TCTN3

protein-coding

tectonic family member 3, the group of Tectonic proteins

Gene summary

This gene encodes a member of the tectonic gene family which functions in Hedgehog signal transduction and development of the neural tube. Mutations in this gene have been associated with Orofaciodigital Syndrome IV and Joubert Syndrom 18. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2012]

Previous symbols:

C10orf61

MANE transcript

NM_015631.6

Inheritance

ClinVar variants

P:82U:257B:152

Top phenotype

Joubert syndrome 18; Orofaciodigital syndrome IV (Mohr-Majewski syndrome)

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr10:95,659,823-95,694,143

External References & Databases

Ensembl (ENSG00000119977)

Transcript & Mutation Effects

hg38 • Region Span ~34.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

orofaciodigital syndrome type 6SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010176

Submitter: Orphanet

orofaciodigital syndrome IVSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009794

Submitter: PanelApp Australia

Meckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018921

Submitter: Orphanet

Joubert syndrome 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013896

Submitter: Labcorp Genetics (formerly Invitae)

orofaciodigital syndrome IVSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009794

Submitter: Orphanet

Joubert syndrome 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013896

Submitter: PanelApp Australia

orofaciodigital syndrome IVSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009794

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

orofaciodigital syndrome IVDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009794

Submitter: G2P

orofaciodigital syndrome IVSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009794

Submitter: Labcorp Genetics (formerly Invitae)

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

TCTN3 was first linked to autosomal recessive orofacialdigital syndrome IV (OFDS IV), Meckel-Gruber syndrome (MKS), and Joubert syndrome (JBTS) in 2012 by homozygosity mapping in several unrelated families with affected children diagnosed with these various ciliopathy conditions (PMID: 22883145). Since then, biallelic alterations in *TCTN3* have been identified in patients presenting with abnormalities in several organ systems including kidneys (cystic), brain (corpus callosum agenesis, molar tooth sign, occipital encephalocele, hypotonia, ataxic gait, developmental delay, intellectual disability), limbs and digits (shortened limbs, polydactyly), liver (bile duct proliferation) and dysmorphic facies; many of which are part of the phenotypic spectrum of the above described ciliopathies (PMIDs: 22883145, 22118024, 34096782) . Given the heterogenous phenotypic manifestations of patients with biallelic variants in *TCTN3*, (highlighted in the first, Thomas et al., study (PMID: 22883145)), but no apparent differences in molecular mechanism of disease pathogenesis, the gene disease association of *TCTN3* has been lumped to the ‘Ciliopathy’ term in adherence with criteria established by the Lumping and Splitting working group. Several other recent studies have also reported patients with biallelic *TCTN3* variants who present with similar symptoms (PMIDs: 26092869, 30629328, 32139166, 34411415, 35170189). Within these reports, many probands present with renal symptoms including cystic kidneys and imaging abnormalities among other clinical findings (PMIDs: 22883145, 26092869, 32139166, 34096782, 34411415). Overall, the genetic evidence included in the curation has reached the maximum of 12 points. Evidence supporting gene-disease relationship not only includes genetic case-level data but also experimental data using mouse models and cell lines derived from patients harboring *TCTN3* mutations. These animal models have recapitulated an array of defects observed in patients including cystic kidneys, skeletal, and neurological abnormalities (PMIDs: 28800946, 29725084). Further, the animal and cell-based studies have demonstrated that absence of Tctn3 results in aberrant Sonic Hedgehog (Shh) signaling via improper modulation of GLI3 protein levels, a key component of Shh pathway and leads to reduced cilia formation, both of which can be rescued by overexpressing wild-type Tctn3 (PMID: 22883145, 28800946, 29725084). The experimental evidence was scored at a total of 4 points. Hence, biallelic pathogenic variants in *TCTN3* are “Definitely” associated with autosomal recessive ciliopathy. Importantly, the genetic and experimental evidence supporting gene-disease validity has been replicated over time in both research and clinical diagnostic settings. This classification was approved by the ClinGen Kideny Cystic and Ciliopathy Disorders Expert Panel on the meeting date 11/10/2022 (SOP Version 8).

Clinical Genomic Database (CGD)

Joubert syndrome 18; Orofaciodigital syndrome IV (Mohr-Majewski syndrome)AR

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Renal

Intervention: Cardiovascular

Rationale: The condition can include congenital cardiac anomalies, and awareness may allow early identification and management

Comments: The condition can include cardiac, renal, and other manifestations

Refs: 22883145

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TCTN3 variants in ClinVar

11 Conditions Cataloged

Orofacial-digital syndrome IVTotal: 481

Joubert syndrome 18Total: 480

not providedTotal: 104

Inborn genetic diseasesTotal: 84

not specifiedTotal: 80

TCTN3-related disorderTotal: 54

Joubert syndrome and related disordersTotal: 9

CiliopathyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015631.6. 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			6 clinvar	140 clinvar		146
missense	1 clinvar	1 clinvar	233 clinvar	10 clinvar	1 clinvar	246
nonsense	4 clinvar	13 clinvar	3 clinvar	1 clinvar		21
start loss	2 clinvar	3 clinvar				5
frameshift	21 clinvar	21 clinvar	8 clinvar			50
splice donor/acceptor (+/-2bp)	2 clinvar	14 clinvar	7 clinvar			23
Total	30	52	257	151	1	491

Highest pathogenic variant AF is 0.00019660068

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 73 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015631.6	RefSeq	NP_056446.4	14	MANE Select
ENST00000371217.10	Ensembl	ENSP00000360261.5	14	MANE Select
NM_001143973.2	RefSeq	NP_001137445.1	10	Standard
NM_001410982.1	RefSeq	NP_001397911.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Anchoring of the basal body to the plasma membrane
Cilium Assembly
Organelle biogenesis and maintenance

Biological Process

apoptotic process
smoothened signaling pathway
positive regulation of apoptotic process
cilium assembly
ciliary basal body-plasma membrane docking

Cellular Component

nucleus
integral component of membrane
ciliary membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371217
Coding exons: 14
Length: 30743
Individuals with no LoFs: 125698
Homozygous LoFs: 0
Heterozygous LoFs: 50
Defined: 125748
p: 0.000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.836	273	315	0.867	0.0000144	3936
Missense (PolyPhen)		63	79.309	0.79436		1064
Synonymous	0.382	115	120	0.956	0.00000570	1219
Loss of Function	1.38	22	30.2	0.728	0.00000135	352

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00054	0.00054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00036	0.00036	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition (By similarity). May be involved in apoptosis regulation. Necessary for signal transduction through the sonic hedgehog (Shh) signaling pathway. {ECO:0000250, ECO:0000269|PubMed:17464193, ECO:0000269|PubMed:22883145}.;
Disease: DISEASE: Orofaciodigital syndrome 4 (OFD4) [MIM:258860]: A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD4 patients have tongue nodules, multiple frenulae, broad flat nose, hypertelorism, and short rib polydactyly with tibial dysplasia (Majewski syndrome). The presence of severe tibial aplasia differentiates OFD4 from OFD1. Additional features of cystic dysplastic kidneys and brain malformation, including occipital encephalocele, are observed in severely affected patients. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Joubert syndrome 18 (JBTS18) [MIM:614815]: A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. JBTS18 patients have vermis agenesis and the molar tooth sign as well as severe kyphoscoliosis. Other features include intrauterine growth retardation, oral anomalies, micrognathism, polydactyly and camptodactyly, joint laxity, horseshoe kidney, and ventricular septal defect. {ECO:0000269|PubMed:22883145}. Note=The disease is caused by mutations affecting the gene represented in this entry. TCTN3-mutated fibroblasts from JBTS18 patients fail to respond to Shh agonists suggesting that at least some of the defects in affected individuals may be secondary to reduced Shh signaling (PubMed:22883145). {ECO:0000269|PubMed:22883145}.;

Recessive Scores

pRec: 0.0867

Intolerance Scores

LoFtool: 0.223
RVIS EVS: 0.24
RVIS percentile EVS: 69.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.141

Gene Damage Prediction

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