Dyslexia

Summary

Dyslexia (MONDO:0005489) is a disease with 23 cohort genes (126 GWAS associations across 9 studies) and 58 clinical trials. Top therapeutic interventions include atomoxetine and levodopa.

At a glance

• Cohort genes: 23
• GWAS associations: 126
• ClinVar variants: 2
• Clinical trials: 58

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dyslexia
Mondo ID	MONDO:0005489
EFO	EFO:0005424
MeSH	D004410
DOID	DOID:4428
ICD-11	1843588689
NCIT	C96410
UMLS	C0476254
MedGen	96906
Is cancer (heuristic)	no

Also known as: dyslexia · dyslexia (disease)

Data availability: 2 ClinVar variants · 126 GWAS associations (9 studies) · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › mental disorder › developmental disorder of mental health › specific developmental disorder › learning disability › reading disorder › dyslexia

Related subtypes (2): alexia, hyperlexia

Genetics & variants

GWAS landscape

126 GWAS associations across 9 studies. Top hits map to 37 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs13082684	1e-16	PPP2R3A	G	0.94
rs11393101	2e-16	ARFGEF2, CSE1L-DT	GA	0.94
rs34349354	8e-15	GGNBP2	CAG	0.95
rs9696811	1e-14	PTPA - IER5L	T	0.94
rs4911257	8e-14	DNMT3B	T	0.95
rs138127836	2e-13	PPP2R1B	ACT	0.95
rs12453682	3e-12	NEUROD2 - PPP1R1B	T	1.06
rs72916919	4e-12	RFTN2	T	0.95
rs12737449	1e-11	C1orf87	G	1.07
rs676217	1e-11	ARL14EP-DT	T	0.95
rs4696277	5e-11	FHIP1A	T	0.95
rs10786387	1e-10	CRTAC1 - R3HCC1L	G	0.95
rs7310615	1e-10	SH2B3	G	1.05
rs41012	1e-10	RPL7P20 - RPLP0P9	C	0.95
rs3839821	3e-10	COG5	CT	0.95
rs10511073	5e-10	CADM2	G	0.96
rs4845687	1e-09	KCNN3 - PMVK	G	0.96
rs373178590	1e-09		GT	0.96
rs13097431	1e-09	MITF	G	1.04
rs906549	1e-09	HNRNPA1P57 - LDHAP3	T	1.04
rs2091329	2e-09	CYB561D1	G	0.95
rs497418	3e-09	LINC01911 - RNU6-692P	C	0.96
rs2624839	3e-09	SEMA3F	T	0.96
rs5904158	3e-09	SLITRK2 - MIR892C	GTA	1.04
rs34732054	4e-09	PCGF6	CT	0.96
rs7625418	4e-09	RALBP1P1 - LINC02053	C	1.06
rs6435017	5e-09	SATB2	T	0.96
rs72841395	5e-09	TANC2	T	0.95
rs375018025	6e-09	CDK8 - WASF3	CA	1.04
rs35131341	6e-09	BCL11B	CG	1.04

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90244674	Doust C	2022	51,800	1,087,070	Discovery of 42 genome-wide significant loci associated with dyslexia.
GCST90244677	Doust C	2022	30,763	582,276	Discovery of 42 genome-wide significant loci associated with dyslexia.
GCST90244676	Doust C	2022	30,287	641,016	Discovery of 42 genome-wide significant loci associated with dyslexia.
GCST90244675	Doust C	2022	21,513	446,054	Discovery of 42 genome-wide significant loci associated with dyslexia.
GCST90244678	Doust C	2022	21,037	504,794	Discovery of 42 genome-wide significant loci associated with dyslexia.
GCST009897	Price KM	2020	4,494	0	Genome-Wide Association Study of Word Reading: Overlap with Risk Genes for Neurodevelopmental Disorders.
GCST002175	Eicher JD	2013	174	4,117	Genome-wide association study of shared components of reading disability and language impairment.
GCST004401	Gialluisi A	2014	0	0	Genome-wide screening for DNA variants associated with reading and language traits.
GCST004402	Gialluisi A	2014	0	0	Genome-wide screening for DNA variants associated with reading and language traits.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	4
Tier 3: regulatory	1
Tier 4: intronic/intergenic	44

MAF distribution

Bucket	Variants
common (>=0.05)	48
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	32
intergenic_variant	10
3_prime_UTR_variant	3
missense_variant	1
unknown	1
regulatory_region_variant	1
5_prime_UTR_variant	1
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs13082684	3	136064324	G>A,C	0.24	intron_variant	PPP2R3A	1e-16	Tier 4: intronic/intergenic
rs11393101	20	49035994		0.31	3_prime_UTR_variant	ARFGEF2, CSE1L-DT	2e-16	Tier 2: splice/UTR
rs34349354	17	36559205	C>CA,CAG	0.44	intron_variant	GGNBP2	8e-15	Tier 4: intronic/intergenic
rs9696811	9	129161251	T>A,C,G	0.31	intron_variant	PTPA - IER5L	1e-14	Tier 4: intronic/intergenic
rs4911257	20	32771768	T>A,C,G	0.39	intron_variant	DNMT3B	8e-14	Tier 4: intronic/intergenic
rs138127836	11	111763848	A>AACT,AAT	0.35	intron_variant	PPP2R1B	2e-13	Tier 4: intronic/intergenic
rs12453682	17	39613752	C>G,T	0.32	intergenic_variant	NEUROD2 - PPP1R1B	3e-12	Tier 4: intronic/intergenic
rs72916919	2	197627592	T>G	0.49	intron_variant	RFTN2	4e-12	Tier 4: intronic/intergenic
rs12737449	1	60040111	G>A,C	0.15	missense_variant	C1orf87	1e-11	Tier 1: coding
rs676217	11	30174210	G>C,T	0.37	intron_variant	ARL14EP-DT	1e-11	Tier 4: intronic/intergenic
rs4696277	4	151614119	T>C	0.49	intron_variant	FHIP1A	5e-11	Tier 4: intronic/intergenic
rs10786387	10	98101555	C>G,T	0.32	intergenic_variant	CRTAC1 - R3HCC1L	1e-10	Tier 4: intronic/intergenic
rs7310615	12	111427245	C>A,G,T	0.5	intron_variant	SH2B3	1e-10	Tier 4: intronic/intergenic
rs41012	5	166060584	C>A,G,T	0.25	intron_variant	RPL7P20 - RPLP0P9	1e-10	Tier 4: intronic/intergenic
rs3839821	7	107315159	CTTT>C,CT,CTT,CTTTT,CTTTTT	0.28	intron_variant	COG5	3e-10	Tier 4: intronic/intergenic
rs10511073	3	85604310	A>C,G,T	0.37	intron_variant	CADM2	5e-10	Tier 4: intronic/intergenic
rs4845687	1	154906435	A>G	0.44	intergenic_variant	KCNN3 - PMVK	1e-09	Tier 4: intronic/intergenic
rs373178590				0.49			1e-09	Tier 4: intronic/intergenic
rs13097431	3	69795512	G>C	0.42	intron_variant	MITF	1e-09	Tier 4: intronic/intergenic
rs906549	2	41426684	C>T	0.36	intron_variant	HNRNPA1P57 - LDHAP3	1e-09	Tier 4: intronic/intergenic
rs2091329	1	109499457	A>G	0.29	3_prime_UTR_variant	CYB561D1	2e-09	Tier 2: splice/UTR
rs497418	2	147085103	A>C,T	0.38	intergenic_variant	LINC01911 - RNU6-692P	3e-09	Tier 4: intronic/intergenic
rs2624839	3	50164798	T>C	0.42	intron_variant	SEMA3F	3e-09	Tier 4: intronic/intergenic
rs5904158	X	145950567	GTA>G,GTATA	0.35	intergenic_variant	SLITRK2 - MIR892C	3e-09	Tier 4: intronic/intergenic
rs34732054	10	103304141	CTTTT>C,CT,CTT,CTTT,CTTTTT,CTTTTTT,CTTTTTTT,CTTTTTTTTTT,CTTTTTTTTTTTTTT	0.43	intron_variant	PCGF6	4e-09	Tier 4: intronic/intergenic
rs7625418	3	180407962	A>C	0.21	intergenic_variant	RALBP1P1 - LINC02053	4e-09	Tier 4: intronic/intergenic
rs6435017	2	199426812	C>A,T	0.43	intron_variant	SATB2	5e-09	Tier 4: intronic/intergenic
rs72841395	17	63393685	C>T	0.23	intron_variant	TANC2	5e-09	Tier 4: intronic/intergenic
rs375018025	13	26524361		0.43	intergenic_variant	CDK8 - WASF3	6e-09	Tier 4: intronic/intergenic
rs35131341	14	99269525	C>CA,CG	0.39	intron_variant	BCL11B	6e-09	Tier 4: intronic/intergenic

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2570695	NM_001039469.3(MARK2):c.1931G>T (p.Arg644Leu)	MARK2	Uncertain significance	criteria provided, single submitter
2571623	NM_003112.5(SP4):c.90dup (p.Asn31Ter)	SP4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OPN1SW	Orphanet:88629	Tritanopia
CHST8	Orphanet:263548	Peeling skin syndrome type A
COX6A1	Orphanet:435998	Autosomal recessive intermediate Charcot-Marie-Tooth disease type D
AIPL1	Orphanet:1872	Cone rod dystrophy
AIPL1	Orphanet:65	Leber congenital amaurosis
FLNC	Orphanet:171445	Muscle filaminopathy
FLNC	Orphanet:63273	FLNC-related handgrip and calf weakness-distal myopathy
FLNC	Orphanet:75249	Familial isolated restrictive cardiomyopathy

Cohort genes → proteins

23 cohort genes, 22 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	21
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
OPN1SW	HGNC:1012	ENSG00000128617	P03999	Short-wave-sensitive opsin 1	gwas
SRSF9	HGNC:10791	ENSG00000111786	Q13242	Serine/arginine-rich splicing factor 9	gwas
SP4	HGNC:11209	ENSG00000105866	Q02446	Transcription factor Sp4	clinvar
STK24	HGNC:11403	ENSG00000102572	Q9Y6E0	Serine/threonine-protein kinase 24	gwas
HDAC9	HGNC:14065	ENSG00000048052	Q9UKV0	Histone deacetylase 9	gwas
CALU	HGNC:1458	ENSG00000128595	O43852	Calumenin	gwas
DYNLL1	HGNC:15476	ENSG00000088986	P63167	Dynein light chain 1, cytoplasmic	gwas
ZFP64	HGNC:15940	ENSG00000020256	Q9NTW7	Zinc finger protein 64	gwas
CHST8	HGNC:15993	ENSG00000124302	Q9H2A9	Carbohydrate sulfotransferase 8	gwas
ATP6V1F	HGNC:16832	ENSG00000128524	Q16864	V-type proton ATPase subunit F	gwas
UNC5D	HGNC:18634	ENSG00000156687	Q6UXZ4	Netrin receptor UNC5D	gwas
CCDC136	HGNC:22225	ENSG00000128596	Q96JN2	Coiled-coil domain-containing protein 136	gwas
COX6A1	HGNC:2277	ENSG00000111775	P12074	Cytochrome c oxidase subunit 6A1, mitochondrial	gwas
KIAA1958	HGNC:23427	ENSG00000165185	Q8N8K9	Uncharacterized protein KIAA1958	gwas
INIP	HGNC:24994	ENSG00000148153	Q9NRY2	SOSS complex subunit C	gwas
GATC	HGNC:25068	ENSG00000257218	O43716	Glutamyl-tRNA(Gln) amidotransferase subunit C, mitochondrial	gwas
TRIAP1	HGNC:26937	ENSG00000170855	O43715	TP53-regulated inhibitor of apoptosis 1	gwas
DUSP26	HGNC:28161	ENSG00000133878	Q9BV47	Dual specificity protein phosphatase 26	gwas
MARK2	HGNC:3332	ENSG00000072518	Q7KZI7	Serine/threonine-protein kinase MARK2	clinvar
AIPL1	HGNC:359	ENSG00000129221	Q9NZN9	Aryl-hydrocarbon-interacting protein-like 1	gwas
FLNC	HGNC:3756	ENSG00000128591	Q14315	Filamin-C	gwas
LINC01317	HGNC:50523			long intergenic non-protein coding RNA 1317	gwas
RBFOX2	HGNC:9906	ENSG00000100320	O43251	RNA binding protein fox-1 homolog 2	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OPN1SW	Short-wave-sensitive opsin 1	Visual pigments are the light-absorbing molecules that mediate vision.
SRSF9	Serine/arginine-rich splicing factor 9	Plays a role in constitutive splicing and can modulate the selection of alternative splice sites.
SP4	Transcription factor Sp4	Binds to GT and GC boxes promoters elements.
STK24	Serine/threonine-protein kinase 24	Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation.
HDAC9	Histone deacetylase 9	Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).
CALU	Calumenin	Involved in regulation of vitamin K-dependent carboxylation of multiple N-terminal glutamate residues.
DYNLL1	Dynein light chain 1, cytoplasmic	Component of dynein, a family of motor proteins essential for movement along microtubules.
ZFP64	Zinc finger protein 64	May be involved in the regulation of mesenchymal cell differentiation through transactivation of NOTCH1 target genes.
CHST8	Carbohydrate sulfotransferase 8	Catalyzes the transfer of sulfate to position 4 of non-reducing N-acetylgalactosamine (GalNAc) residues in both N-glycans and O-glycans.
ATP6V1F	V-type proton ATPase subunit F	Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
UNC5D	Netrin receptor UNC5D	Receptor for the netrin NTN4 that promotes neuronal cell survival.
CCDC136	Coiled-coil domain-containing protein 136	May play a role in acrosome formation in spermatogenesis and in fertilization.
COX6A1	Cytochrome c oxidase subunit 6A1, mitochondrial	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
INIP	SOSS complex subunit C	Component of the SOSS complex, a multiprotein complex that functions downstream of the MRN complex to promote DNA repair and G2/M checkpoint.
GATC	Glutamyl-tRNA(Gln) amidotransferase subunit C, mitochondrial	Allows the formation of correctly charged Gln-tRNA(Gln) through the transamidation of misacylated Glu-tRNA(Gln) in the mitochondria.
TRIAP1	TP53-regulated inhibitor of apoptosis 1	Involved in the modulation of the mitochondrial apoptotic pathway by ensuring the accumulation of cardiolipin (CL) in mitochondrial membranes.
DUSP26	Dual specificity protein phosphatase 26	Inactivates MAPK1 and MAPK3 which leads to dephosphorylation of heat shock factor protein 4 and a reduction in its DNA-binding activity.
MARK2	Serine/threonine-protein kinase MARK2	Serine/threonine-protein kinase.
AIPL1	Aryl-hydrocarbon-interacting protein-like 1	May be important in protein trafficking and/or protein folding and stabilization.
FLNC	Filamin-C	Muscle-specific filamin, which plays a central role in sarcomere assembly and organization.
RBFOX2	RNA binding protein fox-1 homolog 2	RNA-binding protein that regulates alternative splicing events by binding to 5’-UGCAUGU-3’ elements.

Protein-family classification

Druggable: 8 · Difficult: 2 · Unknown: 13 · Druggable fraction: 0.35

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
Phosphatase	1	3.6×	0.563
Antibody/Immunoglobulin	2	2.5×	0.563
Kinase	2	2.4×	0.563
Enzyme (other)	2	1.0×	0.730
GPCR	1	1.0×	0.730
Other/Unknown	13	1.0×	0.730
Transcription factor	2	0.7×	0.786

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OPN1SW	GPCR	yes		GPCR_Rhodpsn, Opsin_blue, Opsin
SRSF9	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, SRSF9_RRM1
SP4	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Sp4-like
STK24	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, Protein_kinase_ATP_BS
HDAC9	Enzyme (other)	yes	3.5.1.98	HDACs, Ureohydrolase_dom_sf, His_deacetylse_dom
CALU	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
DYNLL1	Other/Unknown	no		Dynein_light_chain_typ-1/2, Dynein_light_1/2_CS, DLC_sf
ZFP64	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, C2H2-ZF_domain-containing
CHST8	Other/Unknown	no		Sulfotransferase, Carb_sulfotrans_8-10
ATP6V1F	Other/Unknown	no		ATPase_V1-cplx_fsu_euk, ATPase_V1-cplx_f_g_su, ATPase_V1_fsu_sf
UNC5D	Antibody/Immunoglobulin	yes		Death_dom, TSP1_rpt, ZU5_dom
CCDC136	Other/Unknown	no		Cent_Immune-Sig_Mod
COX6A1	Other/Unknown	no		Cyt_c_oxidase_su6a, Cyt_c_oxidase_su6a_CS, Cyt_c_oxidase_su6a_sf
KIAA1958	Other/Unknown	no		ZMYM2-like_C, KIAA1958
INIP	Other/Unknown	no		SOSSC
GATC	Enzyme (other)	yes	6.3.5.7	GatC, Asp/Glu-ADT_sf_sub_c
TRIAP1	Other/Unknown	no		MDM35_apoptosis
DUSP26	Phosphatase	yes	3.1.3.16	Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, Tyr_Pase_AS
MARK2	Kinase	yes		Prot_kinase_dom, KA1_dom, Ser/Thr_kinase_AS
AIPL1	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, AIP/AIPL1/TTC9
FLNC	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
LINC01317	Other/Unknown	no
RBFOX2	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBFOX1-3

Expression context

Cohort genes with no expression data: 1.

20 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)	22
unknown	1

Top tissues across cohort

Tissue	Cohort genes
tendon of biceps brachii	4
secondary oocyte	3
prefrontal cortex	3
monocyte	2
germinal epithelium of ovary	2
gingival epithelium	2
male germ line stem cell (sensu Vertebrata) in testis	2
left testis	2
right testis	2
embryo	2
ganglionic eminence	2
kidney epithelium	2
hindlimb stylopod muscle	2
Brodmann (1909) area 46	1
sural nerve	1
vena cava	1
body of pancreas	1
endometrium epithelium	1
cerebellar vermis	1
superficial temporal artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OPN1SW	95	tissue_specific	yes	vena cava, sural nerve, Brodmann (1909) area 46
SRSF9	302	ubiquitous	marker	endometrium epithelium, monocyte, body of pancreas
SP4	265	ubiquitous	marker	cerebellar vermis, germinal epithelium of ovary, superficial temporal artery
STK24	295	ubiquitous	marker	secondary oocyte, esophagus squamous epithelium, amniotic fluid
HDAC9	277	ubiquitous	marker	oocyte, monocyte, secondary oocyte
CALU	303	ubiquitous	marker	stromal cell of endometrium, smooth muscle tissue, tendon of biceps brachii
DYNLL1	295	ubiquitous	marker	prefrontal cortex, frontal pole, gingival epithelium
ZFP64	288	ubiquitous	yes	germinal epithelium of ovary, gingival epithelium, secondary oocyte
CHST8	167	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, pituitary gland, adenohypophysis
ATP6V1F	294	ubiquitous	marker	prefrontal cortex, left testis, right testis
UNC5D	117	broad	marker	embryo, ganglionic eminence, endothelial cell
CCDC136	215	ubiquitous	marker	sperm, left testis, right testis
COX6A1	145	ubiquitous	marker	prefrontal cortex, primary visual cortex, frontal cortex
KIAA1958	200	ubiquitous	marker	kidney epithelium, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
INIP	256	ubiquitous	marker	ileal mucosa, kidney epithelium, pons
GATC	258	ubiquitous	marker	tendon of biceps brachii, medial globus pallidus, globus pallidus
TRIAP1	291	ubiquitous	marker	tendon of biceps brachii, tongue squamous epithelium, triceps brachii
DUSP26	218	broad	marker	hindlimb stylopod muscle, gluteal muscle, skeletal muscle tissue of rectus abdominis
MARK2	188	ubiquitous	marker	lower esophagus mucosa, granulocyte, esophagus mucosa
AIPL1	62	tissue_specific	marker	buccal mucosa cell, pancreatic ductal cell, tendon of biceps brachii
FLNC	255	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, tibialis anterior
LINC01317
RBFOX2	144	ubiquitous	marker	cortical plate, embryo, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYNLL1	4,541
FLNC	3,174
HDAC9	3,047
SRSF9	2,949
MARK2	2,461
RBFOX2	2,274
DUSP26	2,216
ATP6V1F	2,214
STK24	2,041
CALU	2,013

Intra-cohort edges

A	B	Sources
CALU	CHST8	intact
CCDC136	DYNLL1	intact
CCDC136	RBFOX2	string_interaction

Structural data

PDB: 14 · AlphaFold-only: 8 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STK24	Q9Y6E0	40
DYNLL1	P63167	21
FLNC	Q14315	14
ATP6V1F	Q16864	8
TRIAP1	O43715	6
AIPL1	Q9NZN9	6
MARK2	Q7KZI7	5
DUSP26	Q9BV47	4
COX6A1	P12074	3
INIP	Q9NRY2	3
HDAC9	Q9UKV0	2
ZFP64	Q9NTW7	2
OPN1SW	P03999	1
RBFOX2	O43251	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CHST8	Q9H2A9	79.90
CALU	O43852	79.82
GATC	O43716	78.61
UNC5D	Q6UXZ4	75.01
SRSF9	Q13242	69.97
CCDC136	Q96JN2	69.24
KIAA1958	Q8N8K9	60.57
SP4	Q02446	39.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 72. Enrichment computed across 23 evidence-associated genes (13 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 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective visual phototransduction due to OPN1SW loss of function	1	878.5×	0.082	OPN1SW
Activation of BIM and translocation to mitochondria	1	219.6×	0.136	DYNLL1
The retinoid cycle in cones (daylight vision)	1	125.5×	0.136	OPN1SW
Netrin mediated repulsion signals	1	97.6×	0.136	UNC5D
Opsins	1	97.6×	0.136	OPN1SW
Reactions specific to the complex N-glycan synthesis pathway	1	87.8×	0.136	CHST8
Cell-extracellular matrix interactions	1	51.7×	0.156	FLNC
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	51.7×	0.156	ATP6V1F
TP53 Regulates Transcription of Genes Involved in Cytochrome C Release	1	41.8×	0.156	TRIAP1
Apoptotic cleavage of cellular proteins	1	36.6×	0.156	STK24
Apoptotic execution phase	1	36.6×	0.156	STK24
FGFR2 alternative splicing	1	32.5×	0.156	RBFOX2
Notch-HLH transcription pathway	1	31.4×	0.156	HDAC9
Transport of Mature Transcript to Cytoplasm	1	29.3×	0.156	SRSF9
Insulin receptor recycling	1	29.3×	0.156	ATP6V1F
Transferrin endocytosis and recycling	1	28.3×	0.156	ATP6V1F
ROS and RNS production in phagocytes	1	25.8×	0.161	ATP6V1F
Aggrephagy	1	19.1×	0.166	DYNLL1
NOTCH1 Intracellular Domain Regulates Transcription	1	18.3×	0.166	HDAC9
Complex IV assembly	1	17.6×	0.166	COX6A1
RNA Polymerase II Transcription Termination	1	16.9×	0.166	SRSF9
COPI-independent Golgi-to-ER retrograde traffic	1	16.0×	0.166	DYNLL1
Intraflagellar transport	1	15.4×	0.166	DYNLL1
Amino acids regulate mTORC1	1	15.4×	0.166	ATP6V1F
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	15.2×	0.166	HDAC9
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	15.2×	0.166	HDAC9
mRNA 3’-end processing	1	15.2×	0.166	SRSF9
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	14.9×	0.166	DYNLL1
Cytoprotection by HMOX1	1	14.2×	0.166	COX6A1
Apoptosis	1	12.9×	0.166	STK24

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 20 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 striated muscle cell differentiation	1	842.6×	0.053	HDAC9
negative regulation of DNA strand resection involved in replication fork processing	1	421.3×	0.053	DYNLL1
protein farnesylation	1	280.9×	0.053	AIPL1
regulation of skeletal muscle fiber development	1	280.9×	0.053	HDAC9
glutaminyl-tRNAGln biosynthesis via transamidation	1	280.9×	0.053	GATC
regulation of neurofibrillary tangle assembly	1	280.9×	0.053	MARK2
establishment or maintenance of cell polarity regulating cell shape	1	210.7×	0.053	MARK2
regulation of translational fidelity	1	168.5×	0.053	GATC
pyramidal neuron differentiation	1	168.5×	0.053	UNC5D
absorption of visible light	1	140.4×	0.053	OPN1SW
RNA metabolic process	1	140.4×	0.053	RBFOX2
negative regulation of phosphorylation	1	140.4×	0.053	DYNLL1
regulation of membrane lipid distribution	1	140.4×	0.053	TRIAP1
regulation of axon regeneration	1	120.4×	0.053	STK24
positive regulation of phospholipid transport	1	120.4×	0.053	TRIAP1
regulation of alternative mRNA splicing, via spliceosome	2	24.4×	0.053	SRSF9, RBFOX2
protein autophosphorylation	2	14.5×	0.053	STK24, MARK2
apoptotic process	4	5.7×	0.053	DYNLL1, UNC5D, TRIAP1, AIPL1
mesenchymal cell differentiation	1	105.3×	0.058	ZFP64
regulation of opsin-mediated signaling pathway	1	84.3×	0.058	AIPL1
positive regulation of intracellular transport	1	84.3×	0.058	DYNLL1
mitochondrion localization	1	84.3×	0.058	MARK2
Golgi lumen acidification	1	84.3×	0.058	ATP6V1F
carbohydrate biosynthetic process	1	76.6×	0.058	CHST8
hormone biosynthetic process	1	70.2×	0.058	CHST8
cellular response to UV-A	1	70.2×	0.058	OPN1SW
phototransduction, visible light	1	64.8×	0.058	AIPL1
endosomal lumen acidification	1	60.2×	0.058	ATP6V1F
intracellular pH reduction	1	60.2×	0.058	ATP6V1F
intermembrane lipid transfer	1	60.2×	0.058	TRIAP1

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 19

Druggability breadth: 9 of 23 evidence-associated genes (39%) 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
STK24	NERATINIB
HDAC9	CELECOXIB
MARK2	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MARK2	45	4
HDAC9	28	4
STK24	18	4
DYNLL1	1	2
OPN1SW	0	0
SRSF9	0	0
SP4	0	0
CALU	0	0
ZFP64	0	0
CHST8	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NERATINIB	4	STK24
BOSUTINIB	4	STK24
GILTERITINIB	4	STK24
NINTEDANIB	4	MARK2, STK24
SUNITINIB	4	MARK2, STK24
QUIZARTINIB	4	STK24
CELECOXIB	4	HDAC9
PHENYLBUTANOIC ACID	4	HDAC9
SODIUM PHENYLBUTYRATE	4	HDAC9
ROMIDEPSIN	4	HDAC9
BELINOSTAT	4	HDAC9
PANOBINOSTAT	4	HDAC9
VORINOSTAT	4	HDAC9
GIVINOSTAT	4	HDAC9
MOMELOTINIB	4	MARK2
FEDRATINIB	4	MARK2
RUXOLITINIB	4	MARK2
BARICITINIB	4	MARK2
TOFACITINIB	4	MARK2
BRIGATINIB	4	MARK2
MIDOSTAURIN	4	MARK2
LOSMAPIMOD	3	STK24
CRENOLANIB	3	MARK2, STK24
DOVITINIB	3	MARK2, STK24
LESTAURTINIB	3	MARK2, STK24
CURCUMIN	3	HDAC9
CAFFEIC ACID	3	HDAC9
PRACINOSTAT	3	HDAC9
TACEDINALINE	3	HDAC9
ENTINOSTAT	3	HDAC9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
HDAC9	1,625	Binding:1612, ADMET:8, Functional:4, Toxicity:1
MARK2	356	Binding:355, Functional:1
STK24	314	Binding:314
DYNLL1	7	Binding:7
SRSF9	2	Binding:2
DUSP26	2	Binding:2
CALU	1	Binding:1
COX6A1	1	Binding:1
AIPL1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HDAC9	3.5.1.98	histone deacetylase
GATC	6.3.5.7	glutaminyl-tRNA synthase (glutamine-hydrolysing)
DUSP26	3.1.3.16	protein-serine/threonine phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
STK24	314
HDAC9	1,625
MARK2	356

Pharmacogenomics

Cohort genes with a PharmGKB record: 22; 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)
NERATINIB	4	STK24
BOSUTINIB	4	STK24
GILTERITINIB	4	STK24
NINTEDANIB	4	MARK2, STK24
SUNITINIB	4	MARK2, STK24
QUIZARTINIB	4	STK24
CELECOXIB	4	HDAC9
PHENYLBUTANOIC ACID	4	HDAC9
SODIUM PHENYLBUTYRATE	4	HDAC9
ROMIDEPSIN	4	HDAC9
BELINOSTAT	4	HDAC9
PANOBINOSTAT	4	HDAC9
VORINOSTAT	4	HDAC9
GIVINOSTAT	4	HDAC9
MOMELOTINIB	4	MARK2
FEDRATINIB	4	MARK2
RUXOLITINIB	4	MARK2
BARICITINIB	4	MARK2
TOFACITINIB	4	MARK2
BRIGATINIB	4	MARK2
MIDOSTAURIN	4	MARK2
LOSMAPIMOD	3	STK24
CRENOLANIB	3	MARK2, STK24
DOVITINIB	3	MARK2, STK24
LESTAURTINIB	3	MARK2, STK24
CURCUMIN	3	HDAC9
CAFFEIC ACID	3	HDAC9
PRACINOSTAT	3	HDAC9
TACEDINALINE	3	HDAC9
ENTINOSTAT	3	HDAC9

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	STK24, HDAC9, MARK2
B	Phased (≥1) drug, not yet approved	1	DYNLL1
C	Druggable family + PDB, no drug	3	OPN1SW, DUSP26, FLNC
D	Druggable family + AlphaFold only, no drug	2	UNC5D, GATC
E	Difficult family or no structure, no drug	14	SRSF9, SP4, CALU, ZFP64, CHST8, ATP6V1F, CCDC136, COX6A1, KIAA1958, INIP (+4 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
OPN1SW	0	—
SRSF9	2	—
SP4	0	—
CALU	1	—
ZFP64	0	—
CHST8	0	—
ATP6V1F	0	—
UNC5D	0	—
CCDC136	0	—
COX6A1	1	—
KIAA1958	0	—
INIP	0	—
GATC	0	—
TRIAP1	0	—
DUSP26	2	—
AIPL1	1	—
FLNC	0	—
LINC01317	0	—
RBFOX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 58.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	51
PHASE4	3
PHASE1/PHASE2	2
PHASE3	1
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00111371	PHASE4	UNKNOWN	Dopaminergic Enhancement of Learning and Memory in Healthy Adults and Patients With Dyslexia
NCT00607919	PHASE4	COMPLETED	Treatment of ADHD With Atomoxetine in Children & Adolescents With ADHD & Comorbid Dyslexia
NCT00716274	PHASE4	COMPLETED	Effects of Atomoxetine on Brain Activation During Attention & Reading Tasks in Participants With ADHD & Comorbid Dyslexia
NCT00065832	PHASE3	COMPLETED	Reading Problems in Children Living in Urban Areas
NCT00818428	PHASE2/PHASE3	UNKNOWN	Randomized Clinical Trial of Phonological Interventions
NCT00919906	PHASE1/PHASE2	COMPLETED	My Scrivener® - Measuring Effectiveness and Dose Response in Children
NCT01012778	PHASE1/PHASE2	COMPLETED	Implementation of Climb Up Program for Children With Attention Deficit Hyperactivity Disorder (ADHD) and Dyslexia in a School in India
NCT03285789	Not specified	ACTIVE_NOT_RECRUITING	Dyslexics’ Visual Attention Field
NCT05780853	Not specified	RECRUITING	A Game-based Neurodevelopmental Assessment for Young Children
NCT05996497	Not specified	RECRUITING	Evaluation of Speech Rhythm Training in Dyslexic Readers Aged 7 to 9 Years
NCT06479850	Not specified	NOT_YET_RECRUITING	A Strength-Based Intervention to Improve Job Interview Skills in Neurodiverse Young Adults
NCT06808555	Not specified	NOT_YET_RECRUITING	Pai.ACT: AI-Driven ACT Chatbot for Mental Health Triage and Service Evaluation
NCT06836115	Not specified	NOT_YET_RECRUITING	Reading and Stuttering
NCT06902610	Not specified	RECRUITING	Examining the Medium-term Effect on Non Inferiority of the Previous Training With the DMD Poppins Clinical for Cognitive, Musical Training in Addition to Bi-monthly Speech and Reading Therapy on Reading Writing Abilities of Pediatric Patients With SLD Reading VS Control Group
NCT07262853	Not specified	RECRUITING	Dual Executive Function Training Package
NCT07459803	Not specified	NOT_YET_RECRUITING	Investigating Individual Differences in Speech Motor Skills in Neurotypical Speakers and Persons With Disordered Speech
NCT07546292	Not specified	RECRUITING	Enhancing Letter-Speech Sound Learning and Reading Network Activation With Transcranial Electrical Stimulation
NCT00061412	Not specified	COMPLETED	Comprehensive Program to Improve Reading and Writing Skills in At-Risk and Dyslexic Children
NCT00245804	Not specified	COMPLETED	Developmental Dyslexia and Functional Maturation of Auditory Cortex
NCT01860027	Not specified	TERMINATED	Eye Movements and Reading Disabilities
NCT01930500	Not specified	COMPLETED	The Effectiveness of Neuropsychological Rehabilitation in Young Dyslexic Adults
NCT02107534	Not specified	UNKNOWN	Group-based Training for Parents of Children With Dyslexia
NCT02345876	Not specified	COMPLETED	Maturation of Auditory Processing in Children With Dyslexia Compared to Average-reading Children
NCT02429739	Not specified	COMPLETED	Working Memory Training for Children With Dyslexia
NCT02622360	Not specified	UNKNOWN	Speech and Short-term Memory Functions in Dyslexia: a Combined MEG and EEG Study
NCT02872870	Not specified	COMPLETED	Developmental Language Difficulties: Behavioural and Electrophysiological Studies
NCT02879786	Not specified	COMPLETED	Study of Hierarchy of Afferents in Postural Control of Children With Dyslexia
NCT03261076	Not specified	UNKNOWN	Reading Remediation and Outcomes in Detention
NCT03364010	Not specified	TERMINATED	Dyslexia, Motor Control and Proprioception
NCT03695068	Not specified	UNKNOWN	Efficacy of a Two-Year Intensive Reading Intervention for Middle School English Learners With Reading Difficulties
NCT03786185	Not specified	UNKNOWN	Neuroplasticity of Multisensory Cortical Areas Induced by Musical Training: a Translational Approach (MusicPlast)
NCT03906097	Not specified	COMPLETED	The Effects of Play and Competition-Based Cognitive Therapy
NCT04157829	Not specified	COMPLETED	Evaluation of the Performance and Safety of a Medical Device Developed to Improve the Reading of Dyslexic Patients
NCT04235465	Not specified	COMPLETED	Dynamic Gait Index in Children With Dyslexia
NCT04244578	Not specified	COMPLETED	Transcranial Direct Current Stimulation in the Treatment of Dyslexia.
NCT04277351	Not specified	COMPLETED	Role of Auditory Cortical Oscillations in Speech Processing and Dyslexia
NCT04384952	Not specified	COMPLETED	Effectiveness of a Parent-administered Reading Therapy Program During Summer Break for Dyslexic Children
NCT04386161	Not specified	COMPLETED	Static and Dynamic Balance in Children With Dyslexia
NCT04586621	Not specified	COMPLETED	Evaluation of the Performance and Safety of the Atoldys/ Lexilens Glasses Developed to Improve the Reading of Dyslexic Subjects
NCT04642859	Not specified	COMPLETED	Training Second-grade Dyslexic Students Using a Computerized Program in Assiut, Egypt

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ATOMOXETINE	4	6
LEVODOPA	4	1
CHEMBL351042	0	1