ClinGen Dosage Sensitivity Curation Page


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Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
22335739 Herman et al. (2012) analyzed variants in TTN by NGS or traditional Sanger sequencing in 312 subjects with dilated cardiomyopathy, 231 subjects with hypertrophic cardiomyopathy, and 249 control subjects. They identified 67 truncating variants in the 312 subjects with cardiomyopathy (including 28 nonsense, 19 frameshift, 19 splicing variants, and one tandem duplication). Three truncating variants were identified in the hypertrophic cardiomyopathy group, and seven in the control subjects. When including only subjects with variants detected by NGS methods, nonsense and frameshift variants were significantly enriched in the dilated cardiomyopathy subjects (35 of 163 [21.5%]) compared to hypertrophic cardiomyopathy subjects (2 of 231 [1%], P=2x10^-12) and controls subjects (2 OF 249 [1%], P = 3x10^-13). Splicing variants were also significantly enriched in the dilated cardiomyopathy subjects (18 of 163 [11%]) compared to hypertrophic cardiomyopathy subjects (1 of 231 [<1%], P=7x10^-8) and control subjects (5 of 249 [2%], P=9x10^-6). However, these splicing variants included variants outside of the canonical +/-1,2 splice-site and functional studies were not performed. All three hypertrophic cardiomyopathy subjects with a TTN truncating variant had a second pathogenic variant in a well-established hypertrophic cardiomyopathy gene. The authors note that the truncating variants identified in dilated cardiomyopathy subjects were over-represented in the A-band region of TTN, and were absent from the Z-disk and M-band regions. Variants in the hypertrophic cardiomyopathy subjects and control subjects were less enriched within the A-band region. Segregation analysis of frameshift and nonsense mutations in 20 families confirmed the segregation of truncating variants with dilated cardiomyopathy. Penetrance in these 20 families was more than 95% for subjects over 40 years of age.
23418287 Norton et al. (2013) analyzed variants in TTN in 17 families with dilated cardiomyopathy (DCM) using WES. They identified seven families in which truncating variants in TTN that segregated with the DCM phenotype (three stopgain, two frameshift and two splice-site variants). The maximum LOD score across the genome in each of the seven families was comparable to the LOD score at the TTN locus. However, the TTN variant was also identified in unaffected individuals for whom DNA was available in some families. The variants segregated as follows: family A (present in 3 of 3 DCM subjects, 1 of 1 cardiovascular anomaly subject, and 2 of 2 unaffected subjects <30 yeas old), family D (3 of 3 DCM subjects, 1 of 1 cardiovascular anomaly subjects), family E (3 of 3 DCM subjects, 1 of 2 cardiovascular anomaly subjects), family F (4 of 4 DCM subjects, 1 of 4 cardiovascular anomaly subjects), family G (3 of 3 DCM subjects, 1 obligate carrier without known heart problems), family B (3 of 3 DCM subjects, 2 of 2 cardiovascular anomaly subjects, and 2 apparently unaffected obligated carriers >70 years old), and family C (3 of 3 affected subjects, 1 obligate carrier with cardiovascular anomaly, and 1 unaffected obligate carrier). The authors also identified two additional families in which TTN truncating variants that did not segregate with the dilated cardiomyopathy phenotype. A frameshift variant in family 14 was identified in 1 of 3 DCM subjects, and a nonsense variant in family 17 was identified in 2 of 3 DCM subjects.
31489791 Roggenbuck et al. (2019) detected a 16.4kb deletion of exons 346 to 362 of the TTN gene (NM_001267550.2:c.96076_107488del) in a proband facial weakness, gait abnormality, skeletal muscle weakness, and dilated cardiomyopathy. The deletion impacted the A-band and M-band regions of the TTN protein. Parental testing confirmed the variant arose de novo in the proband, and the deletion was transmitted to three of the probands sons. Two sons were symptomatic for skeletal muscle weakness as of clinical evaluation at <30 years of age, and the third son declined clinical evaluation.
24503780 Pugh et al. (2014) reanalyzed 766 dilated cardiomyopathy patients who underwent genetic testing at a diagnostic laboratory over a five year period. They identified a pathogenic or likely pathogenic TTN variant in 14% of patients, the majority of which were truncating variants. The authors analyzed the NHLBI ESP cohort and identified truncating variants in 107 of 6,500 (1.65%) control subjects. When comparing the distribution of truncating variants within the TTN gene in cases and controls, the authors found the A-band region was enriched for truncating variants in cases compared to controls (OR = 14.6; 99% confidence interval: 4.32?58.5; P < 2?10^?10), replicating the association discovered in Herman et al. (2012), PMID: 22335739. The authors also found a depletion of truncating variants in the I-band in cases compared to controls (OR = 0.13; 99% confidence interval: 0.04?0.43; P < 2?10^?6).
28045975 Franaszczyk et al. (2017) analyzed variants in the TTN gene in 72 dilated cardiomyopathy probands using NGS (mean age of 34 years old). The authors identified a frameshift or nonsense variant in 17 of 72 probands (23.6%), including 10 of 33 (30.3%) familial dilated cardiomyopathy probands and 7 of 39 (17.9%) sporadic dilated cardiomyopathy probands. Fourteen (87.5%) of the 16 unique truncating variants were in the A-band region of TTN. The authors analyzed the segregation of truncating variants in additional family members for whom DNA was available. The familial TTN truncating variant was identified in 29 relatives: 9 (31%) were affected, 8 (27.6%) were likely affected, one (3.4%) was possibly affected, and the remaining 11 carriers (37.9%) were classified as not affected. Penetrance was estimated as 62.1% when including all relatives, and 82.0% when including only relatives over 40 years of age.

Haploinsufficiency phenotype comments:

Truncating variants in the TTN gene have been associated with autosomal dominant dilated cardiomyopathy-1G (OMIM: 604145) and autosomal recessive Salih myopathy (OMIM: 611705). Pathogenic variants (primarily missense) have also been associated with autosomal dominant tibial muscular dystrophy (OMIM: 600334), autosomal dominant myofibrillar myopathy-9 with early respiratory failure (OMIM: 603689), autosomal dominant familial hypertrophic cardiomyopathy-9 (OMIM: 613765), and autosomal recessive limb-girdle muscular dystrophy-10 (OMIM: 608807). The enrichment of truncating variants in dilated cardiomyopathy cases compared to controls has been demonstrated in multiple studies (including PMIDs: 22335739, 24503780, reviewed in 27493940). Familial segregation has been observed, and incomplete penetrance is documented (PMIDs: 23418287, 28045975). Multiple studies have demonstrated the enrichment of truncating variants in the A-band region of the cardiac isoforms N2B and N2BA in individuals with dilated cardiomyopathy (PMIDs: 22335739, 24503780), and truncating variants in cases are located in more highly expressed exons in cardiac tissue (PMID: 25589632). For these reasons, the haploinsufficiency score is 3. Truncating variants in TTN have been identified in approximately 2% of control subjects, which exceeds the estimated population prevalence of dilated cardiomyopathy (PMID: 25589632). The Genome Aggregation Database (gnomAD) includes 445 unique putative truncating variants in the TTN gene (pLI = 0, LOEUF = 0.33). Progress has been made in elucidating the genotype-phenotype relationship of TTN truncating variants. Assigning pathogenicity to a TTN truncating variant requires consideration of its position within the TTN gene, and its correlation with additional clinical or functional data.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity