Human Gene Module / Chromosome 2 / TTN

TTNtitin

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
20 / 33
Rare Variants / Common Variants
164 / 0
Aliases
TTN, CMD1G,  CMH9,  CMPD4
Associated Syndromes
Tourette syndrome, Bannayan-Riley-Ruvalcaba syndrome (BRRS)
Chromosome Band
2q31.2
Associated Disorders
DD/NDD, ASD, EPS, ID
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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TTN (33 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 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
18 Support De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism Cappi C , et al. (2019) No -
19 Support Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolescent Trio-Based Sample Jiao J , et al. (2019) Yes -
20 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) Yes DD, ID
21 Support - Tuncay IO et al. (2022) Yes ADHD, DD, ID
22 Support - Woodbury-Smith M et al. (2022) Yes -
23 Support - N.Y.) (07/2) Yes -
24 Support - Zhou X et al. (2022) Yes -
25 Support - Wang J et al. (2023) Yes -
26 Support - Tuncay IO et al. (2023) Yes -
27 Support - Cirnigliaro M et al. (2023) Yes -
28 Support - et al. () No Autistic features
29 Support - et al. () No -
30 Support - et al. () Yes ID
31 Highly Cited Reversible unfolding of individual titin immunoglobulin domains by AFM Rief M , et al. (1997) No -
32 Highly Cited Folding-unfolding transitions in single titin molecules characterized with laser tweezers Kellermayer MS , et al. (1997) No -
33 Highly Cited Elasticity and unfolding of single molecules of the giant muscle protein titin Tskhovrebova L , et al. (1997) No -
Rare Variants   (164)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.10360+5464A>T - stop_gained De novo - - 35901164 N.Y.) (07/2)
c.56153G>A p.Trp18718Ter stop_gained Unknown - Unknown 37799141 et al. ()
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.47227C>T p.Pro15743Ser stop_gained De novo - - 35982159 Zhou X et al. (2022)
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.10360+2288T>C - missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.5094G>C p.Glu1698Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7619G>A p.Arg2540His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.34265-579T>C - synonymous_variant De novo - - 31452935 Feliciano P et al. (2019)
c.14602A>G p.Lys4868Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.15659A>G p.Asn5220Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.28875G>C p.Lys9625Asn missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.10360+2008G>T - intron_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.41474G>A p.Arg13825Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.46929T>A p.His15643Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.47447T>C p.Leu15816Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.52117C>T p.Pro17373Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.54085G>A p.Glu18029Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.56143A>T p.Thr18715Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.58672A>G p.Asn19558Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.66136C>T p.Pro22046Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.74339G>A p.Arg24780Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8349G>A p.Arg2783%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.9324G>A p.Glu3108%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.47086C>T p.Arg15696Ter stop_gained De novo - - 31452935 Feliciano P et al. (2019)
c.28312C>T p.Arg9438Ter stop_gained De novo - - 25363760 De Rubeis S , et al. (2014)
c.10360+3611C>T - intron_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.10360+5350G>A - intron_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.10114+2216_10114+2281del - intron_variant De novo - - 35982159 Zhou X et al. (2022)
c.13227C>T p.Ser4409%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.22341C>A p.Pro7447%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.48957T>G p.Val16319%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.75825T>C p.Tyr25275%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.30503C>A p.Thr10168Lys missense_variant Familial Both parents - 38177409 et al. ()
c.13858+4227T>C p.Ile3934= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.5255G>A p.Arg1752His missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.8884G>C p.Ala2962Pro missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.13858+10798C>A p.Ser5450Tyr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.80203A>C p.Lys26735Gln missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.98434G>A p.Val32812Met missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.23624G>A p.Gly7875Glu missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.25105G>A p.Val8369Ile missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.21333G>A p.Met7111Ile missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2399A>G p.Glu800Gly missense_variant Unknown - Simplex 32530565 Suzuki T et al. (2020)
c.184C>T p.Arg62Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.71435G>T p.Gly23812Val missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.75995G>A p.Gly25332Asp missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.908C>T p.Pro303Leu missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.44077C>T p.Pro14693Ser missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.42241G>A p.Ala14081Thr missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.44925T>G p.Phe14975Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.47720G>A p.Arg15907Gln missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.61409G>A p.Arg20470His missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.75872T>A p.Leu25291His missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.62328G>A p.Ser20776= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.26999G>A p.Arg9000His missense_variant De novo - Simplex 31838722 Jiao J , et al. (2019)
c.21642C>T p.Asn7214%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.29049A>G p.Pro9683%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.21506A>G p.Asn7169Ser missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.12428G>C p.Arg4143Thr missense_variant Unknown - Simplex 32530565 Suzuki T et al. (2020)
c.36711G>A p.Val12237%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.52962G>T p.Pro17654%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.94129A>G p.Met31377Val missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.44492G>C p.Gly14831Ala missense_variant De novo - Simplex 31771860 Cappi C , et al. (2019)
c.44798G>A p.Cys14933Tyr missense_variant De novo - Simplex 31771860 Cappi C , et al. (2019)
c.50713C>T p.Arg16905Cys missense_variant De novo - Simplex 31771860 Cappi C , et al. (2019)
c.30358C>A p.Leu10120Ile missense_variant Unknown - Simplex 32530565 Suzuki T et al. (2020)
c.31217T>C p.Val10406Ala missense_variant Unknown - Simplex 32530565 Suzuki T et al. (2020)
c.1653T>C p.Thr551%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.12307G>A p.Val4103Ile missense_variant Unknown - Multiplex 32530565 Suzuki T et al. (2020)
c.5038C>G p.Leu1680Val missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
c.6982G>A p.Val2328Ile missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
c.7969A>G p.Lys2657Glu missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
c.82386G>A p.Thr27462= synonymous_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.13202G>A p.Arg4401Gln missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.30255G>C p.Gln10085His missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.51593A>G p.Asn17198Ser missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.62761C>T p.Pro20921Ser missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.65431C>T p.Pro21811Ser missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.69227T>C p.Ile23076Thr missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.88636G>A p.Val29546Ile missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.89548A>C p.Ile29850Leu missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.43069G>C p.Gly14357Arg missense_variant Unknown - Multiplex 32530565 Suzuki T et al. (2020)
c.15163G>C p.Glu5055Gln missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
c.74339G>A p.Arg24780Gln missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.45197G>C p.Gly15066Ala missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.48025G>A p.Val16009Met missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.85579G>A p.Gly28527Ser missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.73149G>A p.Ser24383= synonymous_variant De novo - Simplex 21572417 O'Roak BJ , et al. (2011)
c.19976C>T p.Thr6659Met missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.14226G>A p.Glu4742%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.13858+10798C>A p.Ser5450Tyr missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.36201A>T p.Glu12067Asp missense_variant Familial Maternal - 37492102 Tuncay IO et al. (2023)
c.39961C>T p.Pro13321Ser missense_variant Familial Maternal - 37492102 Tuncay IO et al. (2023)
c.43624G>A p.Val14542Ile missense_variant Familial Maternal - 37492102 Tuncay IO et al. (2023)
c.48395G>A p.Arg16132His missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
c.61012G>A p.Gly20338Arg missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
c.73391G>A p.Arg24464Gln missense_variant Familial Maternal - 37492102 Tuncay IO et al. (2023)
c.84383G>A p.Arg28128His missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
c.85472G>A p.Arg28491His missense_variant Familial Maternal - 37492102 Tuncay IO et al. (2023)
c.95582A>G p.Tyr31861Cys missense_variant Familial Maternal - 37492102 Tuncay IO et al. (2023)
c.48316A>G p.Thr16106Ala missense_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.65710C>A p.Leu21904Ile missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.97055G>A p.Arg32352His missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.79788C>T p.Ser26596%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.98034T>C p.Cys32678%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.13859-22193C>T p.Pro12077Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.102805G>C p.Ala34269Pro missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
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.34265-570T>G - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.41829dup p.Leu13944SerfsTer8 frameshift_variant De novo - Multiplex 30504930 Guo H , et al. (2018)
c.33808+2T>C - splice_site_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.11707C>A p.Pro3903Thr missense_variant Familial Paternal Simplex 28867142 Krupp DR , et al. (2017)
c.11927C>T p.Thr3976Met missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.12178G>A p.Ala4060Thr missense_variant Familial Paternal Simplex 35190550 Tuncay IO et al. (2022)
c.14327T>C p.Leu4776Ser missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.16001C>T p.Pro5334Leu missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.20222G>A p.Gly6741Asp missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.20828C>A p.Ser6943Tyr missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.24243T>A p.Asp8081Glu missense_variant Familial Paternal Simplex 35190550 Tuncay IO et al. (2022)
c.28733A>G p.Lys9578Arg missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.28997T>C p.Val9666Ala missense_variant Familial Paternal Simplex 35190550 Tuncay IO et al. (2022)
c.7498C>T p.Gln2500Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.31399C>G p.Leu10467Val missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.33742G>A p.Val11248Ile missense_variant Familial Paternal Simplex 35190550 Tuncay IO et al. (2022)
c.33905G>A p.Arg11302Gln missense_variant Familial Paternal Simplex 35190550 Tuncay IO et al. (2022)
c.38639C>T p.Pro12880Leu missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.39653T>C p.Leu13218Ser missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.46942G>A p.Gly15648Arg missense_variant Familial Paternal Simplex 35190550 Tuncay IO et al. (2022)
c.53512C>T p.Arg17838Cys missense_variant Familial Paternal Simplex 35190550 Tuncay IO et al. (2022)
c.54684T>A p.Phe18228Leu missense_variant Familial Paternal Simplex 35190550 Tuncay IO et al. (2022)
c.68422C>T p.Arg22808Cys missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.78308C>A p.Ala26103Asp missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.79760A>T p.Glu26587Val missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.90617G>A p.Arg30206His missense_variant Familial Paternal Simplex 35190550 Tuncay IO et al. (2022)
c.31145-3_31167del - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.48137G>T p.Gly16046Val missense_variant Familial Maternal Simplex 23033978 de Ligt J , et al. (2012)
c.98224G>C p.Gly32742Arg missense_variant Familial Paternal Simplex 23033978 de Ligt J , et al. (2012)
c.98159T>G p.Leu32720Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.103043_103044insA p.Thr34349AspfsTer11 frameshift_variant Familial Paternal Multiplex 38256266 et al. ()
c.46513+1G>A - splice_site_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.15286T>C p.Cys5096Arg missense_variant Familial Paternal Multi-generational 29263846 Yehia L , et al. (2017)
c.8651T>A p.Ile2884Asn missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.10731G>C p.Lys3577Asn missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.18550G>A p.Ala6184Thr missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.18943G>A p.Val6315Met missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.78590C>T p.Pro26197Leu missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.107723T>C p.Ile35908Thr missense_variant De novo - 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 - 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 - 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 - 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 - Simplex 28472652 Willsey AJ , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, 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: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

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."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

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).

7/1/2020
3S
icon
3S

Decreased from 3S to 3S

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
[A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020]
1/1/2020
3S
icon
3S

Decreased from 3S to 3S

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
[De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism.2019] [Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolesce...2019]
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
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [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).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
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).

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
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)

Reports Added
[Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017]
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)

Reports Added
[Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Reversible unfolding of individual titin immunoglobulin domains by AFM.1997] [Folding-unfolding transitions in single titin molecules characterized with laser tweezers.1997] [Elasticity and unfolding of single molecules of the giant muscle protein titin.1997] [Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies.2010] [Pathogenity of some limb girdle muscular dystrophy mutations can result from reduced anchorage to myofibrils and altered stability of calpain 3.2011] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016] [De Novo Coding Variants Are Strongly Associated with Tourette Disorder.2017]
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)

Reports Added
[Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Reversible unfolding of individual titin immunoglobulin domains by AFM.1997] [Folding-unfolding transitions in single titin molecules characterized with laser tweezers.1997] [Elasticity and unfolding of single molecules of the giant muscle protein titin.1997] [Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies.2010] [Pathogenity of some limb girdle muscular dystrophy mutations can result from reduced anchorage to myofibrils and altered stability of calpain 3.2011] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016]
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)

Reports Added
[Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Reversible unfolding of individual titin immunoglobulin domains by AFM.1997] [Folding-unfolding transitions in single titin molecules characterized with laser tweezers.1997] [Elasticity and unfolding of single molecules of the giant muscle protein titin.1997] [Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies.2010] [Pathogenity of some limb girdle muscular dystrophy mutations can result from reduced anchorage to myofibrils and altered stability of calpain 3.2011] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014]
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.

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
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.
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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.
Original Source
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