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Survivors of adolescent and young adult (AYA; age 15-39 years at diagnosis) cancer are a growing population with the potential to live for many decades after treatment completion. Survivors of AYA cancer are at risk for adverse long-term outcomes including chronic conditions, secondary cancers, impaired fertility, poor psychosocial health and health behaviors, and financial toxicity. Furthermore, survivors of AYA cancer from racially minoritized and low socioeconomic status populations experience disparities in these outcomes, including lower long-term survival. Despite these known risks, most survivors of AYA cancer do not receive routine survivorship follow-up care, and research on delivering high-quality, evidence-based survivorship care to these patients is lacking. The need for survivorship care was initially advanced in 2006 by the Institute of Medicine. In 2019, the Quality of Cancer Survivorship Care Framework (QCSCF) was developed to provide an evidence-based framework to define key components of optimal survivorship care. In this commentary focused on survivors of AYA cancer, we apply the QCSCF framework to describe models of care that can be adapted for their unique needs, multilevel factors limiting equitable access to care, and opportunities to address these factors to improve short- and long-term outcomes in this vulnerable population. [ABSTRACT FROM AUTHOR]

Background: Survivors of adolescent and young adult (AYA) cancer experience significant psychological distress and encounter barriers to accessing mental health care. Few studies have investigated racial/ethnic disparities in psychological health outcomes among AYA survivors, and none have compared outcomes within a racially minoritized population. Methods: National Health Interview Survey data (2010–2018) were analyzed that identified non‐Hispanic Black (hereafter, Black) survivors of AYA cancer and age‐ and sex‐matched Black noncancer controls. Sociodemographic factors, chronic health conditions, modifiable behaviors (smoking and alcohol use), and psychological outcomes were assessed with χ2 tests. Logistic regression models, adjusted for survey weights, were used to evaluate the odds of psychological distress by cancer status after adjusting for covariates. Interactions between variables and cancer status were investigated. Results: The study included 334 Black survivors of AYA cancer and 3340 Black controls. Compared to controls, survivors were more likely to report moderate/severe distress (odds ratio [OR], 1.64; p <.001), use mental health care (OR, 1.53; p =.027), report an inability to afford mental health care (OR, 3.82; p <.001), and use medication for anxiety and/or depression (OR, 2.16; p =.001). Forty‐one percent of survivors reported moderate/severe distress, and only 15% used mental health care. Among survivors, ages 18–39 years (vs. 40–64 years) and current smoking (vs. never smoking) were associated with the presence of moderate/severe distress. Among survivors with distress, high poverty status was associated with reduced utilization of mental health care. Conclusions: A cancer diagnosis for a Black AYA is associated with greater psychological distress within an already vulnerable population. Black survivors of adolescent and young adult cancer have higher levels of psychological distress than Black individuals without a history of cancer and are more likely to report an inability to afford mental health care. There is a gap in receipt of mental health care among Black survivors, with approximately 40% of survivors reporting moderate/severe distress and only 15% reporting a mental health care visit. [ABSTRACT FROM AUTHOR]

Purpose: Childhood, adolescent, and young adult (CAYA) cancer survivors (age 0–39 years at diagnosis) are at increased risk of cardiovascular disease (CVD). Family history of early heart disease increases the risk of CVD in the general population; however, it is unknown whether this association is seen in CAYA cancer survivors. Methods: Self-report data from the National Health and Nutrition Examination Survey (2005–2018) were used to identify CAYA survivors (>5 years post-diagnosis). The risk of CVD based on family history status (parent or sibling with a diagnosis of heart attack or angina before age 50 years), personal sociodemographic factors, personal medical history factors, and personal behavioral risk factors was determined using logistic regression models. Results: Included were 95 CAYA survivors with CVD and 491 CAYA survivors without CVD. The odds of CVD were significantly higher in survivors with a first-degree family history of early heart disease (odds ratio [OR]: 2.06, 95% confidence interval [CI]: 1.14–3.74). A history of diabetes (OR: 2.61, 95% CI: 1.41–4.84), hypertension (OR: 1.81, 95% CI: 1.04–3.16), and any smoking (OR: 2.19, 95% CI: 1.19–4.02) was also associated with higher odds of CVD in CAYA survivors. Reporting any physical activity in the past month was associated with lower odds (OR: 0.54, 95% CI: 0.30–0.97) of CVD. Conclusions: Family history of early heart disease was associated with increased odds of CVD in CAYA cancer survivors. Obtaining complete and accurate family history information is important both at time of diagnosis and throughout follow-up. [ABSTRACT FROM AUTHOR]

Purpose: While there are known disparities in socioeconomic status (SES) and health outcomes among racially and ethnically minoritized adolescent and young adult (AYA; ages 15–39 years at diagnosis) cancer survivors compared with White survivors, outcomes in the Asian survivor population are understudied. To better understand the association of an AYA cancer diagnosis with SES and health outcomes within a minoritized population, the current study makes comparisons between individuals of the same race or ethnicity with and without a history of AYA cancer. Methods: Non-Hispanic, Asian AYA cancer survivors and non-Hispanic, Asian age- and sex-matched controls were identified from self-reported data in the National Health Interview Survey (2009–2020). Prevalence of chronic health conditions and socioeconomic factors were compared between groups using chi-square tests. Odds of chronic conditions by SES factors were determined within and between survivors and controls using logistic regression methods. Results: One hundred and thirty-one survivors and 1310 controls were included. Survivors were less likely to be married compared with controls; however, there were no differences in other SES factors examined. Survivors had higher odds of at least one chronic condition diagnosis (odds ratio = 4.17, p < 0.001) compared with controls. Of the chronic conditions assessed, survivors had higher odds of arthritis, pulmonary disease, and hypertension compared with controls. Conclusions: Asian AYA cancer survivors are at increased risk of chronic health conditions compared with Asian individuals without a cancer history. Culturally adapted targeted interventions are needed to improve health outcomes for this population. [ABSTRACT FROM AUTHOR]

Background: In the general population, individuals with minoritized sexual orientation and gender identity have a higher burden of chronic health conditions than heterosexual individuals. However, the extent to which sexual orientation is associated with excess burden of chronic conditions in adolescent and young adult cancer survivors (AYACS) is unknown. Methods: Lesbian, gay, and bisexual (LGB) AYACSs, LGB individuals without a history of cancer, and heterosexual AYACSs were identified by self‐reported data from the cross‐sectional National Health Interview Survey (2013–2020). Socioeconomic factors and the prevalence of chronic health conditions were compared between groups using χ2 tests. Logistic regression methods were used to determine the odds of chronic conditions by socioeconomic factors within and between survivor and comparison groups. Results: One hundred seventy LGB cancer survivors, 1700 LGB individuals without a history of cancer, and 1700 heterosexual cancer survivors were included. Compared with heterosexual survivors, LGB survivors were less likely to be married (p =.001) and more likely to have never been married (p <.001). LGB survivors were more likely to have incomes between 100% and 200% of the federal poverty level than LGB individuals without a history of cancer (p =.012) and heterosexual survivors (p =.021) and were less likely to report incomes >200% the federal poverty level. LGB survivors had higher odds of chronic health conditions than LGB individuals without a history of cancer (odds ratio, 2.45; p <.001) and heterosexual survivors (odds ratio, 2.16; p =.003). Conclusions: LGB AYACSs are at increased risk of having chronic health conditions compared with both LGB individuals without a history of cancer and heterosexual AYACSs. Adolescent and young adult cancer survivors with minoritized sexual orientations face an elevated risk of chronic health conditions compared with both sexual minority individuals without a history of cancer and heterosexual adolescent and young adult cancer survivors. To reduce health outcome disparities, addressing individual‐level barriers to care and implementing system‐wide strategies are essential for improving the well‐being of this population. [ABSTRACT FROM AUTHOR]

Purpose: Survivors of adolescent and young adult (AYA) cancer experience psychological distress and insufficient access to mental health care. Few studies have investigated racial/ethnic disparities in psychological health outcomes in this population. This study compared psychological distress, mental health care use, and inability to afford mental health care between Hispanic/Latino survivors of AYA cancer and Hispanic/Latino controls. Methods: The National Health Interview Survey data (2010–2018) were analyzed to identify Hispanic/Latino survivors of AYA cancer and Hispanic/Latino age‐ and sex‐matched non‐cancer controls. Sociodemographic, chronic health, modifiable factors, and psychological outcomes were compared using chi‐square tests. Logistic regression models with survey weights were used to assess the log‐odds of psychological distress in relation to covariates, along with the cancer group. Interactions were evaluated between each variable and cancer group. Results: The study included 370 Hispanic/Latino survivors of AYA cancer (mean time since diagnosis = 12.34 years) and 3700 Hispanic/Latino controls. Compared to controls, survivors were more likely to report moderate/severe distress (OR = 2.23, p < 0.001), use of mental health care (OR = 2.11, p < 0.001) and inability to afford mental health care (OR = 3.05, p < 0.001). Forty‐one percent of survivors reported moderate/severe distress and only 16% utilized mental health care. Among survivors, having more than two chronic health conditions and public insurance (compared to private insurance) were associated with the presence of moderate/severe distress. Among survivors experiencing moderate/severe distress, lack of insurance was associated with decreased utilization of mental health care. Conclusions: Having cancer as an AYA may exacerbate disparities in psychological health within the Hispanic/Latino population. [ABSTRACT FROM AUTHOR]

Background: Advancements in treatment and supportive care have led to improved survival for adolescents and young adults (AYAs) with cancer; however, a subset of those diagnosed remain at risk for early death (within 2 months of diagnosis). Factors that place AYAs at increased risk of early death have not been well studied. Methods: The Surveillance, Epidemiology, and End Results registry was used to assess risk of early death in AYAs with hematologic malignancies, central nervous system tumors, and solid tumors. Associations between age at diagnosis, sex, race, ethnicity, socioeconomic status, insurance status, rurality, and early death were assessed. Results: A total of 268 501 AYAs diagnosed between 2000 and 2016 were included. Early death percentage was highest in patients diagnosed with hematologic malignancies (3.1%, 95% confidence interval [CI] = 2.9% to 3.2%), followed by central nervous system tumors (2.5%, 95% CI = 2.3% to 2.8%), and solid tumors (1.0%, 95% CI = 0.9% to 1.0%). Age at diagnosis, race, ethnicity, lower socioeconomic status, and insurance status were associated with increased risk of early death in each of the cancer types. For AYAs with hematologic malignancies and solid tumors, risk of early death decreased statistically significantly over time. Conclusions: A subset of AYAs with cancer remains at risk for early death. In addition to cancer type, sociodemographic factors also affect risk of early death. A better understanding of the interplay of factors related to cancer type, treatment, and health systems that place certain AYA subsets at higher risk for early death is needed to address these disparities and improve outcomes. [ABSTRACT FROM AUTHOR]

Background: There is a growing population of adolescent and young adult (AYA) cancer survivors (ages 15–39 years), and they have an elevated risk of developing cardiovascular disease (CVD). Little is known about the contribution of sociodemographic and modifiable factors to the risk of CVD in AYA survivors and whether these factors differentially modulate their risk compared with that in the general population. The current study sought to fill these gaps. Methods: Self‐reported data from the US National Health Interview Survey (2009–2018) were used to identify AYA cancer survivors (≥2 years postdiagnosis) and age‐matched and sex‐matched controls. The risk of CVD based on sociodemographic factors (sex, race/ethnicity, income, education) and modifiable risk factors (diabetes, body mass index, smoking, physical activity) was determined within and between survivors and controls using logistic regression models. Results: In total, 4766 AYA cancer survivors and 47,660 controls were included. The odds of CVD were significantly higher in survivors than in controls by sex, race/ethnicity, income, education, smoking status, and physical activity. An annual household income <$50,000 disproportionately increased the odds of CVD in survivors. One third of survivors reported no moderate‐to‐vigorous–intensity physical activity (MVPA). Performing any MVPA lowered the odds of CVD in survivors (odds ratio, 0.61; 95% CI, 0.450.81) and controls (odds ratio, 0.68; 95% CI, 0.61–0.77). Conclusions: Sociodemographic and modifiable risk factors increased the odds of CVD in AYA survivors, in some cases disproportionately, compared with controls. Understanding health behavior trajectories among different sociodemographic populations is needed to identify opportunities to lower the risk of CVD. Performing any MVPA is particularly important for AYA survivors. Sociodemographic and modifiable risk factors affect the risk of cardiovascular disease in survivors of adolescent and young adult cancers. Performing any amount of moderate‐to‐vigorous physical activity significantly lowered the odds of cardiovascular disease in survivors. [ABSTRACT FROM AUTHOR]

Background: There is a growing population of adolescent and young adult (AYA, age 15-39 years) acute leukemia survivors in whom long-term mortality outcomes are largely unknown. Methods: The current study utilized the Surveillance, Epidemiology, and End Results (SEER) registry to assess long-term outcomes of AYA acute leukemia 5-year survivors. The impact of diagnosis age, sex, race/ethnicity, socioeconomic status, and decade of diagnosis on long-term survival were assessed utilizing an accelerated failure time model. Results: A total of 1,938 AYA acute lymphoblastic leukemia (ALL) and 2,350 AYA acute myeloid leukemia (AML) survivors diagnosed between 1980 and 2009 were included with a median follow-up of 12.3 and 12.7 years, respectively. Ten-year survival for ALL and AML survivors was 87% and 89%, respectively, and 99% for the general population. Survival for AYA leukemia survivors remained below that of the age-adjusted general population at up to 30 years of follow-up. Primary cancer mortality was the most common cause of death in early survivorship with noncancer causes of death becoming more prevalent in later decades of follow-up. Male AML survivors had significantly worse survival than females (survival time ratio: 0.61, 95% confidence interval: 0.45-0.82). Conclusions: AYA leukemia survivors have higher mortality rates than the general population that persist for decades after diagnosis. Impact: While there have been improvements in late mortality, long-term survival for AYA leukemia survivors remains below that of the general population. Studies investigating risk factors for mortality and disparities in late effects among long-term AYA leukemia survivors are needed. [ABSTRACT FROM AUTHOR]

Background: Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy and can predispose individuals to sudden death. Most pediatric HCM patients host a known pathogenic variant in a sarcomeric gene. With the increase in exome sequencing (ES) in clinical settings, incidental variants in HCM-associated genes are being identified more frequently. Diagnostic interpretation of incidental variants is crucial to enhance clinical patient management. We sought to use amino acid-level signal-to-noise (S:N) analysis to establish pathogenic hotspots in sarcomeric HCM-associated genes as well as to refine the 2015 American College of Medical Genetics (ACMG) criteria to predict incidental variant pathogenicity. Methods and Results: Incidental variants in HCM genes (MYBPC3, MYH7, MYL2, MYL3, ACTC1, TPM1, TNNT2, TNNI3, and TNNC1) were obtained from a clinical ES referral database (Baylor Genetics) and compared to rare population variants (gnomAD) and variants from HCM literature cohort studies. A subset of the ES cohort was clinically evaluated at Texas Children's Hospital. We compared the frequency of ES and HCM variants at specific amino acid locations in coding regions to rare variants (MAF < 0.0001) in gnomAD. S:N ratios were calculated at the gene- and amino acid-level to identify pathogenic hotspots. ES cohort variants were re-classified using ACMG criteria with S:N analysis as a correlate for PM1 criteria, which reduced the burden of variants of uncertain significance. In the clinical validation cohort, the majority of probands with cardiomyopathy or family history hosted likely pathogenic or pathogenic variants. Conclusions: Incidental variants in HCM-associated genes were common among clinical ES referrals, although the majority were not disease-associated. Leveraging amino acid-level S:N as a clinical tool may improve the diagnostic discriminatory ability of ACMG criteria by identifying pathogenic hotspots. [ABSTRACT FROM AUTHOR]

The majority of childhood cancer patients survive well into adulthood, but remain at risk for psychological late effects that can impact overall health and quality of life. The current narrative review summarizes the literature on psychological late effects, including anxiety, depression, psychological distress, post-traumatic stress disorder, suicidality, psychoactive medication use, and post-traumatic growth in survivors of childhood cancers. While results were mixed, many studies demonstrated that psychological symptoms occurred at levels higher than would be expected in the general population. Treatment, environmental, and behavioral risk factors, as well as symptom onset and trajectory merit further investigation. [ABSTRACT FROM AUTHOR]

Background: Although there are growing numbers of adolescent and young adult (AYA) Hodgkin lymphoma (HL) survivors, long-term overall survival (OS) patterns and disparities in this population are underreported. The aim of the current study was to assess the impact of race/ethnicity, socioeconomic status (SES), rurality, diagnosis age, sex, and HL stage over time on long-term survival in AYA HL survivors. Methods: The authors used the Surveillance, Epidemiology, and End Results (SEER) registry to identify survivors of HL diagnosed as AYAs (ages 15-39 years) between the years 1980 and 2009 and who were alive 5 years after diagnosis. An accelerated failure time model was used to estimate survival over time and compare survival between groups. Results: There were 15,899 5-year survivors of AYA HL identified, with a median follow-up of 14.4 years and range up to 33.9 years from diagnosis. Non-Hispanic black survivors had inferior survival compared with non-Hispanic white survivors [survival time ratio (STR): 0.71, P = 0.002]. Male survivors, older age at diagnosis, those diagnosed at higher stages, and those living in areas of higher SES deprivation had unfavorable long-term survival. There was no evidence of racial or sex-based survival disparities changing over time. Conclusions: Racial, SES, and sex-based disparities persist well into survivorship among AYA HL survivors. [ABSTRACT FROM AUTHOR]

Anthracyclines, chemotherapeutic agents that have contributed to significant improvements in cancer survival, also carry risk of both acute and chronic cardiotoxicity. This has led to significantly elevated risks of cardiac morbidity and mortality among cancer survivors treated with these agents. Certain treatment related, demographic, and medical factors increase an individual's risk of anthracycline induced cardiotoxicity; however, significant variability among those affected suggests that there is an underlying genetic predisposition to anthracycline induced cardiotoxicity. The current narrative review seeks to summarize the literature to date that has identified genetic variants associated with anthracycline induced cardiotoxicity. These include variants found in genes that encode proteins associated with anthracycline transportation and metabolism, those that encode proteins associated with the generation of reactive oxygen species, and those known to be associated with cardiac disease. While there is strong evidence that susceptibility to anthracycline induced cardiotoxicity has genetic underpinnings, the majority of work to date has been candidate gene analyses. Future work should focus on genome‐wide analyses including genome‐wide association and sequencing‐based studies to confirm and expand these findings. [ABSTRACT FROM AUTHOR]

Background: Although there are a growing number of survivors of adolescent and young adult (AYA) cancer, to the authors' knowledge the long-term overall survival (OS) patterns for AYA cancer survivors are underreported. The objective of the current study was to assess the long-term survival of AYA cancer survivors and identify factors associated with diminished long-term survival.Methods: The authors used The University of Texas MD Anderson Cancer Center's tumor registry to identify 5-year survivors of cancer diagnosed as AYAs (ages 15-39 years) between the years 1970 and 2005, and who were alive 5 years after diagnosis. Kaplan-Meier curves were used to estimate OS rates over time, and Cox proportional hazards models were fitted to evaluate the association of covariates with OS.Results: The authors identified 16,728 individuals who were 5-year survivors of cancer and were diagnosed as AYAs with a median follow-up of 20.0 years. The 10-year, 20-year, and 25-year OS rates were 86% (95% confidence interval [95% CI], 85%-86%), 74% (95% CI, 73%-75%), and 68% (95% CI, 67%-68%), respectively, all of which were lower than the age-adjusted estimated survival rates of the general population. Long-term OS improved for AYAs diagnosed between 2000 and 2005 compared with those diagnosed in the prior decades (P < .001). Older age at the time of diagnosis, receipt of radiation, and diagnoses including central nervous system tumors and breast cancer each were associated with diminished long-term survival.Conclusions: AYA cancer survivors have inferior long-term survival compared with the general population. Studies investigating the prevalence and types of late treatment effects and causes of death among AYA survivors are needed to more accurately identify AYAs who are at highest risk of early or late mortality. [ABSTRACT FROM AUTHOR]

Purpose: Whether cardiovascular disease (CVD) risk differs according to race and cancer type among survivors of childhood or young adulthood cancers is unknown. Methods: Data from the years 1973–2011 were analyzed using the Surveillance, Epidemiology, and End Results (SEER) registries. Cases were categorized by ICD-0-3/WHO 2008 Adolescent and Young Adult classification. CVD death was determined by ICD-10 codes for diseases of the heart, atherosclerosis, cerebrovascular diseases, or other diseases of the arteries. Cox proportional hazards models were fitted to evaluate the hazard ratio (HR) and 95% confidence intervals (CIs) for the effects of race on time-to-event outcomes. Results: A total of 164,316 cases of childhood and young adult primary cancers were identified. There were 43,335 total and 1466 CVD deaths among Black and White survivors. Black survivors had higher risks of all-cause mortality (HR: 1.75, 95% CI: 1.70–1.7) and CVD mortality (HR: 2.13, 95% CI: 1.85–2.46) compared to White survivors. The increased risk of CVD for Black survivors compared to White survivors persisted at 5-years (HR: 2.38, 95% CI: 1.83–3.10), 10-years (HR: 2.59, 95% CI: 2.09–3.21), and 20-years (HR: 2.31, 95% CI: 1.95–2.74) postdiagnosis, and varied by cancer type, with the highest HRs for melanoma (HR: 8.16, 95% CI: 1.99–33.45) and thyroid cancer (HR: 3.43, 95% CI: 1.75–6.73). Conclusions: Black survivors of childhood or young adulthood cancers have a higher risk of CVD mortality compared to Whites that varies by cancer type. Knowledge of at-risk populations is important to guide surveillance recommendations and behavioral interventions. Further study is needed to understand the etiology of racial differences in CVD mortality in this population. [ABSTRACT FROM AUTHOR]

The article presents a study that deals with the potential mechanisms and factors contributing to lower cardiorespiratory fitness in survivors of childhood cancer.

Background As utilization of clinical exome sequencing (ES) has expanded, criteria for evaluating the diagnostic weight of incidentally identified variants are critical to guide clinicians and researchers. This is particularly important in genes associated with dilated cardiomyopathy (DCM), which can cause heart failure and sudden death. We sought to compare the frequency and distribution of incidentally identified variants in DCM-associated genes between a clinical referral cohort with those in control and known case cohorts to determine the likelihood of pathogenicity among those undergoing genetic testing for non-DCM indications. Methods and Results A total of 39 rare, non- TTN DCM-associated genes were identified and evaluated from a clinical ES testing referral cohort (n=14 005, Baylor Genetic Laboratories) and compared with a DCM case cohort (n=9442) as well as a control cohort of population variants (n=141 456) derived from the gnomAD database. Variant frequencies in each cohort were compared. Signal-to-noise ratios were calculated comparing the DCM and ES cohort with the gnomAD cohort. The likely pathogenic/pathogenic variant yield in the DCM cohort (8.2%) was significantly higher than in the ES cohort (1.9%). Based on signal-to-noise and correlation analysis, incidental variants found in FLNC , RBM20 , MYH6 , DSP , ABCC9 , JPH2 , and NEXN had the greatest chance of being DCM-associated. Conclusions The distribution of pathogenic variants between the ES cohort and the DCM case cohort was gene specific, and variants found in the ES cohort were similar to variants found in the control cohort. Incidentally identified variants in specific genes are more associated with DCM than others.

Background: TTN , the largest gene in the human body, encodes TTN (titin), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN , particularly truncating variants (TTNtvs), have been implicated in the pathogenicity of cardiomyopathy. Despite this link, there is also a high burden of TTNtvs in the ostensibly healthy general population. This complicates the diagnostic interpretation of incidentally identified TTNtvs, which are of increasing abundance given expanding clinical exome sequencing., Methods: Incidentally identified TTNtvs were obtained from a large referral database of clinical exome sequencing (Baylor Genetics) and compared with rare population variants from genome aggregation database and cardiomyopathy-associated variants from cohort studies in the literature. A subset of TTNtv-positive children evaluated for cardiomyopathy at Texas Children's Hospital was retrospectively reviewed for clinical features of cardiomyopathy. Amino acid-level signal-to-noise analysis was performed., Results: Pathological hotspots were identified within the A-band and N-terminal I-band that closely correlated with regions of high percent-spliced in of exons. Incidental TTNtvs and population TTNtvs did not localize to these regions. Variants were reclassified based on current American College of Medical Genetics and Genomics criteria with incorporation of signal-to-noise analysis among Texas Children's Hospital cases. Those reclassified as likely pathogenic or pathogenic were more likely to have evidence of cardiomyopathy on echocardiography than those reclassified as variants of unknown significance., Conclusions: Incidentally found TTNtvs are common among clinical exome sequencing referrals. Pathological hotspots within the A-band of TTN may be informative in determining variant pathogenicity when incorporated into current American College of Medical Genetics and Genomics guidelines.