THOC2

protein-coding

THO complex subunit 2, the group of THO complex

Gene summary

The TREX multiprotein complex binds specifically to spliced mRNAs to facilitate mRNA export. The protein encoded by this gene is a member of the THO complex, a subset of the TREX complex. The encoded protein interacts with the THOC1 protein.[provided by RefSeq, Jun 2010]

Previous symbols:

CXorf3
MRX12
MRX35

MANE transcript

NM_001081550.2

Inheritance

ClinVar variants

P:25U:501B:51

Top phenotype

Intellectual developmental disorder, X-linked 12

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chrX:123,600,561-123,733,056

External References & Databases

Ensembl (ENSG00000125676)

Transcript & Mutation Effects

hg38 • Region Span ~132.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked, syndromic, Kumar typeMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010496

Submitter: Ambry Genetics

intellectual developmental disorder, X-linked, syndromic, Kumar typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010496

Submitter: Orphanet

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*THOC2* was first reported in relation to X-linked complex neurodevelopmental disorder in 2015 (Kumar et al., PMID: 26166480). *THOC2* encodes a member of the THO sub-complex, which is an essential component of the large TREX complex involved in mRNA export, chromosome alignment, mitotic progression, and genomic stability in humans. The reported *THOC2* variants, except one, were detected in affected males and are associated with an X-linked recessive pattern of inheritance. Affected males present with speech delay, intellectual disability (borderline to profound), hypotonia, short stature, gait disturbances, variable brain MRI anomalies, and behavior problems (PMIDs: 26166480, 29851191, 32116545). Additional features in a subset of individuals can include microcephaly, seizures, movement disorders, overweight, respiratory abnormalities, and congenital defects. Twenty variants (17 missense, 1 splice, 1 splice region, and 1 intragenic deletion) reported in 20 probands in 4 publications (PMIDs: 26166480, 29851191, 32116545, 35183220) are included in this curation. Variants can be inherited from unaffected carrier mothers or arise *de novo*. Asymptomatic female carriers have highly skewed X-chromosome inactivation. The only reported female patient — a severely affected girl with developmental and epileptic encephalopathy and a *de novo* *THOC2* missense variant (PMID: 29851191) — was not included in this curation; her X-chromosome inactivation status is unknown. Large families have been reported with evidence of strong segregation in multiple affected males, including one family with 11 affected males (PMID: 26166480). The mechanism of disease is suggested to be altered gene product structure leading to partial loss of function (PMID: 32116545). Missense variants lead to decreased protein stability of THOC2 and its TREX-complex partners, while the splicing-defective variants and the intragenic deletion result in C-terminally truncated proteins with partial loss of the RNA binding domain (PMIDs: 29851191, 32116545). *THOC2* is highly constrained for both missense (Z = 5.53, gnomAD v2.1.1) and loss-of-function variants (pLI = 1). This gene-disease relationship is also supported by experimental evidence, including biochemical function, and cell culture, mouse, and yeast models (PMIDs: 22314234, 23222130, 23749989, 38331934). Another THO complex gene, *THOC6*, is also implicated in a neurodevelopmental disorder (PMID: 15998806). In summary, there is definitive evidence supporting the relationship between *THOC2* and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 6, 2024 (SOP Version 11).

intellectual developmental disorder, X-linked, syndromic, Kumar typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010496

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked, syndromic, Kumar typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010496

Submitter: G2P

intellectual developmental disorder, X-linked, syndromic, Kumar typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010496

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 12XL

Manifestation: Craniofacial; Genitourinary; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26166480

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to THOC2 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 201

X-linked intellectual disability-short stature-overweight syndromeTotal: 66

Inborn genetic diseasesTotal: 57

not specifiedTotal: 54

THOC2-related disorderTotal: 28

Intellectual disabilityTotal: 4

Arthrogryposis multiplex congenita 7, X-linkedTotal: 1

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001081550.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			44 clinvar	38 clinvar	6 clinvar	88
missense	5 clinvar	18 clinvar	354 clinvar	6 clinvar	1 clinvar	384
nonsense			31 clinvar			31
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	72 clinvar			74
Total	6	19	501	44	7	577

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001081550.2	RefSeq	NP_001075019.1	38	MANE Select
ENST00000245838.13	Ensembl	ENSP00000245838.8	38	MANE Select
NM_001441235.1	RefSeq	NP_001428164.1	38	Standard
NM_001441236.1	RefSeq	NP_001428165.1	38	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
thoc2	Danio rerio	Structure: hepatocyte Quality: increased size abnormal

Gene / Model

Organism

Observed Phenotype

thoc2

Danio rerio

Structure: hepatocyte

Quality: increased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA transport - Homo sapiens (human)
Spliceosome - Homo sapiens (human)
Gene expression (Transcription)
RNA Polymerase II Transcription
Metabolism of RNA

Biological Process

RNA export from nucleus
mRNA export from nucleus
RNA splicing
poly(A)+ mRNA export from nucleus
mRNA 3'-end processing

Molecular Function

mRNA binding
protein binding

Cellular Component

transcription export complex
THO complex
THO complex part of transcription export complex
nuclear chromosome, telomeric region
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000245838
Coding exons: 38
Length: 132495
Individuals with no LoFs: 116512
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 116513
p: 0.00000429

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.53	178	539	0.330	0.0000389	10545
Missense (PolyPhen)		13	109.03	0.11923		2322
Synonymous	0.201	183	186	0.981	0.0000135	2793
Loss of Function	6.99	1	58.9	0.0170	0.00000433	1237

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000039	0.000032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for efficient export of polyadenylated RNA and spliced mRNA. Acts as component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NFX1 pathway. The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production. THOC2 (and probably the THO complex) is involved in releasing mRNA from nuclear speckle domains. Required for NXF1 localization to the nuclear rim. Plays a role for proper neuronal development. {ECO:0000269|PubMed:11979277, ECO:0000269|PubMed:15833825, ECO:0000269|PubMed:15998806, ECO:0000269|PubMed:17190602, ECO:0000269|PubMed:18974867, ECO:0000269|PubMed:22893130, ECO:0000269|PubMed:23222130, ECO:0000269|PubMed:26166480}.;

Recessive Scores

pRec: 0.118

Intolerance Scores

LoFtool: 0.0182
RVIS EVS: -0.58
RVIS percentile EVS: 18.59

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Indispensability pred.: N
Indispensability score: 0.215

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium