RTTN

Summary

RTTN (rotatin, HGNC:18654) is a protein-coding gene on chromosome 18q22.2, encoding Rotatin (Q86VV8). Involved in the genetic cascade that governs left-right specification. It is a selective cancer dependency (DepMap: 48.8% of cell lines).

This gene encodes a large protein whose specific function is unknown. Absence of the orthologous protein in mouse results in embryonic lethality with deficient axial rotation, abnormal differentiation of the neural tube, and randomized looping of the heart tube during development. In human, mutations in this gene are associated with polymicrogyria with seizures. In human fibroblasts this protein localizes at the ciliary basal bodies. Given the intracellular localization of this protein and the phenotypic effects of mutations, this gene is suspected of playing a role in the maintenance of normal ciliary structure which in turn effects the developmental process of left-right organ specification, axial rotation, and perhaps notochord development.

Source: NCBI Gene 25914 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephalic primordial dwarfism due to RTTN deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 1,516 total — 45 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 85
• Cancer dependency (DepMap): dependent in 48.8% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_173630

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18654
Approved symbol	RTTN
Name	rotatin
Location	18q22.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP434G145
Ensembl gene	ENSG00000176225
Ensembl biotype	protein_coding
OMIM	610436
Entrez	25914

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 8 protein_coding, 7 nonsense_mediated_decay, 7 retained_intron, 5 protein_coding_CDS_not_defined

ENST00000255674, ENST00000578780, ENST00000579021, ENST00000579986, ENST00000580034, ENST00000581161, ENST00000581583, ENST00000581709, ENST00000583043, ENST00000583765, ENST00000638251, ENST00000638298, ENST00000638799, ENST00000639128, ENST00000639487, ENST00000640376, ENST00000640393, ENST00000640408, ENST00000640525, ENST00000640654, ENST00000640736, ENST00000640769, ENST00000640931, ENST00000677824, ENST00000679113, ENST00000917940, ENST00000917941

RefSeq mRNA: 2 — MANE Select: NM_173630 NM_001318520, NM_173630

CCDS: CCDS42443

Canonical transcript exons

ENST00000640769 — 49 exons

Exon	Start	End
ENSE00001346236	70140100	70140188
ENSE00002727494	70205628	70205687
ENSE00003467376	70197624	70197738
ENSE00003469947	70176675	70176845
ENSE00003473803	70188108	70188223
ENSE00003478173	70030012	70030109
ENSE00003479284	70065829	70065922
ENSE00003483846	70030876	70030981
ENSE00003492744	70150608	70150733
ENSE00003499090	70149971	70150087
ENSE00003499288	70005198	70005267
ENSE00003510989	70145612	70145783
ENSE00003513293	70028724	70028801
ENSE00003519991	70047971	70048188
ENSE00003524452	70127502	70127741
ENSE00003529219	70054131	70054284
ENSE00003540502	70168855	70169067
ENSE00003547321	70092110	70092220
ENSE00003551090	70199414	70199504
ENSE00003555503	70196501	70196648
ENSE00003557249	70020615	70020817
ENSE00003560467	70087989	70088147
ENSE00003562506	70128358	70128546
ENSE00003567309	70092676	70092804
ENSE00003568811	70075352	70075541
ENSE00003571789	70139599	70139716
ENSE00003576674	70166919	70167031
ENSE00003578069	70134473	70134541
ENSE00003582393	70190538	70190719
ENSE00003583274	70166062	70166188
ENSE00003586401	70109498	70109717
ENSE00003590636	70086613	70086684
ENSE00003596087	70059850	70060042
ENSE00003609965	70114445	70114599
ENSE00003628487	70006381	70006484
ENSE00003629863	70073906	70073994
ENSE00003637144	70204086	70204263
ENSE00003645677	70135184	70135280
ENSE00003650444	70142288	70142387
ENSE00003669996	70017407	70017674
ENSE00003671401	70057742	70057832
ENSE00003673349	70148901	70149037
ENSE00003681311	70201894	70201983
ENSE00003686734	70051411	70051548
ENSE00003687287	70205128	70205315
ENSE00003689802	70193288	70193453
ENSE00003691983	70121556	70121700
ENSE00003693558	70024722	70024848
ENSE00003802050	70003031	70004236

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 96.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.6367 / max 234.2335, expressed in 1699 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172363	11.5246	1658
172352	1.3926	244
172364	0.3235	131
172351	0.2023	64
172353	0.0882	39
172360	0.0333	16
172356	0.0213	4
172354	0.0156	7
172361	0.0154	5
172362	0.0153	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	96.81	gold quality
oocyte	CL:0000023	96.42	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.26	gold quality
tibialis anterior	UBERON:0001385	89.64	silver quality
calcaneal tendon	UBERON:0003701	88.93	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.31	gold quality
corpus callosum	UBERON:0002336	88.19	gold quality
bone marrow cell	CL:0002092	87.94	gold quality
right lobe of liver	UBERON:0001114	85.03	gold quality
deltoid	UBERON:0001476	84.95	silver quality
right testis	UBERON:0004534	84.58	gold quality
left testis	UBERON:0004533	84.27	gold quality
colonic epithelium	UBERON:0000397	84.18	gold quality
testis	UBERON:0000473	83.83	gold quality
ventricular zone	UBERON:0003053	83.67	gold quality
sural nerve	UBERON:0015488	83.67	gold quality
pancreatic ductal cell	CL:0002079	83.07	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	82.44	gold quality
thymus	UBERON:0002370	82.19	gold quality
nerve	UBERON:0001021	82.12	gold quality
tibial nerve	UBERON:0001323	82.12	gold quality
spinal cord	UBERON:0002240	82.05	gold quality
adrenal tissue	UBERON:0018303	81.75	gold quality
inferior vagus X ganglion	UBERON:0005363	81.71	gold quality
left ovary	UBERON:0002119	81.61	gold quality
lateral nuclear group of thalamus	UBERON:0002736	81.36	gold quality
right hemisphere of cerebellum	UBERON:0014890	81.12	gold quality
cerebellar hemisphere	UBERON:0002245	81.02	gold quality
sperm	CL:0000019	81.00	gold quality
cerebellar cortex	UBERON:0002129	80.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-6	yes	3970.60
E-ANND-3	yes	8.44

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting RTTN, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-4761-5P	99.51	66.69	804
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-532-5P	98.43	67.53	760

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 48.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 10)

• Study characterizing mouse rotatin gene. (PMID:11900971)
• RTTN mutations therefore link aberrant ciliary function to abnormal development and organization of the cortex in human individuals. (PMID:22939636)
• RTTN mutations cause primary microcephaly and primordial dwarfism in humans. (PMID:26608784)
• We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN-associated diseases and ciliary dysfunction. (PMID:26940245)
• RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly, contributing to building full-length centrioles. (PMID:28811500)
• We here report three individuals from two unrelated families with novel mutations in the RTTN gene. The phenotype consisted of microcephaly, short stature, pachygyria or polymicrogyria, colpocephaly, hypoplasia of the corpus callosum and superior vermis. These findings provide further confirmation of the phenotype related to pathogenic variants in RTTN. (PMID:29883675)
• We identified, by trio based whole exome sequencing, a homozygous missense mutation in the RTTN gene (c.2953A>G; p.(Arg985Gly)) in one Moroccan patient from a consanguineous family. (PMID:30121372)
• Data show that PPP1R35 acts downstream of, and forms a complex with, RTTN, a microcephaly protein required for distal centriole elongation. (PMID:30168418)
• Study reports on a consanguineous family with three adult members with primary microcephaly, developmental delay, primordial dwarfism, and brachydactyly segregating a homozygous splice site variant NM_173630.3:c.5648-5T>A in RTTN. The variant RTTN allele results in a nonhypomorphic skipping of exon 42 and a frameshift [(NP_775901.3:p.Ala1883Glyfs*6)]. (PMID:30927481)
• Human Microcephaly Protein RTTN Is Required for Proper Mitotic Progression and Correct Spindle Position. (PMID:34207628)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rttn	ENSDARG00000004131
mus_musculus	Rttn	ENSMUSG00000023066
rattus_norvegicus	Rttn	ENSRNOG00000038200
drosophila_melanogaster	ana3	FBGN0266111

Protein

Protein identifiers

Rotatin — Q86VV8 (reviewed: Q86VV8)

All UniProt accessions (12): A0A1W2PPP3, A0A1W2PPP7, A0A1W2PQI7, A0A1W2PR21, A0A1W2PR32, A0A1W2PR96, A0A7I2V5W4, A0A7I2V670, Q86VV8, J3KSV7, J3KT00, J3KTD2

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the genetic cascade that governs left-right specification. Plays a role in the maintenance of a normal ciliary structure. Required for correct asymmetric expression of NODAL, LEFTY and PITX2.

Subunit / interactions. Interacts with PPP1R35; this interaction allows the mutual recruitment to the centriole.

Subcellular location. Cytoplasm. Cytoskeleton. Cilium basal body. Microtubule organizing center. Centrosome.

Disease relevance. Microcephaly, short stature, and polymicrogyria with or without seizures (MSSP) [MIM:614833] A disease characterized by many irregular small gyri in the brain surface and fusion of the molecular layer over multiple small gyri, which gives a festooned appearance to the cortical surface, without abnormal neuronal migration. Polymicrogyria is a heterogeneous disorder, considered to be the result of postmigratory abnormal cortical organization. MSSP patients have moderate to severe intellectual disability, poor speech, dysarthria and seizures. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be due to an intron retention. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the rotatin family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q86VV8-1	1	yes
Q86VV8-2	2
Q86VV8-3	3
Q86VV8-4	4

RefSeq proteins (2): NP_001305449, NP_775901* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR029249	Rotatin_N	Domain
IPR030791	Rotatin	Family

Pfam: PF14726

UniProt features (28 total): sequence conflict 8, splice variant 6, sequence variant 6, compositionally biased region 3, region of interest 2, modified residue 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86VV8-F1	77.49	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 (2): 310, 811

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 331 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_CENTRIOLE_ASSEMBLY, GOBP_CILIUM_ORGANIZATION, GOCC_CENTROSOME, GOBP_ORGANELLE_ASSEMBLY, TGACATY_UNKNOWN, chr18q22, FISCHER_DREAM_TARGETS, GOBP_CELL_PROJECTION_ORGANIZATION, MODULE_95, GOBP_CENTROSOME_DUPLICATION, GOCC_CENTRIOLE, MARSON_BOUND_BY_E2F4_UNSTIMULATED

GO Biological Process (5): centriole replication (GO:0007099), determination of left/right symmetry (GO:0007368), centriole-centriole cohesion (GO:0010457), ciliary basal body organization (GO:0032053), cilium organization (GO:0044782)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (8): centrosome (GO:0005813), centriole (GO:0005814), ciliary basal body (GO:0036064), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cilium (GO:0005929), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
microtubule organizing center	3
cellular anatomical structure	3
cell cycle process	2
intracellular membraneless organelle	2
centrosome duplication	1
centriole assembly	1
determination of bilateral symmetry	1
left/right pattern formation	1
centrosome cycle	1
microtubule organizing center organization	1
cilium organization	1
organelle organization	1
plasma membrane bounded cell projection organization	1
binding	1
centriole	1
cilium	1
intracellular anatomical structure	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

1520 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RTTN	PPP1R35	Q8TAP8	736
RTTN	STIL	Q15468	708
RTTN	DNAH11	Q96DT5	692
RTTN	POC5	Q8NA72	650
RTTN	LEFTY2	O00292	637
RTTN	WDR62	O43379	633
RTTN	CEP120	Q8N960	632
RTTN	POC1B	Q8TC44	624
RTTN	CEP295	Q9C0D2	622
RTTN	CCDC102B	Q68D86	606
RTTN	CPAP	Q9HC77	582
RTTN	CEP135	Q66GS9	566
RTTN	CEP85	Q6P2H3	564
RTTN	INVS	Q9Y283	554
RTTN	EN1	Q05925	548

IntAct

9 interactions, top by confidence:

A	B	Type	Score
RTTN	DHX9	psi-mi:“MI:0915”(physical association)	0.400
HCST	TMEM120B	psi-mi:“MI:0914”(association)	0.350
TACSTD2	RIMOC1	psi-mi:“MI:0914”(association)	0.350
OPALIN	GPR89A	psi-mi:“MI:0914”(association)	0.350
HLA-B	RAB29	psi-mi:“MI:0914”(association)	0.350
CEP135	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
DISC1	RTTN	psi-mi:“MI:0915”(physical association)	0.000
hmsF	RTTN	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (26): RTTN (Proximity Label-MS), RTTN (Affinity Capture-MS), RTTN (Affinity Capture-RNA), RTTN (Affinity Capture-MS), RTTN (Proximity Label-MS), RTTN (Proximity Label-MS), RTTN (Affinity Capture-MS), RTTN (Affinity Capture-MS), RTTN (Proximity Label-MS), RTTN (Proximity Label-MS), RTTN (Affinity Capture-MS), RTTN (Affinity Capture-MS), RTTN (Affinity Capture-MS), RTTN (Affinity Capture-MS), RTTN (Affinity Capture-MS)

ESM2 similar proteins: A1A535, A2AIV2, A2RRP1, A8XSV3, D3YVL2, F1QJX5, F1QN74, Q09263, Q0KK59, Q14D04, Q19317, Q3UHQ6, Q3URV1, Q3V129, Q571H0, Q5JWR5, Q5PQS3, Q5RHR6, Q5SPP5, Q5TYW4, Q5U430, Q5WNI9, Q5ZLS8, Q61QK6, Q620W3, Q642P2, Q69YN4, Q69ZR2, Q6GN08, Q6TNU3, Q6ZQ18, Q6ZT12, Q7Z3E5, Q86VV8, Q8BL99, Q8GY23, Q8H0T4, Q8IGJ0, Q8K2A7, Q8R4Y8

Diamond homologs: Q86VV8, Q8R4Y8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1516 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	45
Likely pathogenic	36
Uncertain significance	629
Likely benign	551
Benign	145

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068742	NM_173630.4(RTTN):c.4975C>T (p.Gln1659Ter)	Pathogenic
1323539	NM_173630.4(RTTN):c.3577C>T (p.Arg1193Ter)	Pathogenic
1350368	NM_173630.4(RTTN):c.1123C>T (p.Gln375Ter)	Pathogenic
1356646	NM_173630.4(RTTN):c.673C>T (p.Gln225Ter)	Pathogenic
1363003	NM_173630.4(RTTN):c.4444dup (p.Tyr1482fs)	Pathogenic
1424070	NM_173630.4(RTTN):c.3175_3178del (p.Asp1059fs)	Pathogenic
1442504	NM_173630.4(RTTN):c.6398del (p.Asn2133fs)	Pathogenic
1452808	NM_173630.4(RTTN):c.1678del (p.Ile560fs)	Pathogenic
1879404	GRCh37/hg19 18q22.2(chr18:67671387-67809623)x1	Pathogenic
1931372	NM_173630.4(RTTN):c.964C>T (p.Arg322Ter)	Pathogenic
1952936	NM_173630.4(RTTN):c.2053G>T (p.Glu685Ter)	Pathogenic
2056518	NM_173630.4(RTTN):c.2886G>A (p.Trp962Ter)	Pathogenic
2066689	NM_173630.4(RTTN):c.4966dup (p.Thr1656fs)	Pathogenic
2175258	NM_173630.4(RTTN):c.3238_3241del (p.Val1080fs)	Pathogenic
2187465	NM_173630.4(RTTN):c.2708del (p.Leu902_Leu903insTer)	Pathogenic
2192249	NM_173630.4(RTTN):c.4425_4428dup (p.Leu1477fs)	Pathogenic
2498168	NM_173630.4(RTTN):c.2670_2670+2del	Pathogenic
2682264	NM_173630.4(RTTN):c.5747del (p.Glu1916fs)	Pathogenic
2707767	NM_173630.4(RTTN):c.4984del (p.Arg1662fs)	Pathogenic
2742375	NM_173630.4(RTTN):c.4737del (p.Phe1579fs)	Pathogenic
280213	NM_173630.4(RTTN):c.3589_3590del (p.Thr1196_Asp1197insTer)	Pathogenic
2817115	NM_173630.4(RTTN):c.1491dup (p.Ser498fs)	Pathogenic
2998897	NM_173630.4(RTTN):c.1885C>T (p.Arg629Ter)	Pathogenic
3004752	NM_173630.4(RTTN):c.5201C>G (p.Ser1734Ter)	Pathogenic
3242822	NC_000018.9:g.(?67801689)(67806972_?)del	Pathogenic
3242823	NC_000018.9:g.(?67753829)(67788956_?)del	Pathogenic
3253093	NM_173630.4(RTTN):c.3653T>A (p.Leu1218Ter)	Pathogenic
3338911	NM_173630.4(RTTN):c.4124G>A (p.Trp1375Ter)	Pathogenic
3606782	NM_173630.4(RTTN):c.4909C>T (p.Arg1637Ter)	Pathogenic
3638749	NM_173630.4(RTTN):c.2941del (p.Ser981fs)	Pathogenic

SpliceAI

9638 predictions. Top by Δscore:

Variant	Effect	Δscore
18:70028722:A:AC	donor_gain	1.0000
18:70028723:C:CC	donor_gain	1.0000
18:70028723:CTTTA:C	donor_gain	1.0000
18:70030006:TGTTA:T	donor_loss	1.0000
18:70030007:GTTAC:G	donor_loss	1.0000
18:70030008:TTACC:T	donor_loss	1.0000
18:70030009:TACC:T	donor_loss	1.0000
18:70030010:A:AG	donor_loss	1.0000
18:70030011:C:CA	donor_loss	1.0000
18:70030105:ATTGG:A	acceptor_gain	1.0000
18:70030107:TGG:T	acceptor_gain	1.0000
18:70030110:C:CC	acceptor_gain	1.0000
18:70030980:CA:C	acceptor_gain	1.0000
18:70030982:C:CC	acceptor_gain	1.0000
18:70051493:C:CT	acceptor_gain	1.0000
18:70054125:GCTTA:G	donor_loss	1.0000
18:70054126:CTTAC:C	donor_loss	1.0000
18:70054127:TTA:T	donor_loss	1.0000
18:70054128:TA:T	donor_loss	1.0000
18:70054129:A:AC	donor_gain	1.0000
18:70054130:C:CC	donor_gain	1.0000
18:70054130:CCTA:C	donor_gain	1.0000
18:70054285:C:CC	acceptor_gain	1.0000
18:70054289:T:C	acceptor_gain	1.0000
18:70057736:GCTTA:G	donor_loss	1.0000
18:70057737:CTTAC:C	donor_loss	1.0000
18:70057738:TTACC:T	donor_loss	1.0000
18:70057739:TAC:T	donor_loss	1.0000
18:70057740:A:AC	donor_gain	1.0000
18:70057740:A:AG	donor_loss	1.0000

AlphaMissense

14546 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:70092145:A:G	W1370R	0.998
18:70092145:A:T	W1370R	0.998
18:70088048:A:G	W1415R	0.997
18:70088048:A:T	W1415R	0.997
18:70092130:A:G	W1375R	0.997
18:70092130:A:T	W1375R	0.997
18:70205193:A:G	W52R	0.997
18:70205193:A:T	W52R	0.997
18:70205294:C:A	R18M	0.997
18:70092790:A:C	F1306L	0.995
18:70092790:A:T	F1306L	0.995
18:70092792:A:G	F1306L	0.995
18:70109566:A:G	W1279R	0.995
18:70109566:A:T	W1279R	0.995
18:70205293:C:A	R18S	0.995
18:70205293:C:G	R18S	0.995
18:70092205:A:G	W1350R	0.993
18:70092205:A:T	W1350R	0.993
18:70197663:A:C	F218L	0.993
18:70197663:A:T	F218L	0.993
18:70197665:A:G	F218L	0.993
18:70205282:A:G	L22P	0.993
18:70205294:C:G	R18T	0.993
18:70075531:A:T	V1462D	0.992
18:70086662:A:G	L1442P	0.992
18:70017596:A:G	W2078R	0.991
18:70017596:A:T	W2078R	0.991
18:70088131:A:G	L1387P	0.991
18:70128504:A:C	S999R	0.991
18:70128504:A:T	S999R	0.991

dbSNP variants (sampled 300 via entrez): RS1000043719 (18:70009109 C>T), RS1000048876 (18:70100710 G>C), RS1000071167 (18:70081130 G>A), RS1000077062 (18:70037747 A>C), RS1000107803 (18:70057171 T>A), RS1000117464 (18:70050653 G>A), RS1000121108 (18:70160671 A>G), RS1000123691 (18:70179030 C>G,T), RS1000141772 (18:70159608 C>T), RS1000175706 (18:70117757 T>A,C), RS1000182462 (18:70204811 T>C), RS1000204228 (18:70137428 C>T), RS1000206367 (18:70005355 T>C), RS1000214729 (18:70069322 C>T), RS1000259379 (18:70110967 G>C)

Disease associations

OMIM: gene MIM:610436 | disease phenotypes: MIM:614833

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephalic primordial dwarfism due to RTTN deficiency	Definitive	Autosomal recessive
bilateral generalized polymicrogyria	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
microcephalic primordial dwarfism due to RTTN deficiency	Definitive	AR

Mondo (4): microcephalic primordial dwarfism due to RTTN deficiency (MONDO:0018764), microcephaly (MONDO:0001149), neurodevelopmental disorder (MONDO:0700092), bilateral generalized polymicrogyria (MONDO:0013907)

Orphanet (1): Microcephalic cortical malformations-short stature due to RTTN deficiency (Orphanet:468631)

HPO phenotypes

85 total (30 of 85 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000122	Unilateral renal agenesis
HP:0000125	Pelvic kidney
HP:0000160	Narrow mouth
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000308	Microretrognathia
HP:0000315	Abnormality of the orbital region
HP:0000319	Smooth philtrum
HP:0000340	Sloping forehead
HP:0000358	Posteriorly rotated ears
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000520	Proptosis
HP:0000543	Optic disc pallor
HP:0000568	Microphthalmia
HP:0000582	Upslanted palpebral fissure
HP:0000601	Hypotelorism
HP:0000609	Optic nerve hypoplasia
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000883	Thin ribs
HP:0000964	Eczematoid dermatitis
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001274	Agenesis of corpus callosum

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST003542_197	Night sleep phenotypes	7.000000e-06
GCST004599_136	Mean platelet volume	1.000000e-39
GCST004616_37	Platelet distribution width	3.000000e-20
GCST008152_130	Weight	5.000000e-06
GCST009391_139	Metabolite levels	3.000000e-06
GCST010285_1	Hypopharyngeal or laryngeal cancer	3.000000e-09
GCST90002395_289	Mean platelet volume	3.000000e-21
GCST90002396_1	Mean reticulocyte volume	6.000000e-20
GCST90002396_2	Mean reticulocyte volume	4.000000e-14
GCST90002400_254	Plateletcrit	6.000000e-15

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width
EFO:0004338	body weight
EFO:0010475	deoxycholate measurement
EFO:0010701	mean reticulocyte volume
EFO:0007985	platelet crit

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Testosterone	decreases expression, affects cotreatment	2
Tretinoin	decreases expression	2
Aflatoxin B1	increases expression, increases methylation	2
Cadmium Chloride	increases abundance, increases expression	2
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
bisphenol A	decreases methylation	1
trichostatin A	affects expression	1
arsenite	affects expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	affects expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Air Pollutants	increases expression, affects cotreatment, increases abundance	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Calcitriol	decreases expression, affects cotreatment	1
Doxorubicin	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants