye disease	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA1F	Orphanet:178333	Åland Islands eye disease
CACNA1F	Orphanet:1872	Cone rod dystrophy
CACNA1F	Orphanet:714070	Incomplete congenital stationary night blindness, Schubert-Bornschein type
CABP4	Orphanet:714070	Incomplete congenital stationary night blindness, Schubert-Bornschein type
CABP4	Orphanet:98784	Sleep-related hypermotor epilepsy
WHRN	Orphanet:231178	Usher syndrome type 2
WHRN	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
PHKA2	Orphanet:264580	Glycogen storage disease due to liver phosphorylase kinase deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CACNA1F	HGNC:1393	ENSG00000102001	O60840	Voltage-dependent L-type calcium channel subunit alpha-1F	gencc,clinvar
CABP4	HGNC:1386	ENSG00000175544	P57796	Calcium-binding protein 4	clinvar
WHRN	HGNC:16361	ENSG00000095397	Q9P202	Whirlin	clinvar
PHKA2	HGNC:8926	ENSG00000044446	P46019	Phosphorylase b kinase regulatory subunit alpha, liver isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CACNA1F	Voltage-dependent L-type calcium channel subunit alpha-1F	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
CABP4	Calcium-binding protein 4	Involved in normal synaptic function through regulation of Ca(2+) influx and neurotransmitter release in photoreceptor synaptic terminals and in auditory transmission.
WHRN	Whirlin	Involved in hearing and vision as member of the USH2 complex.
PHKA2	Phosphorylase b kinase regulatory subunit alpha, liver isoform	Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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
Ion channel	1	27.9×	0.142
Scaffold/PPI	1	4.3×	0.392
Enzyme (other)	1	3.0×	0.392
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1F	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, Ion_trans_dom
CABP4	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
WHRN	Scaffold/PPI	no		PDZ, Whirlin_HN-like_dom2, PDZ_sf
PHKA2	Enzyme (other)	yes	2.7.11.19	PHK_A/B_su, 6-hairpin_glycosidase_sf, GH15-like

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
parotid gland	1
right hemisphere of cerebellum	1
cardia of stomach	1
vena cava	1
ventral tegmental area	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
apex of heart	1
right lobe of liver	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNA1F	143	tissue_specific	marker	parotid gland, granulocyte, right hemisphere of cerebellum
CABP4	226	broad	marker	vena cava, cardia of stomach, ventral tegmental area
WHRN	226	ubiquitous	marker	right adrenal gland cortex, left adrenal gland, right adrenal gland
PHKA2	266	ubiquitous	marker	right lobe of liver, right uterine tube, apex of heart

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WHRN	2,499
CABP4	1,897
CACNA1F	1,616
PHKA2	1,070

Intra-cohort edges

A	B	Sources
CABP4	CACNA1F	biogrid_interaction, string_interaction

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WHRN	Q9P202	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PHKA2	P46019	81.36
CACNA1F	O60840	67.46
CABP4	P57796	65.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 4 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
Glycogen metabolism	1	951.7×	0.006	PHKA2
Glycogen breakdown (glycogenolysis)	1	380.7×	0.008	PHKA2
Sensory processing of sound by outer hair cells of the cochlea	1	102.0×	0.018	WHRN
Sensory processing of sound by inner hair cells of the cochlea	1	81.6×	0.018	WHRN
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.020	PHKA2
Metabolism	1	5.8×	0.165	PHKA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cerebellar Purkinje cell layer formation	1	2106.5×	0.005	WHRN
paranodal junction maintenance	1	2106.5×	0.005	WHRN
inner ear receptor cell differentiation	1	842.6×	0.005	WHRN
negative regulation of voltage-gated calcium channel activity	1	842.6×	0.005	CACNA1F
photoreceptor cell morphogenesis	1	702.2×	0.005	CABP4
retinal bipolar neuron differentiation	1	702.2×	0.005	CABP4
visual perception	2	39.8×	0.005	CACNA1F, CABP4
sensory perception of light stimulus	1	468.1×	0.007	WHRN
retinal cone cell development	1	351.1×	0.008	CABP4
retina homeostasis	1	280.9×	0.009	WHRN
detection of mechanical stimulus involved in sensory perception of sound	1	234.1×	0.009	WHRN
auditory receptor cell stereocilium organization	1	210.7×	0.009	WHRN
inner ear receptor cell stereocilium organization	1	210.7×	0.009	WHRN
detection of light stimulus involved in visual perception	1	162.0×	0.011	CACNA1F
calcium ion import across plasma membrane	1	135.9×	0.012	CACNA1F
glycogen metabolic process	1	131.7×	0.012	PHKA2
phototransduction	1	123.9×	0.012	CABP4
establishment of protein localization	1	108.0×	0.013	WHRN
generation of precursor metabolites and energy	1	86.0×	0.015	PHKA2
protein modification process	1	61.1×	0.020	PHKA2
establishment of localization in cell	1	40.1×	0.029	WHRN
carbohydrate metabolic process	1	34.0×	0.033	PHKA2
sensory perception of sound	1	25.2×	0.042	WHRN
positive regulation of gene expression	1	9.7×	0.103	WHRN
signal transduction	1	4.0×	0.227	CABP4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CACNA1F	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1F	48	4
CABP4	0	0
WHRN	0	0
PHKA2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1F
IMIPRAMINE	4	CACNA1F
HALOFANTRINE	4	CACNA1F
DROPERIDOL	4	CACNA1F
SAQUINAVIR	4	CACNA1F
DULOXETINE	4	CACNA1F
DIAZEPAM	4	CACNA1F
SERTINDOLE	4	CACNA1F
QUINIDINE	4	CACNA1F
LAMIVUDINE	4	CACNA1F
PIMOZIDE	4	CACNA1F
PHENYTOIN	4	CACNA1F
TERFENADINE	4	CACNA1F
CISAPRIDE	4	CACNA1F
SOLIFENACIN	4	CACNA1F
NIFEDIPINE	4	CACNA1F
DILTIAZEM	4	CACNA1F
NILOTINIB	4	CACNA1F
ASTEMIZOLE	4	CACNA1F
TERODILINE	4	CACNA1F
CLOZAPINE	4	CACNA1F
MIBEFRADIL	4	CACNA1F
DOFETILIDE	4	CACNA1F
THIORIDAZINE	4	CACNA1F
PAROXETINE	4	CACNA1F
DONEPEZIL	4	CACNA1F
IBUTILIDE	4	CACNA1F
SUNITINIB	4	CACNA1F
HALOPERIDOL	4	CACNA1F
DASATINIB	4	CACNA1F

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CACNA1F	221	Binding:135, Functional:79, Toxicity:5, ADMET:2
PHKA2	48	Binding:48

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PHKA2	2.7.11.19	phosphorylase kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CACNA1F	221

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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.

Compound	Max phase	Cohort target (bioactivity)
BEPRIDIL	4	CACNA1F
IMIPRAMINE	4	CACNA1F
HALOFANTRINE	4	CACNA1F
DROPERIDOL	4	CACNA1F
SAQUINAVIR	4	CACNA1F
DULOXETINE	4	CACNA1F
DIAZEPAM	4	CACNA1F
SERTINDOLE	4	CACNA1F
QUINIDINE	4	CACNA1F
LAMIVUDINE	4	CACNA1F
PIMOZIDE	4	CACNA1F
PHENYTOIN	4	CACNA1F
TERFENADINE	4	CACNA1F
CISAPRIDE	4	CACNA1F
SOLIFENACIN	4	CACNA1F
NIFEDIPINE	4	CACNA1F
DILTIAZEM	4	CACNA1F
NILOTINIB	4	CACNA1F
ASTEMIZOLE	4	CACNA1F
TERODILINE	4	CACNA1F
CLOZAPINE	4	CACNA1F
MIBEFRADIL	4	CACNA1F
DOFETILIDE	4	CACNA1F
THIORIDAZINE	4	CACNA1F
PAROXETINE	4	CACNA1F
DONEPEZIL	4	CACNA1F
IBUTILIDE	4	CACNA1F
SUNITINIB	4	CACNA1F
HALOPERIDOL	4	CACNA1F
DASATINIB	4	CACNA1F

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1F
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PHKA2
E	Difficult family or no structure, no drug	2	CABP4, WHRN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CABP4	0	CACNA1F
WHRN	0	—
PHKA2	48	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.