Human Gene Module / Chromosome 2 / TTN

TTNtitin

Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
10 / 20
Rare Variants / Common Variants
53 / 0
Aliases
TTN, CMD1G,  CMH9,  CMPD4
Associated Syndromes
Tourette syndrome, Bannayan-Riley-Ruvalcaba syndrome (BRRS)
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
2q31.2
Associated Disorders
ASD, DD/NDD, EPS
Relevance to Autism

Rare mutations in the TTN gene have been identified with autism (O'Roak et al., 2011 & 2012).

Molecular Function

Key component in the assembly and functioning of vertebrate striated muscles. Contributes to fine balance of forces between two halves of the sarcomere.

Reports related to TTN (19 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies. Charton K , et al. (2010) No -
2 Primary Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. O'Roak BJ , et al. (2011) Yes -
3 Recent Recommendation Pathogenity of some limb girdle muscular dystrophy mutations can result from reduced anchorage to myofibrils and altered stability of calpain 3. Ermolova N , et al. (2011) No -
4 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
5 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
6 Support Diagnostic exome sequencing in persons with severe intellectual disability. de Ligt J , et al. (2012) No Epilepsy, ASD
7 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
8 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
9 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
10 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. Takata A , et al. (2016) No -
11 Positive Association De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Willsey AJ , et al. (2017) No -
12 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder. Krupp DR , et al. (2017) Yes -
13 Recent Recommendation Germline TTN variants are enriched in PTEN-wildtype Bannayan-Riley-Ruvalcaba syndrome. Yehia L , et al. (2017) No ASD/DD
14 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. Takata A , et al. (2018) Yes -
15 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes. Guo H , et al. (2018) Yes -
16 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Ruzzo EK , et al. (2019) Yes -
17 Highly Cited Reversible unfolding of individual titin immunoglobulin domains by AFM. Rief M , et al. (1997) No -
18 Highly Cited Folding-unfolding transitions in single titin molecules characterized with laser tweezers. Kellermayer MS , et al. (1997) No -
19 Highly Cited Elasticity and unfolding of single molecules of the giant muscle protein titin. Tskhovrebova L , et al. (1997) No -
Rare Variants   (53)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2138G>A p.Arg713Gln missense_variant - - - 29263846 Yehia L , et al. (2017)
c.23497G>C p.Gly7833Arg missense_variant - - - 29263846 Yehia L , et al. (2017)
c.28549G>A p.Val9517Met missense_variant - - - 29263846 Yehia L , et al. (2017)
c.29317G>A p.Ala9773Thr missense_variant - - - 29263846 Yehia L , et al. (2017)
c.33856G>A p.Glu11286Lys missense_variant - - - 29263846 Yehia L , et al. (2017)
c.66187G>C p.Val22063Leu missense_variant - - - 29263846 Yehia L , et al. (2017)
c.68770G>A p.Ala22924Thr missense_variant - - - 29263846 Yehia L , et al. (2017)
c.80425G>A p.Gly26809Ser missense_variant - - - 29263846 Yehia L , et al. (2017)
c.92488G>A p.Val30830Ile missense_variant - - - 29263846 Yehia L , et al. (2017)
c.99154C>T p.Arg33052Cys missense_variant - - - 29263846 Yehia L , et al. (2017)
c.104575C>T p.Arg34859Trp missense_variant - - - 29263846 Yehia L , et al. (2017)
c.104981G>A p.Ser34994Asn missense_variant - - - 29263846 Yehia L , et al. (2017)
c.28312C>T p.Arg9438Ter stop_gained De novo NA - 25363760 De Rubeis S , et al. (2014)
c.5255G>A p.Arg1752His missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.8884G>C p.Ala2962Pro missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.23624G>A p.Gly7875Glu missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.25105G>A p.Val8369Ile missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.71435G>T p.Gly23812Val missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.75995G>A p.Gly25332Asp missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.44077C>T p.Pro14693Ser missense_variant De novo NA Simplex 30504930 Guo H , et al. (2018)
c.184C>T p.Arg62Cys missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.34186+1G>A - splice_site_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.34942+2T>C - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.44725+3del - splice_site_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.48137G>T p.Gly16046Val missense_variant Familial Maternal - 23033978 de Ligt J , et al. (2012)
c.98224G>C p.Gly32742Arg missense_variant Familial Paternal - 23033978 de Ligt J , et al. (2012)
c.74339G>A p.Arg24780Gln missense_variant De novo NA Simplex 22495309 O'Roak BJ , et al. (2012)
c.19976C>T p.Thr6659Met missense_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.13202G>A p.Arg4401Gln missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.82386G>A p.Thr27462%3D synonymous_variant De novo NA Simplex 29346770 Takata A , et al. (2018)
c.48316A>G p.Thr16106Ala missense_variant De novo NA Multiplex 31398340 Ruzzo EK , et al. (2019)
c.65710C>A p.Leu21904Ile missense_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.97055G>A p.Arg32352His missense_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.45197G>C p.Gly15066Ala missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.48025G>A p.Val16009Met missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.85579G>A p.Gly28527Ser missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.34265-570T>G - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.73149G>A p.Ser24383%3D synonymous_variant De novo NA Simplex 21572417 O'Roak BJ , et al. (2011)
c.11707C>A p.Pro3903Thr missense_variant Familial Paternal Simplex 28867142 Krupp DR , et al. (2017)
c.41829dup p.Leu13944SerfsTer8 frameshift_variant De novo NA Multiplex 30504930 Guo H , et al. (2018)
c.31145-3_31167del - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.15286T>C p.Cys5096Arg missense_variant Familial Paternal Multi-generational 29263846 Yehia L , et al. (2017)
c.46513+1G>A - splice_site_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.8651T>A p.Ile2884Asn missense_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.10731G>C p.Lys3577Asn missense_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.18550G>A p.Ala6184Thr missense_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.18943G>A p.Val6315Met missense_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.78590C>T p.Pro26197Leu missense_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.107723T>C p.Ile35908Thr missense_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.17297G>C;c.17672G>C;c.17873G>C;c.36788G>C;c.39569G>C;c.44492G>C p.Gly5766Ala;p.Gly5891Ala;p.Gly5958Ala;p.Gly12263Ala;p.Gly13190Ala;p.Gly14831Ala missense_variant De novo NA Simplex 28472652 Willsey AJ , et al. (2017)
c.17603G>A;c.17978G>A;c.18179G>A;c.G37094G>A;c.39875G>Ac.44798G>A p.Cys5868Tyr;p.Cys5993Tyr;p.Cys6060Tyr;p.Cys12365Tyr;p.Cys13292Tyr;p.Cys14933Tyr missense_variant De novo NA Simplex 28472652 Willsey AJ , et al. (2017)
c.23518C>T;c.23893C>T;c.24094C>T;c.43009C>T;c.45790C>T;c.50713C>T p.Arg7840Cys;p.Arg7965Cys;p.Arg8032Cys;p.Arg14337Cys;p.Arg15264Cys;p.Arg16905Cys missense_variant De novo NA Simplex 28472652 Willsey AJ , et al. (2017)
c.73472T>C;c.73847T>Cc.74048T>C;c.92963T>C;c.95744T>C;c.100667T>C p.Ile24491Thr;p.Ile24616Thr;p.Ile24683Thr;p.Ile30988Thr;p.Ile31915Thr;p.Ile33556Thr missense_variant De novo NA Simplex 28472652 Willsey AJ , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

A rare, synonymous de novo mutation in the TTN gene has been identified in an individual with autism (O'Roak et al., 2011). Many synonymous and missense mutations were observed in controls as well. De novo missense variants in the TTN gene have subsequently been identified in four unrelated ASD probands from the Simons Simplex Collection; these variants were not observed in controls (PMIDs 22495309, 22542183). Yehia et al., 2017 demonstrated that rare germline variants in TTN were enriched in patients with PTEN-wildtype Bannayan-Riley-Ruvalcaba syndrome (BRRS), a disorder characterized by macrocephaly in combination with intestinal hamartomatous polyposis, vascular malformations, lipomas, and genital lentiginosis; ASD/developmental delay was a frequently observed phenotype in BRRS patients with germline TTN variants (4/12 individuals in Table 1 in this report).

Score Delta: Decreased from 4S to 3S

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A rare, synonymous de novo mutation in the TTN gene has been identified in an individual with autism (O'Roak et al., 2011). Many synonymous and missense mutations were observed in controls as well. De novo missense variants in the TTN gene have subsequently been identified in four unrelated ASD probands from the Simons Simplex Collection; these variants were not observed in controls (PMIDs 22495309, 22542183). Yehia et al., 2017 demonstrated that rare germline variants in TTN were enriched in patients with PTEN-wildtype Bannayan-Riley-Ruvalcaba syndrome (BRRS), a disorder characterized by macrocephaly in combination with intestinal hamartomatous polyposis, vascular malformations, lipomas, and genital lentiginosis; ASD/developmental delay was a frequently observed phenotype in BRRS patients with germline TTN variants (4/12 individuals in Table 1 in this report).

Reports Added
[New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

A rare, synonymous de novo mutation in the TTN gene has been identified in an individual with autism (O'Roak et al., 2011). Many synonymous and missense mutations were observed in controls as well. De novo missense variants in the TTN gene have subsequently been identified in four unrelated ASD probands from the Simons Simplex Collection; these variants were not observed in controls (PMIDs 22495309, 22542183). Yehia et al., 2017 demonstrated that rare germline variants in TTN were enriched in patients with PTEN-wildtype Bannayan-Riley-Ruvalcaba syndrome (BRRS), a disorder characterized by macrocephaly in combination with intestinal hamartomatous polyposis, vascular malformations, lipomas, and genital lentiginosis; ASD/developmental delay was a frequently observed phenotype in BRRS patients with germline TTN variants (4/12 individuals in Table 1 in this report).

10/1/2018
4S
icon
4S

Decreased from 4S to 4S

Description

A rare, synonymous de novo mutation in the TTN gene has been identified in an individual with autism (O'Roak et al., 2011). Many synonymous and missense mutations were observed in controls as well. De novo missense variants in the TTN gene have subsequently been identified in four unrelated ASD probands from the Simons Simplex Collection; these variants were not observed in controls (PMIDs 22495309, 22542183). Yehia et al., 2017 demonstrated that rare germline variants in TTN were enriched in patients with PTEN-wildtype Bannayan-Riley-Ruvalcaba syndrome (BRRS), a disorder characterized by macrocephaly in combination with intestinal hamartomatous polyposis, vascular malformations, lipomas, and genital lentiginosis; ASD/developmental delay was a frequently observed phenotype in BRRS patients with germline TTN variants (4/12 individuals in Table 1 in this report).

10/1/2017
4
icon
4

Decreased from 4 to 4

Description

A rare, synonymous de novo mutation in the TTN gene has been identified in an individual with autism (O'Roak et al., 2011). Many synonymous and missense mutations were observed in controls as well. De novo missense variants in the TTN gene have subsequently been identified in four unrelated ASD probands from the Simons Simplex Collection; these variants were not observed in controls (PMIDs 22495309, 22542183)

4/1/2017
4
icon
4

Decreased from 4 to 4

Description

A rare, synonymous de novo mutation in the TTN gene has been identified in an individual with autism (O'Roak et al., 2011). Many synonymous and missense mutations were observed in controls as well. De novo missense variants in the TTN gene have subsequently been identified in four unrelated ASD probands from the Simons Simplex Collection; these variants were not observed in controls (PMIDs 22495309, 22542183)

4/1/2016
4
icon
4

Decreased from 4 to 4

Description

A rare, synonymous de novo mutation in the TTN gene has been identified in an individual with autism (O'Roak et al., 2011). Many synonymous and missense mutations were observed in controls as well. De novo missense variants in the TTN gene have subsequently been identified in four unrelated ASD probands from the Simons Simplex Collection; these variants were not observed in controls (PMIDs 22495309, 22542183)

1/1/2016
4
icon
4

Decreased from 4 to 4

Description

A rare, synonymous de novo mutation in the TTN gene has been identified in an individual with autism (O'Roak et al., 2011). Many synonymous and missense mutations were observed in controls as well. De novo missense variants in the TTN gene have subsequently been identified in four unrelated ASD probands from the Simons Simplex Collection; these variants were not observed in controls (PMIDs 22495309, 22542183)

7/1/2015
6
icon
4

Decreased from 6 to 4

Description

A rare, synonymous de novo mutation in the TTN gene has been identified in an individual with autism (O'Roak et al., 2011). Many synonymous and missense mutations were observed in controls as well. De novo missense variants in the TTN gene have subsequently been identified in four unrelated ASD probands from the Simons Simplex Collection; these variants were not observed in controls (PMIDs 22495309, 22542183)

1/1/2015
6
icon
6

Decreased from 6 to 6

Description

A rare, synonymous de novo mutation in the TTN gene has been identified in an individual with autism (O'Roak et al., 2011). Many synonymous and missense mutations were observed in controls as well.

7/1/2014
No data
icon
6

Increased from No data to 6

Description

A rare, synonymous de novo mutation in the TTN gene has been identified in an individual with autism (O'Roak et al., 2011). Many synonymous and missense mutations were observed in controls as well.

4/1/2014
No data
icon
6

Increased from No data to 6

Description

A rare, synonymous de novo mutation in the TTN gene has been identified in an individual with autism (O'Roak et al., 2011). Many synonymous and missense mutations were observed in controls as well.

Krishnan Probability Score

Score 0.48522780078407

Ranking 7396/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 1.2111137710581E-32

Ranking 18176/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.95088327929501

Ranking 18665/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 17

Ranking 121/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score -0.1783209180586

Ranking 14917/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
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