ADAMTSL4

Summary

ADAMTSL4 (ADAMTS like 4, HGNC:19706) is a protein-coding gene on chromosome 1q21.2, encoding ADAMTS-like protein 4 (Q6UY14). Positive regulation of apoptosis.

This gene is a member of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)-like gene family and encodes a protein with seven thrombospondin type 1 repeats. The thrombospondin type 1 repeat domain is found in many proteins with diverse biological functions including cellular adhesion, angiogenesis, and patterning of the developing nervous system. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 54507 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ectopia lentis 2, isolated, autosomal recessive (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 1,404 total — 126 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 16
• MANE Select transcript: NM_019032

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19706
Approved symbol	ADAMTSL4
Name	ADAMTS like 4
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP434K1772
Ensembl gene	ENSG00000143382
Ensembl biotype	protein_coding
OMIM	610113
Entrez	54507

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000271643, ENST00000369038, ENST00000369039, ENST00000369041, ENST00000483335, ENST00000489159, ENST00000674043, ENST00000674058, ENST00000886069, ENST00000886070, ENST00000886071, ENST00000886072, ENST00000886073, ENST00000886074, ENST00000886075

RefSeq mRNA: 5 — MANE Select: NM_019032 NM_001288607, NM_001288608, NM_001378596, NM_019032, NM_025008

CCDS: CCDS30852, CCDS72908, CCDS91048, CCDS955

Canonical transcript exons

ENST00000271643 — 19 exons

Exon	Start	End
ENSE00000959733	150556162	150556366
ENSE00000959735	150557945	150558149
ENSE00001044251	150557150	150557335
ENSE00001044255	150558473	150558649
ENSE00001044264	150557494	150557623
ENSE00001071939	150555429	150555565
ENSE00001071941	150556621	150556793
ENSE00001071942	150556939	150557050
ENSE00001366278	150552543	150552600
ENSE00001371076	150554365	150554467
ENSE00001378861	150549822	150549895
ENSE00001378961	150552898	150553253
ENSE00001381959	150553426	150554122
ENSE00001865625	150549408	150549499
ENSE00002696455	150552205	150552308
ENSE00003470232	150559287	150559466
ENSE00003550487	150558962	150559165
ENSE00003650252	150559761	150559905
ENSE00003910429	150560060	150560933

Expression profiles

Bgee: expression breadth ubiquitous, 216 present calls, max score 98.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.1763 / max 491.0417, expressed in 1346 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5127	13.9696	1213
5126	0.9691	421
5130	0.8035	285
201725	0.5155	223
201726	0.3429	122
5131	0.3386	144
5128	0.1845	107
5129	0.0528	27

Top tissues by expression

279 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	98.40	gold quality
mucosa of stomach	UBERON:0001199	97.94	gold quality
lower esophagus mucosa	UBERON:0035834	97.86	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.47	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.88	gold quality
lower esophagus	UBERON:0013473	95.85	gold quality
tibial nerve	UBERON:0001323	95.80	gold quality
left uterine tube	UBERON:0001303	95.54	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.34	gold quality
esophagus	UBERON:0001043	95.21	gold quality
esophagus mucosa	UBERON:0002469	94.94	gold quality
apex of heart	UBERON:0002098	94.90	gold quality
placenta	UBERON:0001987	94.80	gold quality
upper lobe of left lung	UBERON:0008952	94.77	gold quality
omental fat pad	UBERON:0010414	94.33	gold quality
peritoneum	UBERON:0002358	94.25	gold quality
endocervix	UBERON:0000458	94.02	gold quality
upper lobe of lung	UBERON:0008948	93.94	gold quality
descending thoracic aorta	UBERON:0002345	93.76	gold quality
body of uterus	UBERON:0009853	93.75	gold quality
left coronary artery	UBERON:0001626	93.63	gold quality
right atrium auricular region	UBERON:0006631	93.57	gold quality
right lung	UBERON:0002167	93.56	gold quality
granulocyte	CL:0000094	93.49	gold quality
ascending aorta	UBERON:0001496	93.34	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.34	gold quality
thoracic aorta	UBERON:0001515	93.26	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.20	gold quality
ectocervix	UBERON:0012249	92.93	gold quality
coronary artery	UBERON:0001621	92.80	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.98
E-GEOD-124858	no	28.99

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

24 targeting ADAMTSL4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-5581-5P	97.91	66.50	965
HSA-MIR-562	97.66	65.63	698
HSA-MIR-3184-3P	96.96	66.91	845
HSA-MIR-6854-5P	96.77	65.96	848
HSA-MIR-4264	96.35	64.76	1480
HSA-MIR-576-3P	96.14	65.63	773
HSA-MIR-3162-5P	95.67	67.53	794
HSA-MIR-6877-5P	93.84	61.41	74

Literature-anchored findings (GeneRIF, showing 17)

• Mutations in ADAMTSL4 are responsible for autosomal-recessive simple ectopia lentis and this proteins affectsthe development of the zonular fibers. (PMID:19200529)
• Herein we show a consanguineous family that carries a novel homozygous splice mutation IVS4-1G>A/IVS4-1G>A in ADAMTSL4 responsible for isolated autosomal recessive ectopia lentis. (PMID:20141359)
• This study confirms that homozygous mutations in ADAMTSL4 are associated with autosomal-recessive ectopia lentis in British families. (PMID:20564469)
• Ectopia lentis et pupillae is associated with a number of malformations primarily in the anterior segment of the eye. (PMID:20702823)
• The results emphasize the association of ADAMTSL4 null mutations with isolated ectopia lentis and the presence of a founder mutation in the European population. (PMID:21051722)
• Enhanced fibrillin-1 deposition in the presence of ADAMTSL4 and colocalization of ADAMTSL4 with fibrillin-1 in the ECM of cultured fibroblasts suggest a potential role for ADAMTSL4 in the formation or maintenance of the zonule. (PMID:21989719)
• Mutations in ADAMTSL4 appear to cause earlier manifestation of ectopia lentis and are associated with increased axial length. (PMID:22736615)
• This is the first detailed report of a possible genetic determinant of craniosynostosis with ectopia lentis. (PMID:22871183)
• Patients from a family with ectopia lentis et pupillae (ELP) in four generations have autosomal recessive ELP caused by novel mutations in ADAMTSL4. (PMID:23426735)
• We have confirmed the gene and protein expression of ADAMTSL4 in human ocular tissue. The pattern of expression may suggest further functions of this gene beyond those suggested by its causative role in isolated ectopia lentis. (PMID:23846871)
• Compound heterozygous c.1783dupT and c. 2594G>A mutations of ADAMTSL4 gene were causative mutations for this family with isolated non-syndromic ectopia lentis (PMID:24802351)
• ADAMTSL4 mutations are the main cause for isolated ectopia lentis with an early onset of symptoms and possible severe ocular complications. (PMID:25975359)
• study reports a novel founder mutation in ADAMTSL4 gene in children of Bukharian Jewish origin presenting with early-onset bilateral ectopia lentis (PMID:26653794)
• A recurrent pathogenic ADAMTSL4 variant is a major cause of early onset autosomal recessive ectopia lentis in a Cook Island Maori population and associated with a common haplotype, suggesting a founder effect. (PMID:28394649)
• Novel ADAMTSL4 gene mutations in Chinese patients with isolated ectopia lentis. (PMID:35042684)
• Biallelic ADAMTSL4 variants in a Chinese cohort of congenital ectopia lentis: Implications for genotype-phenotype relationships. (PMID:36208099)
• Mutations in ADAMTSL4 cause a unique form of autosomal-recessive congenital ectopia lentis. (PMID:39278391)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000063407
mus_musculus	Adamtsl4	ENSMUSG00000015850
rattus_norvegicus	Adamtsl4	ENSRNOG00000049385

Paralogs (25): ADAMTS6 (ENSG00000049192), ADAMTS2 (ENSG00000087116), PAPLN (ENSG00000100767), ADAMTS8 (ENSG00000134917), ADAMTS7 (ENSG00000136378), ADAMTS14 (ENSG00000138316), ADAMTS17 (ENSG00000140470), ADAMTS18 (ENSG00000140873), ADAMTS10 (ENSG00000142303), ADAMTS16 (ENSG00000145536), ADAMTS19 (ENSG00000145808), ADAMTS12 (ENSG00000151388), ADAMTS1 (ENSG00000154734), ADAMTS5 (ENSG00000154736), ADAMTS3 (ENSG00000156140), ADAMTSL3 (ENSG00000156218), ADAMTS4 (ENSG00000158859), ADAMTS13 (ENSG00000160323), ADAMTS9 (ENSG00000163638), ADAMTS15 (ENSG00000166106), ADAMTS20 (ENSG00000173157), ADAMTSL1 (ENSG00000178031), ADAMTSL5 (ENSG00000185761), THSD4 (ENSG00000187720), ADAMTSL2 (ENSG00000197859)

Protein

Protein identifiers

ADAMTS-like protein 4 — Q6UY14 (reviewed: Q6UY14)

Alternative names: Thrombospondin repeat-containing protein 1

All UniProt accessions (2): Q6UY14, A0A669KBE7

UniProt curated annotations — full annotation on UniProt →

Function. Positive regulation of apoptosis. May facilitate FBN1 microfibril biogenesis.

Subunit / interactions. Interacts with CTSB. Interacts with FBN1.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in colon, heart, leukocyte, liver, lung, skeletal muscle, spleen, testis and placenta. Weaker expression in bone marrow, brain tissue, kidney and pancreas. Expression studies in fetal tissues reveal strong expression in heart, kidney, liver, lung and skeletal muscle, but weaker expression in fetal brain and skin.

Post-translational modifications. N-glycosylated. Can be O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS family members. Can also be C-glycosylated with one or two mannose molecules on tryptophan residues within the consensus sequence W-X-X-W of the TPRs. N- and C-glycosylations can also facilitate secretion.

Disease relevance. Ectopia lentis 2, isolated, autosomal recessive (ECTOL2) [MIM:225100] An ocular abnormality characterized by partial or complete displacement of the lens from its space resulting from defective zonule formation. The disease is caused by variants affecting the gene represented in this entry. Ectopia lentis et pupillae (ECTOLP) [MIM:225200] An ocular abnormality characterized by displacement of the lenses and the pupils, associated with other ocular anomalies, but without systemic manifestations. The condition is usually bilateral, with the lenses and pupils displaced in opposite directions. Additional signs include enlarged corneal diameter, increased corneal astigmatism, increased anterior chamber depth, thinning and flattening of the iris with loss of crypts, angle malformation caused by enlarged iris processes, persistent pupillary membrane, loss of zonular fibers, tilted disk, and increased axial length. Secondary manifestations include refractive errors, glaucoma, early cataract development, and retinal detachment. Membrane formation on the posterior aspect of the iris has been observed both in histologic sections and on ultrasound biomicroscopy. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6UY14-1	1	yes
Q6UY14-2	2
Q6UY14-3	3

RefSeq proteins (5): NP_001275536, NP_001275537, NP_001365525, NP_061905, NP_079284 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR010294	ADAMTS_spacer1	Domain
IPR010909	PLAC	Domain
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR045371	ADAMTS_CR_3	Domain
IPR050439	ADAMTS_ADAMTS-like	Family

Pfam: PF00090, PF05986, PF08686, PF19030, PF19236

UniProt features (21 total): domain 7, compositionally biased region 4, splice variant 3, glycosylation site 2, sequence variant 2, signal peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UY14-F1	65.18	0.13

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (2): 490, 773

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-5083635	Defective B3GALTL causes PpS
R-HSA-5173214	O-glycosylation of TSR domain-containing proteins
R-HSA-1643685	Disease
R-HSA-3781865	Diseases of glycosylation
R-HSA-3906995	Diseases associated with O-glycosylation of proteins
R-HSA-392499	Metabolism of proteins
R-HSA-5173105	O-linked glycosylation
R-HSA-5668914	Diseases of metabolism
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 165 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, SP3_Q3, MAZ_Q6, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_UP, RICKMAN_METASTASIS_DN, GOZGIT_ESR1_TARGETS_UP, GRADE_COLON_AND_RECTAL_CANCER_DN, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, TGGAAA_NFAT_Q4_01, chr1q21, GOCC_ENDOPLASMIC_RETICULUM_LUMEN, GOCC_INTERSTITIAL_MATRIX, GOMF_PROTEASE_BINDING

GO Biological Process (5): epithelial cell development (GO:0002064), apoptotic process (GO:0006915), extracellular matrix organization (GO:0030198), positive regulation of apoptotic process (GO:0043065), pigment cell development (GO:0070285)

GO Molecular Function (3): protease binding (GO:0002020), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (4): interstitial matrix (GO:0005614), endoplasmic reticulum lumen (GO:0005788), extracellular matrix (GO:0031012), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Diseases associated with O-glycosylation of proteins	1
O-linked glycosylation	1
Diseases of metabolism	1
Diseases of glycosylation	1
Post-translational protein modification	1
Disease	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell development	2
epithelial cell differentiation	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
extracellular structure organization	1
external encapsulating structure organization	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
pigment cell differentiation	1
enzyme binding	1
protein binding	1
binding	1
extracellular matrix	1
endoplasmic reticulum	1
intracellular organelle lumen	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

926 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAMTSL4	FBN1	P35555	940
ADAMTSL4	LTBP1	P22064	568
ADAMTSL4	LTBP2	Q14767	545
ADAMTSL4	LTBP3	Q9NS15	513
ADAMTSL4	FBN2	P35556	496
ADAMTSL4	P3H2	Q8IVL5	478
ADAMTSL4	LOX	P28300	447
ADAMTSL4	COL16A1	Q07092	446
ADAMTSL4	CPAMD8	Q8IZJ3	439
ADAMTSL4	MCL1	Q07820	434
ADAMTSL4	FBN3	Q75N90	429
ADAMTSL4	ADAM11	O75078	417
ADAMTSL4	MFAP4	P55083	416
ADAMTSL4	TSR1	Q2NL82	412
ADAMTSL4	MFAP2	P55001	401

IntAct

48 interactions, top by confidence:

A	B	Type	Score
STK16	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.620
Hoxa1	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.570
ADAMTSL4	Hoxa1	psi-mi:“MI:0915”(physical association)	0.570
ADAMTSL4	CYP2S1	psi-mi:“MI:0915”(physical association)	0.550
CTSB	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.540
CTSB	ADAMTSL4	psi-mi:“MI:0403”(colocalization)	0.540
Lox	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.520
ADAMTSL4	COL8A1	psi-mi:“MI:0915”(physical association)	0.490
TUBGCP4	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.490
ADAMTSL4	AQP1	psi-mi:“MI:0915”(physical association)	0.490
SALL2	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.490
ADAMTSL4	EXOSC1	psi-mi:“MI:0915”(physical association)	0.370
ADAMTSL4	DBF4B	psi-mi:“MI:0915”(physical association)	0.370
ADAMTSL4	DISP1	psi-mi:“MI:0915”(physical association)	0.370
ADAMTSL4	TOP3B	psi-mi:“MI:0915”(physical association)	0.370
ADAMTSL4	TNK2	psi-mi:“MI:0915”(physical association)	0.370
ADAMTSL4	CFP	psi-mi:“MI:0915”(physical association)	0.370
ADAMTSL4	AMMECR1	psi-mi:“MI:0915”(physical association)	0.370
ADAMTSL4	MIIP	psi-mi:“MI:0915”(physical association)	0.370
LOX	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (257): ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid), ADAMTSL4 (Two-hybrid)

ESM2 similar proteins: A0JNA2, C0HL12, E1BBQ2, O02695, O14514, O19131, O60241, O75325, P0C5H6, P37889, P50555, P55107, P55108, P57110, P97737, P98095, Q05BQ1, Q08DX6, Q27977, Q29RN8, Q3UHD1, Q4FZU4, Q4V9Z5, Q505J3, Q53EL9, Q5R7Y0, Q5SZI1, Q5T848, Q60519, Q658N2, Q6AX42, Q6UXD5, Q6UY14, Q6WN34, Q7TSK2, Q7TSK7, Q80T21, Q80XH4, Q86TH1, Q8CGM1

Diamond homologs: A1KZ92, A2A8L5, A2AJ76, A2VEC9, A4IGL7, A7MBJ4, B3EWY9, B3EWZ3, B3EWZ8, C0HL12, C5IAW9, D3YXG0, D3ZTD8, F1LW30, F1NWE3, G5EBF1, G5ECS8, O08721, O08722, O08747, O14514, O15146, O15394, O55005, O60241, O60242, O95185, O95428, P07996, P10586, P11680, P11834, P13590, P22648, P27918, P32736, P35440, P35441, P35442, P35446

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1404 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	126
Likely pathogenic	27
Uncertain significance	519
Likely benign	585
Benign	60

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1032056	NM_019032.6(ADAMTSL4):c.963dup (p.Thr322fs)	Pathogenic
1177405	NM_019032.6(ADAMTSL4):c.1436del (p.Gly479fs)	Pathogenic
1209964	NM_019032.6(ADAMTSL4):c.2254C>T (p.Gln752Ter)	Pathogenic
1349	NM_019032.6(ADAMTSL4):c.1785T>G (p.Tyr595Ter)	Pathogenic
1381763	NM_019032.6(ADAMTSL4):c.2936G>A (p.Trp979Ter)	Pathogenic
1390256	NM_019032.6(ADAMTSL4):c.1486_1487dup (p.Pro497fs)	Pathogenic
1403007	NM_019032.6(ADAMTSL4):c.184del (p.Val62fs)	Pathogenic
1417781	NM_019032.6(ADAMTSL4):c.1855C>T (p.Gln619Ter)	Pathogenic
1431775	NM_019032.6(ADAMTSL4):c.877dup (p.Gln293fs)	Pathogenic
1457756	NM_019032.6(ADAMTSL4):c.2237G>A (p.Arg746His)	Pathogenic
1527845	NM_019032.6(ADAMTSL4):c.963_964insT (p.Thr322fs)	Pathogenic
1685502	NM_019032.6(ADAMTSL4):c.950G>A (p.Trp317Ter)	Pathogenic
1899102	NM_019032.6(ADAMTSL4):c.602del (p.Ala201fs)	Pathogenic
1899209	NM_019032.6(ADAMTSL4):c.445C>T (p.Arg149Ter)	Pathogenic
1910447	NM_019032.6(ADAMTSL4):c.477T>A (p.Tyr159Ter)	Pathogenic
1915899	NM_019032.6(ADAMTSL4):c.1159dup (p.Arg387fs)	Pathogenic
1919041	NM_019032.6(ADAMTSL4):c.745dup (p.Leu249fs)	Pathogenic
1921077	NM_019032.6(ADAMTSL4):c.287dup (p.Arg98fs)	Pathogenic
1931988	NM_019032.6(ADAMTSL4):c.2568del (p.Glu857fs)	Pathogenic
1932133	NM_019032.6(ADAMTSL4):c.406del (p.Glu136fs)	Pathogenic
1952046	NM_019032.6(ADAMTSL4):c.350del (p.Gln117fs)	Pathogenic
1958578	NM_019032.6(ADAMTSL4):c.1832del (p.Pro611fs)	Pathogenic
1958747	NM_019032.6(ADAMTSL4):c.1844del (p.Val615fs)	Pathogenic
1998418	NM_019032.6(ADAMTSL4):c.2644G>T (p.Glu882Ter)	Pathogenic
2000001	NM_019032.6(ADAMTSL4):c.318_319del (p.Pro108fs)	Pathogenic
2033481	NM_019032.6(ADAMTSL4):c.141G>A (p.Trp47Ter)	Pathogenic
2034435	NM_019032.6(ADAMTSL4):c.1933C>T (p.Gln645Ter)	Pathogenic
2044400	NM_019032.6(ADAMTSL4):c.2054G>A (p.Trp685Ter)	Pathogenic
2074973	NM_019032.6(ADAMTSL4):c.1537_1545delinsGCTAGGCCCAGCTAGGCCTAGCTAGGCCCAGCTAGGCCGGGGCTAG (p.Leu513_Ile515delinsAlaArgProSerTer)	Pathogenic
2077593	NM_019032.6(ADAMTSL4):c.2574_2575del (p.Cys858fs)	Pathogenic

SpliceAI

3079 predictions. Top by Δscore:

Variant	Effect	Δscore
1:150552203:A:AG	acceptor_gain	1.0000
1:150552204:G:GG	acceptor_gain	1.0000
1:150552204:GA:G	acceptor_gain	1.0000
1:150552204:GAGA:G	acceptor_gain	1.0000
1:150552533:T:TA	acceptor_gain	1.0000
1:150552534:G:A	acceptor_gain	1.0000
1:150552538:TGCA:T	acceptor_loss	1.0000
1:150552539:GCA:G	acceptor_loss	1.0000
1:150552541:A:AG	acceptor_gain	1.0000
1:150552541:AG:A	acceptor_gain	1.0000
1:150552542:G:GC	acceptor_gain	1.0000
1:150552542:GG:G	acceptor_gain	1.0000
1:150552542:GGCC:G	acceptor_gain	1.0000
1:150552542:GGCCC:G	acceptor_gain	1.0000
1:150552597:GGAG:G	donor_gain	1.0000
1:150552598:GAGG:G	donor_gain	1.0000
1:150554364:GCCCT:G	acceptor_gain	1.0000
1:150554467:GGTGA:G	donor_loss	1.0000
1:150554468:G:GC	donor_loss	1.0000
1:150554469:T:G	donor_loss	1.0000
1:150555427:A:AG	acceptor_gain	1.0000
1:150555428:G:GT	acceptor_gain	1.0000
1:150555572:G:T	donor_gain	1.0000
1:150556253:C:CA	acceptor_gain	1.0000
1:150556254:G:A	acceptor_gain	1.0000
1:150556365:GG:G	donor_gain	1.0000
1:150556365:GGGT:G	donor_loss	1.0000
1:150556366:GG:G	donor_gain	1.0000
1:150556366:GGT:G	donor_loss	1.0000
1:150556367:G:A	donor_loss	1.0000

AlphaMissense

6858 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:150554449:T:A	W406R	1.000
1:150554449:T:C	W406R	1.000
1:150554451:G:C	W406C	1.000
1:150554451:G:T	W406C	1.000
1:150557963:G:C	W732C	1.000
1:150557963:G:T	W732C	1.000
1:150558143:G:C	W792C	1.000
1:150558143:G:T	W792C	1.000
1:150558640:G:C	W850C	1.000
1:150558640:G:T	W850C	1.000
1:150554404:T:A	C391S	0.999
1:150554404:T:C	C391R	0.999
1:150554405:G:C	C391S	0.999
1:150554406:C:G	C391W	0.999
1:150554428:T:C	F399L	0.999
1:150554429:T:G	F399C	0.999
1:150554430:C:A	F399L	0.999
1:150554430:C:G	F399L	0.999
1:150554450:G:C	W406S	0.999
1:150555458:T:A	C422S	0.999
1:150555458:T:C	C422R	0.999
1:150555459:G:A	C422Y	0.999
1:150555459:G:C	C422S	0.999
1:150555460:C:G	C422W	0.999
1:150555479:T:C	F429L	0.999
1:150555480:T:G	F429C	0.999
1:150555481:C:A	F429L	0.999
1:150555481:C:G	F429L	0.999
1:150556664:G:C	W540C	0.999
1:150556664:G:T	W540C	0.999

dbSNP variants (sampled 300 via entrez): RS1000118867 (1:150551951 A>T), RS1000915642 (1:150556083 G>A), RS1001041115 (1:150550755 C>T), RS1001073707 (1:150550510 G>A), RS1001074053 (1:150550222 T>C), RS1001435183 (1:150554204 T>C,G), RS1001450254 (1:150556963 G>A,C), RS1001535362 (1:150551497 G>A,T), RS1001566564 (1:150551202 G>A,C,T), RS1001695935 (1:150551515 T>C), RS1002021828 (1:150561087 G>A), RS1002456090 (1:150560791 A>AG), RS1002539861 (1:150550019 A>G), RS1002569625 (1:150549647 G>A), RS1002582786 (1:150554298 A>G,T)

Disease associations

OMIM: gene MIM:610113 | disease phenotypes: MIM:225200, MIM:225100, MIM:603595, MIM:123100

GenCC curated gene-disease

Disease	Classification	Inheritance
ectopia lentis 2, isolated, autosomal recessive	Definitive	Autosomal recessive
ectopia lentis et pupillae	Strong	Autosomal recessive
isolated ectopia lentis	Supportive	Autosomal dominant

Mondo (6): ectopia lentis et pupillae (MONDO:0009153), ectopia lentis 2, isolated, autosomal recessive (MONDO:0009152), craniosynostosis with ectopia lentis (MONDO:0011347), breast ductal adenocarcinoma (MONDO:0005590), isolated ectopia lentis (MONDO:0015998), craniosynostosis (MONDO:0015469)

Orphanet (2): Isolated ectopia lentis (Orphanet:1885), Craniosynostosis (Orphanet:1531)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000272	Malar flattening
HP:0000303	Mandibular prognathia
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000541	Retinal detachment
HP:0000639	Nystagmus
HP:0000646	Amblyopia
HP:0000822	Hypertension
HP:0001083	Ectopia lentis
HP:0001387	Joint stiffness
HP:0009917	Persistent pupillary membrane
HP:0009918	Ectopia pupillae
HP:0011003	High myopia
HP:0012805	Iris transillumination defect
HP:0100543	Cognitive impairment

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001966_1	Rhegmatogenous retinal detachment	1.000000e-07
GCST003720_3	Migraine	1.000000e-08
GCST005196_187	Coronary artery disease	3.000000e-07
GCST010002_366	Refractive error	3.000000e-15
GCST010042_97	Asthma	2.000000e-09
GCST010696_11	Cortical thickness (min-P)	2.000000e-23
GCST010697_17	Cortical surface area (min-P)	9.000000e-09
GCST010698_23	Subcortical volume (min-P)	2.000000e-08
GCST010699_48	Brain morphology (min-P)	3.000000e-08
GCST010700_28	Cortical thickness (MOSTest)	8.000000e-38
GCST010701_113	Cortical surface area (MOSTest)	9.000000e-12
GCST010702_126	Subcortical volume (MOSTest)	4.000000e-09
GCST010703_244	Brain morphology (MOSTest)	9.000000e-12
GCST90000025_767	Appendicular lean mass	5.000000e-26

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004980	appendicular lean mass

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
C566357	Craniosynostosis with Ectopia Lentis (supp.)
C563268	Ectopia Lentis with Ectopia of Pupil (supp.)
C536184	Familial ectopia lentis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance	3
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	3
Cadmium Chloride	decreases expression, increases expression	3
Air Pollutants	decreases expression, affects expression, increases abundance	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
sulforaphane	decreases expression	1
aflatoxin B2	decreases methylation	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
abrine	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Allergens	decreases expression	1
Cadmium	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Diazinon	increases methylation	1
Estradiol	affects cotreatment, decreases expression	1
Nickel	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Oils	decreases expression	1
Quercetin	increases expression	1

Clinical trials (associated diseases)

28 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery
NCT00077831	Not specified	COMPLETED	Child and Infant Learning Project
NCT00106977	Not specified	COMPLETED	Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
NCT00367796	Not specified	COMPLETED	Genetic Analysis of Craniosynostosis, Philadelphia Type
NCT00769847	Not specified	WITHDRAWN	Endoscopic Treatment for Isolated, Single Suture Craniosynostosis
NCT00773643	Not specified	COMPLETED	Osteogenic Profiling of Tissue From Children With Craniosynostosis
NCT01898650	Not specified	COMPLETED	MRI for Non-invasive Evaluation of Brain Stress
NCT02287805	Not specified	COMPLETED	Qualitative and Quantitative Study Which Aims to Determine the Specifics of the Announcement for the Diagnosis of Patients With Craniosynostosis and Their Parents to Better Support Them in Their Care
NCT02561728	Not specified	WITHDRAWN	Hanger Helmet Study
NCT03025763	Not specified	ACTIVE_NOT_RECRUITING	Network Of Clinical Research Studies On Craniosynostosis, Skull Malformations With Premature Fusion Of Skull Bones
NCT03231085	Not specified	COMPLETED	Comparison of the Rate of Preoperative Haemoglobin After Administration of Epoetin Alpha Associated With an Oral Medical Supplementation Versus Intravenous Before Surgery of Craniosynostosis at the Child
NCT04704284	Not specified	COMPLETED	Comparing MRI to CT on Pediatric Craniosynostosis.
NCT05911139	Not specified	ENROLLING_BY_INVITATION	Influence of General Anesthesia on the Dynamic Changes in Brain Damage Markers During and After Craniosynostosis Operations in Infancy
NCT06928727	Not specified	RECRUITING	Ocular Characteristics in Patients With Craniosynostosis