ACD

Summary

ACD (ACD shelterin complex subunit and telomerase recruitment factor, HGNC:25070) is a protein-coding gene on chromosome 16q22.1, encoding Adrenocortical dysplasia protein homolog (Q96AP0). Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. It is a selective cancer dependency (DepMap: 25.9% of cell lines).

This gene encodes a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin telomeric complex, which functions to maintain telomere length and to protect telomere ends. Through its interaction with other components, this protein plays a key role in the assembly and stabilization of this complex, and it mediates the access of telomerase to the telomere. Multiple transcript variants encoding different isoforms have been found for this gene. This gene, which is also referred to as TPP1, is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I.

Source: NCBI Gene 65057 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuronal ceroid lipofuscinosis (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 2,687 total — 108 pathogenic, 87 likely-pathogenic
• Phenotypes (HPO): 90
• Cancer dependency (DepMap): dependent in 25.9% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001082486

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25070
Approved symbol	ACD
Name	ACD shelterin complex subunit and telomerase recruitment factor
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	Ptop, Pip1, Tpp1, Tint1
Ensembl gene	ENSG00000102977
Ensembl biotype	protein_coding
OMIM	609377
Entrez	65057

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 22 retained_intron, 19 protein_coding, 9 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000219251, ENST00000602320, ENST00000602382, ENST00000602423, ENST00000602519, ENST00000602622, ENST00000602656, ENST00000602780, ENST00000602850, ENST00000602860, ENST00000602945, ENST00000620761, ENST00000695641, ENST00000695648, ENST00000695649, ENST00000695650, ENST00000695656, ENST00000695657, ENST00000695658, ENST00000695659, ENST00000695660, ENST00000695661, ENST00000695662, ENST00000695663, ENST00000695694, ENST00000695695, ENST00000695696, ENST00000695697, ENST00000695698, ENST00000695699, ENST00000695700, ENST00000695701, ENST00000695702, ENST00000695709, ENST00000695710, ENST00000695711, ENST00000695712, ENST00000695713, ENST00000695731, ENST00000695732, ENST00000695733, ENST00000695734, ENST00000695735, ENST00000695736, ENST00000896207, ENST00000896208, ENST00000938871, ENST00000938872, ENST00000957224, ENST00000957225, ENST00000957226

RefSeq mRNA: 3 — MANE Select: NM_001082486 NM_001082486, NM_001410884, NM_022914

CCDS: CCDS10842, CCDS42181, CCDS92179

Canonical transcript exons

ENST00000620761 — 12 exons

Exon	Start	End
ENSE00000844202	67659903	67660045
ENSE00001943429	67660122	67660260
ENSE00003502012	67658928	67659079
ENSE00003507372	67658720	67658816
ENSE00003527690	67659537	67659613
ENSE00003562308	67659229	67659263
ENSE00003611675	67659702	67659795
ENSE00003629179	67658555	67658641
ENSE00003676212	67659375	67659419
ENSE00003964859	67657986	67658362
ENSE00003964864	67657762	67657853
ENSE00003964866	67657512	67657684

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 94.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.8242 / max 80.1037, expressed in 1775 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157807	10.5687	1744
157808	2.4240	1357
157806	0.2947	149
157810	0.2744	99
157809	0.1955	57
157805	0.0669	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	94.87	gold quality
cerebellar hemisphere	UBERON:0002245	94.24	gold quality
cerebellar cortex	UBERON:0002129	94.15	gold quality
oocyte	CL:0000023	93.79	gold quality
cerebellum	UBERON:0002037	93.67	gold quality
secondary oocyte	CL:0000655	92.04	gold quality
pituitary gland	UBERON:0000007	91.44	gold quality
adenohypophysis	UBERON:0002196	91.39	gold quality
left ovary	UBERON:0002119	91.05	gold quality
right frontal lobe	UBERON:0002810	90.90	gold quality
right ovary	UBERON:0002118	90.72	gold quality
right testis	UBERON:0004534	90.66	gold quality
granulocyte	CL:0000094	90.58	gold quality
left testis	UBERON:0004533	90.55	gold quality
right uterine tube	UBERON:0001302	89.94	gold quality
body of uterus	UBERON:0009853	89.83	gold quality
endocervix	UBERON:0000458	89.54	gold quality
paraflocculus	UBERON:0005351	89.50	gold quality
cervix squamous epithelium	UBERON:0006922	89.27	silver quality
testis	UBERON:0000473	89.05	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.01	gold quality
cortical plate	UBERON:0005343	88.98	gold quality
lower esophagus	UBERON:0013473	88.98	gold quality
thymus	UBERON:0002370	88.95	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.80	gold quality
ovary	UBERON:0000992	88.74	gold quality
cingulate cortex	UBERON:0003027	88.57	gold quality
anterior cingulate cortex	UBERON:0009835	88.50	gold quality
ganglionic eminence	UBERON:0004023	88.38	gold quality
left uterine tube	UBERON:0001303	88.29	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.68
E-CURD-10	no	45.97

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 25.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• a paper that firstly reported cloning of human TTP1 (PTOP) and its biological function at telomere. TPP1 interacts with both POT1 and TIN2, heterodimerizes with POT1 and regulates POT1 telomeric recruitment and telomere length. (PMID:15181449)
• TINT1 localized to telomeres via TIN2, where it functions as a negative regulator of telomerase-mediated telomere elongation. (PMID:15380063)
• Sequencing of ACD in 15 patients with clinical features of IMAGe syndrome, adrenal hypoplasia congenita, or congenital adrenal insufficiency revealed no coding mutations, but three novel SNPs were identified (PMID:16504561)
• coordinated interactions among TPP1, TIN2, TRF1, and TRF2 may ensure robust assembly of the telosome, telomere targeting of its subunits, and, ultimately, regulated telomere maintenance (PMID:16880378)
• findings highlight the critical role of TPP1 in telomere maintenance, and support a yin-yang model in which TPP1 and POT1 function as a unit to protect human telomeres, by both positively and negatively regulating telomerase access to telomere DNA (PMID:17237767)
• crystal structure of human TPP1 reveals an oligonucleotide/oligosaccharide-binding fold that is structurally similar to the beta-subunit of the telomere end-binding protein of a ciliated protozoan; TPP1 is the missing beta-subunit of human POT1 (PMID:17237768)
• REVIEW:TPP1 as a critical mediator of control of telomerase activity (PMID:17373762)
• No mutations were identified in ACD in this collection of patients with ACTH resistance phenotypes. However, the newly identified SNPs in ACD should be more closely examined for possible links to disease. (PMID:17466001)
• Tpp1 is required for the protective function of Pot1 proteins. (PMID:17632522)
• Increased expression of TPP1 correlates with resistance to radiation in human laryngeal cancer cell lines. (PMID:19424630)
• Studies indicate that TPP1 and POT1can form heterodimers that bind to the telomeric single-stranded DNA, an activity that is central for telomere end capping. (PMID:19648609)
• POT1-TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation. (PMID:20094033)
• TIN2-anchored TPP1 plays a major role in the recruitment of telomerase to telomeres in human cells. (PMID:20404094)
• Mouse gene deletion experiments revealed DNA-damage-response pathways that threaten chromosome ends and how the components of the telomeric shelterin complex prevent activation of these pathways.[Shelterin] (PMID:21209389)
• The presence of dysfunctional telomeres in chronic lymphocytic leukemia did not correlate with telomere shortening or chromatin marks deregulation but with a down-regulation of 2 shelterin genes: ACD and TINF2. (PMID:21355086)
• Human telomere POT1-TPP1 complex and its role in telomerase activity regulation. (PMID:21461822)
• Multiple POT1-TPP1 proteins coat and compact long telomeric single-stranded DNA. (PMID:21596049)
• Human UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication. (PMID:21829167)
• Altered expression of TPP1 in fibroblast-like synovial cells might be involved in the pathogenesis of rheumatoid arthritis. (PMID:21833529)
• Study shows that the OB-fold domain of the telomere-binding protein TPP1 recruits telomerase to telomeres through an association with the telomerase reverse transcriptase TERT; data define a potential interface for telomerase-TPP1 interaction required for telomere maintenance and implicate defective telomerase recruitment in telomerase-related disease. (PMID:22863003)
• POT1-TPP1 regulates telomeric overhang structural dynamics. (PMID:22981946)
• The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. (PMID:23103865)
• Phosphorylation of TPP1 regulates cell cycle-dependent telomerase recruitment. (PMID:23509301)
• Coordinated interactions of multiple POT1-TPP1 proteins with telomere DNA. (PMID:23616058)
• Akt regulates TPP1 homodimerization and telomere protection. (PMID:23862686)
• Telomere-binding protein TPP1 modulates telomere homeostasis and confers radioresistance to human colorectal cancer cells. (PMID:24260532)
• Suppression of telomere-binding protein TPP1 resulted in telomere dysfunction and enhanced radiation sensitivity in telomerase-negative osteosarcoma cell line. (PMID:24513288)
• G-quadruplex formation in telomeres enhances POT1/TPP1 protection against RPA binding. (PMID:24516170)
• Shelterin protein TPP 1 interacts with hTERT and recruits hTERT onto the telomeres, suggesting that TPP 1 might be involved in regulation of telomere shortening. (PMID:24721976)
• Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation. (PMID:25128433)
• The shelterin component TPP1 is a binding partner and substrate for the deubiquitinating enzyme USP7. (PMID:25172512)
• The data support a causal relationship between a TPP1 mutation and bone marrow disorders in a family. (PMID:25205116)
• Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. (PMID:25233904)
• Clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785). (PMID:25505254)
• a novel ACD mutation(p.G223V)is detected; ACD is a novel gene involved in childhood pre-B acute lymphoblastic leukemia and may play a functional role in enhancing leukemia cell survival (PMID:26345285)
• Dissecting Fission Yeast Shelterin Interactions via MICro-MS Links Disruption of Shelterin Bridge to Tumorigenesis. (PMID:26365187)
• The Insertion in Fingers Domain in Human Telomerase Can Mediate Enzyme Processivity and Telomerase Recruitment to Telomeres in a TPP1-Dependent Manner. (PMID:26503784)
• POT1-TPP1 Binding and Unfolding of Telomere DNA Discriminates against Structural Polymorphism. (PMID:27173378)
• NEK6-mediated phosphorylation of human TPP1 regulates telomere length through telomerase recruitment. (PMID:27396482)
• Shelterin Telomere Protection Protein 1 Reduction Causes Telomere Attrition and Cellular Senescence via Sirtuin 1 Deacetylase in Chronic Obstructive Pulmonary Disease. (PMID:27559927)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	acd	ENSDARG00000078055
mus_musculus	Acd	ENSMUSG00000038000
rattus_norvegicus	Acd	ENSRNOG00000038973

Protein

Protein identifiers

Adrenocortical dysplasia protein homolog — Q96AP0 (reviewed: Q96AP0)

Alternative names: POT1 and TIN2-interacting protein

All UniProt accessions (19): Q96AP0, A0A8Q3SHY1, A0A8Q3SHY4, A0A8Q3SHZ0, A0A8Q3SI14, A0A8Q3SI32, A0A8Q3SI48, A0A8Q3SI54, A0A8Q3WKN9, A0A8Q3WKP4, A0A8Q3WKP5, A0A8Q3WKU3, A0A8Q3WLR8, A0A8Q3WLT1, A0A8Q3WM11, A0A8Q3WM19, R4GMR6, R4GND4, R4GNJ5

UniProt curated annotations — full annotation on UniProt →

Function. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends. Without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Promotes binding of POT1 to single-stranded telomeric DNA. Modulates the inhibitory effects of POT1 on telomere elongation. The ACD-POT1 heterodimer enhances telomere elongation by recruiting telomerase to telomeres and increasing its processivity. May play a role in organogenesis.

Subunit / interactions. Component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP ACD and POT1. Forms heterodimers with POT1. Identified in a complex with POT1 and single-stranded telomeric DNA. Interacts with STN1 and TINF2.

Subcellular location. Nucleus. Chromosome. Telomere.

Disease relevance. Dyskeratosis congenita, autosomal dominant, 6 (DKCA6) [MIM:616553] A form of dyskeratosis congenita, a rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. The disease is caused by variants affecting the gene represented in this entry. Dyskeratosis congenita, autosomal recessive, 7 (DKCB7) [MIM:616553] A form of dyskeratosis congenita, a rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96AP0-3	3	yes
Q96AP0-2	2

RefSeq proteins (3): NP_001075955, NP_001397813, NP_075065 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019437	TPP1/Est3	Domain
IPR028631	ACD	Family

Pfam: PF10341

UniProt features (39 total): helix 11, strand 10, sequence variant 4, region of interest 3, compositionally biased region 3, modified residue 2, chain 1, cross-link 1, splice variant 1, sequence conflict 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
5H65	X-RAY DIFFRACTION	2.1
5UN7	X-RAY DIFFRACTION	2.1
5XYF	X-RAY DIFFRACTION	2.2
2I46	X-RAY DIFFRACTION	2.7
7S1T	X-RAY DIFFRACTION	2.9
5I2X	X-RAY DIFFRACTION	3
5I2Y	X-RAY DIFFRACTION	3
7QXA	ELECTRON MICROSCOPY	3.2
9SHZ	ELECTRON MICROSCOPY	3.2
9QAX	ELECTRON MICROSCOPY	3.3
7TRE	ELECTRON MICROSCOPY	3.5
9SHY	ELECTRON MICROSCOPY	3.53
9QAZ	ELECTRON MICROSCOPY	3.6
8SOJ	ELECTRON MICROSCOPY	3.8
9QAY	ELECTRON MICROSCOPY	3.8
9SI0	ELECTRON MICROSCOPY	3.8
7QXB	ELECTRON MICROSCOPY	3.9
7QXS	ELECTRON MICROSCOPY	3.9
8SOK	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96AP0-F1	63.09	0.22

Functional residue map

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

Post-translational modifications (3): 381, 25, 349

Function

Pathways and Gene Ontology

Reactome pathways

28 pathways

ID	Pathway
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine
R-HSA-110329	Cleavage of the damaged pyrimidine
R-HSA-110330	Recognition and association of DNA glycosylase with site containing an affected purine
R-HSA-110331	Cleavage of the damaged purine
R-HSA-1221632	Meiotic synapsis
R-HSA-171306	Packaging Of Telomere Ends
R-HSA-171319	Telomere Extension By Telomerase
R-HSA-174411	Polymerase switching on the C-strand of the telomere
R-HSA-174414	Processive synthesis on the C-strand of the telomere
R-HSA-174417	Telomere C-strand (Lagging Strand) Synthesis
R-HSA-174430	Telomere C-strand synthesis initiation
R-HSA-174437	Removal of the Flap Intermediate from the C-strand
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-9670095	Inhibition of DNA recombination at telomere
R-HSA-1474165	Reproduction
R-HSA-1500620	Meiosis
R-HSA-157579	Telomere Maintenance
R-HSA-1640170	Cell Cycle
R-HSA-180786	Extension of Telomeres
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-73884	Base Excision Repair
R-HSA-73886	Chromosome Maintenance
R-HSA-73894	DNA Repair
R-HSA-73927	Depurination
R-HSA-73928	Depyrimidination
R-HSA-73929	Base-Excision Repair, AP Site Formation
R-HSA-8953897	Cellular responses to stimuli

MSigDB gene sets: 621 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, GOBP_EPITHELIUM_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, KOBAYASHI_EGFR_SIGNALING_24HR_UP, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, WWTAAGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_TELOMERE_MAINTENANCE_VIA_TELOMERASE, chr16q22, PID_TELOMERASE_PATHWAY, GOBP_VACUOLE_ORGANIZATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_TELOMERE_CAPPING, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT

GO Biological Process (15): telomere maintenance (GO:0000723), skeletal system development (GO:0001501), urogenital system development (GO:0001655), intracellular protein transport (GO:0006886), telomere maintenance via telomerase (GO:0007004), telomere capping (GO:0016233), embryonic limb morphogenesis (GO:0030326), protection from non-homologous end joining at telomere (GO:0031848), telomere assembly (GO:0032202), positive regulation of telomere maintenance (GO:0032206), negative regulation of telomere maintenance via telomerase (GO:0032211), segmentation (GO:0035282), protein localization to chromosome, telomeric region (GO:0070198), establishment of protein localization to telomere (GO:0070200), regulation of establishment of protein localization to telomere (GO:0070203)

GO Molecular Function (6): telomerase inhibitor activity (GO:0010521), telomeric repeat DNA binding (GO:0042162), protein-containing complex binding (GO:0044877), DNA polymerase binding (GO:0070182), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (8): chromosome, telomeric region (GO:0000781), nuclear telomere cap complex (GO:0000783), nucleoplasm (GO:0005654), telomerase holoenzyme complex (GO:0005697), nuclear body (GO:0016604), shelterin complex (GO:0070187), nucleus (GO:0005634), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Telomere Maintenance	3
Telomere C-strand (Lagging Strand) Synthesis	3
Depyrimidination	2
Depurination	2
Extension of Telomeres	2
Meiosis	1
Processive synthesis on the C-strand of the telomere	1
Cellular Senescence	1
Reproduction	1
Cell Cycle	1
Chromosome Maintenance	1
Cellular responses to stimuli	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
telomere organization	2
system development	2
telomerase activity	2
telomere maintenance	2
binding	2
nuclear protein-containing complex	2
intracellular membraneless organelle	2
DNA metabolic process	1
renal system development	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
RNA-templated DNA biosynthetic process	1
telomere maintenance via telomere lengthening	1
telomere-telomerase complex assembly	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
telomere capping	1
telomere maintenance in response to DNA damage	1
cellular component assembly	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
telomere maintenance via telomerase	1
regulation of telomere maintenance via telomerase	1
negative regulation of telomere maintenance via telomere lengthening	1
negative regulation of DNA biosynthetic process	1
regionalization	1
protein localization to chromosome	1
establishment of protein localization to chromosome	1
establishment of protein localization to telomere	1
regulation of establishment of protein localization to chromosome	1
enzyme inhibitor activity	1
sequence-specific DNA binding	1
enzyme binding	1
nucleic acid binding	1
chromosomal region	1
telomere cap complex	1
nuclear lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

762 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACD	TINF2	Q9BSI4	999
ACD	TERF1	P54274	998
ACD	POT1	Q9NUX5	998
ACD	TERF2	Q15554	993
ACD	TERF2IP	Q9NYB0	967
ACD	NUPR2	A6NF83	759
ACD	TNKS	O95271	701
ACD	CTC1	Q2NKJ3	677
ACD	STN1	Q9H668	658
ACD	CFI	P05156	658
ACD	WRN	Q14191	582
ACD	GNRH1	P01148	536
ACD	TERT	O14746	524
ACD	WNT3A	P56704	516
ACD	GNRH2	O43555	513

IntAct

157 interactions, top by confidence:

A	B	Type	Score
TERF2IP	TERF2	psi-mi:“MI:0914”(association)	0.970
ACD	TINF2	psi-mi:“MI:0915”(physical association)	0.960
TINF2	ACD	psi-mi:“MI:0915”(physical association)	0.960
ACD	TINF2	psi-mi:“MI:0914”(association)	0.960
ACD	POT1	psi-mi:“MI:0915”(physical association)	0.930
POT1	ACD	psi-mi:“MI:0915”(physical association)	0.930
TERF1	TNKS	psi-mi:“MI:0914”(association)	0.850
TERF2	ACD	psi-mi:“MI:0914”(association)	0.810
ACD	TERF2	psi-mi:“MI:0914”(association)	0.810
ACD	TERF2	psi-mi:“MI:0403”(colocalization)	0.810
ACD	TERF1	psi-mi:“MI:0915”(physical association)	0.780
TERF1	ACD	psi-mi:“MI:0914”(association)	0.780
ACD	POT1	psi-mi:“MI:0915”(physical association)	0.690
POT1	ACD	psi-mi:“MI:0915”(physical association)	0.690
ACD	TINF2	psi-mi:“MI:0915”(physical association)	0.690

BioGRID (125): ACD (Two-hybrid), ACD (Affinity Capture-MS), ACD (Two-hybrid), POT1 (Reconstituted Complex), ACD (Affinity Capture-MS), ACD (Affinity Capture-MS), ACD (Affinity Capture-MS), ACD (Affinity Capture-MS), ACD (Affinity Capture-MS), ACD (Affinity Capture-MS), ACD (Two-hybrid), ACD (Affinity Capture-MS), POT1 (Affinity Capture-MS), ACD (Affinity Capture-MS), TERF2IP (Affinity Capture-MS)

ESM2 similar proteins: A0JMF1, A2CI97, A3KNA7, A6NE52, B2GV47, E7FAW3, P60330, Q06ZW3, Q0VDN7, Q12769, Q1M161, Q2NKJ3, Q2YDQ5, Q3SYW0, Q3T1I9, Q3U6Q4, Q4FZR5, Q5EE38, Q5PNP6, Q5RDX3, Q5SUQ9, Q5TYP4, Q5ZIB8, Q6AYM1, Q6DG91, Q6IRN0, Q6NSI4, Q6NYX6, Q6P4K6, Q6PH58, Q6ZNJ1, Q6ZPG2, Q6ZQA0, Q7T006, Q7ZVM9, Q80TE0, Q80VA5, Q8BJW5, Q8BMG1, Q8C779

Diamond homologs: Q4FZR5, Q5EE38, Q96AP0

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
ACD	“form complex”	POT1/ACD	binding
ACD	up-regulates	TERT	binding
NEK6	“up-regulates activity”	ACD	phosphorylation
RNF8	“up-regulates quantity by stabilization”	ACD	polyubiquitination
ACD	“down-regulates activity”	RPA2	binding
ACD	“down-regulates activity”	RPA1	binding
ACD	“down-regulates activity”	RPA3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Telomere C-strand (Lagging Strand) Synthesis	6	74.9×	2e-08
Processive synthesis on the C-strand of the telomere	5	62.4×	1e-06
Removal of the Flap Intermediate from the C-strand	5	52.0×	2e-06
Extension of Telomeres	5	49.3×	3e-06
Telomere Extension By Telomerase	6	44.9×	5e-07
Polymerase switching on the C-strand of the telomere	6	41.6×	6e-07
Telomere Maintenance	5	30.2×	3e-05
Packaging Of Telomere Ends	5	18.0×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
telomere maintenance via telomerase	5	44.7×	1e-05
negative regulation of telomere maintenance via telomerase	5	44.7×	1e-05
positive regulation of telomere maintenance	5	31.1×	5e-05
telomere maintenance	7	22.8×	8e-06
substantia nigra development	5	22.3×	2e-04
protein folding	7	8.8×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

2687 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	108
Likely pathogenic	87
Uncertain significance	1233
Likely benign	1029
Benign	36

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065450	NM_000391.4(TPP1):c.987_989del (p.Glu329del)	Pathogenic
1068518	NM_000391.4(TPP1):c.38_68del (p.Leu13fs)	Pathogenic
1073169	NM_000391.4(TPP1):c.1218T>A (p.Tyr406Ter)	Pathogenic
1073897	NM_000391.4(TPP1):c.1626G>A (p.Trp542Ter)	Pathogenic
1074191	NM_000391.4(TPP1):c.1323_1326del (p.Ser440_Tyr441insTer)	Pathogenic
1074509	NM_000391.4(TPP1):c.754_757del (p.Ala252fs)	Pathogenic
1074909	NM_000391.4(TPP1):c.408del (p.Glu137fs)	Pathogenic
1076930	NM_000391.4(TPP1):c.509-2A>G	Pathogenic
1373459	NM_000391.4(TPP1):c.1468G>T (p.Glu490Ter)	Pathogenic
1386990	NM_000391.4(TPP1):c.1540G>T (p.Gly514Ter)	Pathogenic
1409463	NM_000391.4(TPP1):c.52A>T (p.Lys18Ter)	Pathogenic
1416477	NC_000011.10:g.6615330del	Pathogenic
1416739	NM_000391.4(TPP1):c.177_194del (p.Arg60_Val65del)	Pathogenic
1452558	NM_000391.4(TPP1):c.1496del (p.Pro499fs)	Pathogenic
1455654	NM_000391.4(TPP1):c.1548_1551dup (p.Val518Ter)	Pathogenic
1458603	NM_000391.4(TPP1):c.472C>T (p.Gln158Ter)	Pathogenic
1459474	NM_000391.4(TPP1):c.1558del (p.Arg520fs)	Pathogenic
1471492	NM_000391.4(TPP1):c.3G>C (p.Met1Ile)	Pathogenic
155685	GRCh38/hg38 16q12.1-22.1(chr16:49685521-68401712)x3	Pathogenic
1675447	NM_000391.4(TPP1):c.1288_1289dup (p.Leu430_Ser431insTer)	Pathogenic
1686271	NM_000391.4(TPP1):c.899del (p.Gly300fs)	Pathogenic
1696130	NM_000391.4(TPP1):c.790C>T (p.Gln264Ter)	Pathogenic
188850	NM_000391.4(TPP1):c.972_979del (p.Ser324fs)	Pathogenic
189179	NM_000391.4(TPP1):c.1379G>A (p.Trp460Ter)	Pathogenic
1995567	NM_000391.4(TPP1):c.1477_1478dup (p.Leu494fs)	Pathogenic
1995893	NM_000391.4(TPP1):c.702T>G (p.Tyr234Ter)	Pathogenic
2001644	NM_000391.4(TPP1):c.966del (p.Thr322_Val323insTer)	Pathogenic
2012420	NM_000391.4(TPP1):c.917del (p.Gln306fs)	Pathogenic
2028961	NM_000391.4(TPP1):c.175_195del (p.Glu59_Val65del)	Pathogenic
207561	NM_000391.4(TPP1):c.311T>A (p.Leu104Ter)	Pathogenic

SpliceAI

1517 predictions. Top by Δscore:

Variant	Effect	Δscore
16:67659373:A:AC	donor_gain	1.0000
16:67659374:C:CC	donor_gain	1.0000
16:67659374:CT:C	donor_gain	1.0000
16:67659420:C:CC	acceptor_gain	1.0000
16:67659531:ACTT:A	donor_loss	1.0000
16:67659532:CTTA:C	donor_loss	1.0000
16:67659533:TTA:T	donor_loss	1.0000
16:67659535:A:AC	donor_gain	1.0000
16:67659535:ACCA:A	donor_loss	1.0000
16:67659536:C:CC	donor_gain	1.0000
16:67659536:CCAA:C	donor_gain	1.0000
16:67659610:CGGG:C	acceptor_gain	1.0000
16:67659614:C:CC	acceptor_gain	1.0000
16:67659614:CT:C	acceptor_loss	1.0000
16:67659625:C:CT	acceptor_gain	1.0000
16:67659698:TCA:T	donor_loss	1.0000
16:67659699:CACC:C	donor_loss	1.0000
16:67659700:A:AC	donor_gain	1.0000
16:67659701:C:CC	donor_gain	1.0000
16:67659701:C:CT	donor_loss	1.0000
16:67659701:CCGCG:C	donor_gain	1.0000
16:67659794:CCCTG:C	acceptor_loss	1.0000
16:67659796:CTGCA:C	acceptor_loss	1.0000
16:67658718:AC:A	donor_gain	0.9900
16:67658719:CC:C	donor_gain	0.9900
16:67658828:GAACT:G	acceptor_gain	0.9900
16:67658923:CTGA:C	donor_loss	0.9900
16:67658924:TGA:T	donor_loss	0.9900
16:67658925:GACCG:G	donor_loss	0.9900
16:67658926:ACC:A	donor_loss	0.9900

AlphaMissense

2906 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:67659582:A:G	F123S	0.994
16:67659775:A:G	F88S	0.992
16:67659602:G:C	F116L	0.991
16:67659602:G:T	F116L	0.991
16:67659604:A:G	F116L	0.991
16:67659581:G:C	F123L	0.990
16:67659581:G:T	F123L	0.990
16:67659583:A:G	F123L	0.990
16:67659603:A:G	F116S	0.990
16:67659961:C:G	D62H	0.989
16:67657818:G:C	F414L	0.988
16:67657818:G:T	F414L	0.988
16:67657820:A:G	F414L	0.988
16:67659960:T:A	D62V	0.988
16:67660187:A:G	W12R	0.988
16:67660187:A:T	W12R	0.988
16:67659964:A:G	S61P	0.986
16:67660185:C:A	W12C	0.986
16:67660185:C:G	W12C	0.986
16:67659940:A:G	C69R	0.985
16:67659945:A:T	V67D	0.985
16:67659774:G:C	F88L	0.983
16:67659774:G:T	F88L	0.983
16:67659776:A:G	F88L	0.983
16:67658952:C:A	W207C	0.982
16:67658952:C:G	W207C	0.982
16:67659402:A:T	V144D	0.981
16:67660183:A:G	I13T	0.980
16:67658797:A:T	V222D	0.979
16:67659959:G:C	D62E	0.979

dbSNP variants (sampled 300 via entrez): RS1000930506 (16:67661455 T>C), RS1001091321 (16:67661814 G>A,T), RS1004936452 (16:67661314 C>A,T), RS1005021608 (16:67657132 G>C), RS1005124259 (16:67660589 C>A,G,T), RS1005212795 (16:67657706 A>G), RS1005222650 (16:67657904 T>C), RS1006777863 (16:67658242 G>A,T), RS1010390618 (16:67657102 G>A), RS1011064739 (16:67659581 G>A), RS1011399056 (16:67658319 A>T), RS1011451663 (16:67658497 G>A,T), RS1012127877 (16:67661678 G>A), RS1012789108 (16:67657429 C>T), RS1013547623 (16:67659887 G>A,C)

Disease associations

OMIM: gene MIM:609377 | disease phenotypes: MIM:204500, MIM:616553, MIM:609270, MIM:618131, MIM:256730, MIM:105830, MIM:614541

GenCC curated gene-disease

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis	Definitive	Autosomal recessive
neuronal ceroid lipofuscinosis 2	Definitive	Autosomal recessive
dyskeratosis congenita, autosomal dominant 6	Strong	Autosomal dominant
autosomal recessive spinocerebellar ataxia 7	Strong	Autosomal recessive
ACD-related short telomere syndrome	Strong	Semidominant
Hoyeraal-Hreidarsson syndrome	Supportive	Autosomal dominant
hereditary isolated aplastic anemia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis	Definitive	AR
ACD-related short telomere syndrome	Definitive	SD

Mondo (16): neuronal ceroid lipofuscinosis 2 (MONDO:0008769), dyskeratosis congenita, autosomal dominant 6 (MONDO:0014690), ACD-related short telomere syndrome (MONDO:0100569), autosomal recessive spinocerebellar ataxia 7 (MONDO:0012235), severe combined immunodeficiency due to CARMIL2 deficiency (MONDO:0029134), neuronal ceroid lipofuscinosis (MONDO:0016295), Angelman syndrome (MONDO:0007113), intellectual disability (MONDO:0001071), dyskeratosis congenita, autosomal recessive 7 (MONDO:0800370), congenital nervous system disorder (MONDO:0002320), retinal disorder (MONDO:0005283), hereditary neoplastic syndrome (MONDO:0015356), juvenile neuronal ceroid lipofuscinosis (MONDO:0019262), chromosome 16q22 deletion syndrome (MONDO:0013798), Hoyeraal-Hreidarsson syndrome (MONDO:0018045)

Orphanet (12): OBSOLETE: Late infantile neuronal ceroid lipofuscinosis (Orphanet:168491), CLN2 disease (Orphanet:228349), OBSOLETE: Juvenile neuronal ceroid lipofuscinosis (Orphanet:79264), Hoyeraal-Hreidarsson syndrome (Orphanet:3322), Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia (Orphanet:284324), EBV-induced lymphoproliferative disease due to CARMIL2 deficiency (Orphanet:542301), Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263), Angelman syndrome (Orphanet:72), Inherited cancer-predisposing syndrome (Orphanet:140162), 16q22 deletion syndrome (Orphanet:658540), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

90 total (30 of 90 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000012	Urinary urgency
HP:0000164	Abnormality of the dentition
HP:0000252	Microcephaly
HP:0000488	Retinopathy
HP:0000529	Progressive visual loss
HP:0000546	Retinal degeneration
HP:0000550	Undetectable electroretinogram
HP:0000639	Nystagmus
HP:0000641	Dysmetric saccades
HP:0000651	Diplopia
HP:0000657	Oculomotor apraxia
HP:0000666	Horizontal nystagmus
HP:0000750	Delayed speech and language development
HP:0000958	Dry skin
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001310	Dysmetria
HP:0001311	Abnormal nervous system electrophysiology
HP:0001321	Cerebellar hypoplasia
HP:0001336	Myoclonus

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002539_84	Schizophrenia	2.000000e-08
GCST006803_42	Schizophrenia	4.000000e-08
GCST010002_113	Refractive error	2.000000e-14
GCST010083_248	Hemoglobin levels	1.000000e-11
GCST010725_20	Malaria	4.000000e-69
GCST010725_33	Malaria	2.000000e-67
GCST010725_51	Malaria	1.000000e-55

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D017204	Angelman Syndrome	C10.228.662.075; C16.131.077.095; C16.131.260.040; C16.320.180.040; C16.320.447.250
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D012164	Retinal Diseases	C11.768
C531619	Happy puppet syndrome (formerly) (supp.)
C536068	Hoyeraal Hreidarsson syndrome (supp.)
C563753	Spinocerebellar Ataxia, Autosomal Recessive 7 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	decreases expression	1
jinfukang	increases expression	1
MT19c compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Troglitazone	decreases expression	1
Acetaminophen	increases expression	1
Caffeine	increases phosphorylation	1
Doxorubicin	decreases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Hydrogen Peroxide	affects expression	1
Lead	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Mustard Gas	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Rotenone	decreases expression	1
Selenomethionine	affects expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Cyclosporine	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SB17	HAP1 ACD (-) 1	Cancer cell line	Male
CVCL_SB18	HAP1 ACD (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT02893254	PHASE3	COMPLETED	Efficacy and Safety of IBI303 in Adult Patients With Active Ankylosing Spondylitis
NCT03882918	PHASE3	TERMINATED	An Open-Label Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of OV101 in Individuals With Angelman Syndrome
NCT06415344	PHASE3	ENROLLING_BY_INVITATION	Long-term Extension of GTX-102 in Angelman Syndrome
NCT06617429	PHASE3	ACTIVE_NOT_RECRUITING	Phase 3 Efficacy and Safety Study of GTX-102 in Pediatric Subjects With Angelman Syndrome (AS)
NCT06914609	PHASE3	RECRUITING	REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome
NCT07605429	PHASE3	NOT_YET_RECRUITING	Phase III Clinical Study of Rugonersen in Angelman Syndrome.
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01659606	PHASE2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT02056665	PHASE2	COMPLETED	Study to Evaluate the Efficacy and Safety of Minocycline in Angelman Syndrome
NCT02996305	PHASE2	COMPLETED	A Study in Adults and Adolescents With Angelman Syndrome (STARS)
NCT05011851	PHASE2	COMPLETED	An Open-Label Study of the Safety, Tolerability, and Pharmacokinetics of Oral NNZ-2591 in Angelman Syndrome
NCT05630066	PHASE2	COMPLETED	A Study to Investigate the Pharmacokinetics (PK) and Safety and to Provide Proof of Mechanism of Alogabat in Children and Adolescents Aged 5-17 Years With Angelman Syndrome (AS) With Deletion Genotype.
NCT07157254	PHASE2	RECRUITING	A Safety and Efficacy Study of GTX-102 in Subjects With Deletion- or Nondeletion-type Angelman Syndrome (AS)
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT00337636	PHASE1	COMPLETED	Study of HuCNS-SC Cells in Patients With Infantile or Late Infantile Neuronal Ceroid Lipofuscinosis (NCL)
NCT01238315	PHASE1	WITHDRAWN	Safety and Efficacy Study of HuCNS-SC in Subjects With Neuronal Ceroid Lipofuscinosis
NCT00151216	PHASE1	COMPLETED	Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis
NCT06817590	PHASE1	RECRUITING	Nucleoside Therapy in Patients With Telomere Biology Disorders
NCT00829439	PHASE1	COMPLETED	Study on Tolerability of Levodopa/Carbidopa in Children With Angelman Syndrome
NCT03109756	PHASE1	COMPLETED	Single Dose Pharmacokinetic (PK) Study
NCT04428281	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of RO7248824 in Participants With Angelman Syndrome (AS)
NCT04863794	PHASE1	COMPLETED	A Study To Assess Distribution Of RO7248824 In The Central Nervous System Following Single Intrathecal Doses Of [89zr] Labeled RO7248824 In Healthy Male Participants
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT07582484	PHASE1/PHASE2	NOT_YET_RECRUITING	Gene Therapy Trial for CLN6 Batten Disease
NCT01873924	Not specified	RECRUITING	Clinical and Neuropsychological Investigations in Batten Disease