Amyloid transthyretin (ATTR) amyloidosis is characterized by pathologic accumulation of extracellular protein arising from unstable transthyretin (TTR) tetramers, which dissociate into monomers that misfold, aggregate, and form insoluble fibrils that are resistant to proteolysis (Finsterer et al., 2019). TTR misfolding can lead to two distinct forms of amyloidosis: hereditary (ATTRv) and wild-type (ATTRwt) (Yamamoto and Yokochi, 2019). ATTRv is a rare hereditary disease transmitted as an autosomal dominant manner (Adams et al., 2016; Adams et al., 2021a). It is caused by mutations in the transthyretin gene located on chromosome 18 (18q12.1). There is considerable heterogeneity in the clinical presentation of ATTRv, ranging from primarily cardiac, primarily neuropathic, or other progressive multisystem disorders (Rapezzi et al., 2010). ATTRv usually proves fatal within 7–12 years from the onset of symptoms, causing a heavy economic burden for families and society (Takeshima et al., 2019; Galan et al., 2021).

ATTRv is an underdiagnosed disease and the true incidence and prevalence are currently unknown (Obi et al., 2022). Its global prevalence is traditionally and somewhat anecdotally estimated as 5,000 to 10,000 persons but only several countries in Europe and Japan have relatively exact prevalence (Sousa et al., 1995; Kato-Motozaki et al., 2008; Dardiotis et al., 2009; Ines et al., 2018; Lauppe et al., 2021). In epidemic regions such as Portugal, Sweden, and Japan, the prevalence varies from 10/100,000 to 100/100,000 people. Recently, the prevalence of transthyretin familial amyloid polyneuropathy (ATTR-FAP) in China was estimated to be approximately 2000 (range 435–10,134) [1,347.7 million persons in total] (Schmidt et al., 2018). However, the prevalence estimation and information supporting prevalence calculations were extracted from records yielded by reference-databases searches, conference proceedings and published cases or case series, which certainly had it underestimated.

Previous prevalence estimation was given using traditional methods, namely, case reports, epidemiological surveys and patient registries (Ikeda et al., 2002; Ines et al., 2018). These traditional methods are prone to underestimations due to diagnostic bias and small sample size. In recent years, population-based genomic sequencing projects provided a new genetic perspective on the estimation of disease-related prevalences (Lahuerta Pueyo et al., 2019). To date, several studies have employed publicly available large-population databases to infer pathogenicity, penetrance or prevalence of rare diseases (Rutten et al., 2016; Lahuerta Pueyo et al., 2019; Liu et al., 2019). Herein, we utilized an integrated world population and Chinese population genomic sequencing databases to reevaluate the ATTRv prevalence in the mainland Chinese population.

This is the first study to identify and investigate the prevalence of disease-causing TTR variants in the Chinese mainland population. The estimated prevalence interval of ATTRv was 18.9–74.9/100,000 based on the public exome ChinaMAP and commercial exome databases. The lower limit of the prevalence interval was as high as or near 20-fold higher than that in Japan (prevalence: 1/100,000) concluded by traditional epidemiological methods (Kato-Motozaki et al., 2008). Our results suggested that ATTRv in the Chinese was observed much more prevalent than previously recognized.

To determine whether the prevalence in China is high, we estimated the prevalence of different populations and various cohorts using gnomAD data. The gnomAD database consisted of eight ethnic groups but not all populations were equally represented, with the European population being the most represented and the Asian and Latino the least represented (Collins et al., 2020). Noteworthy, these databases did not contain the Chinese population. Comparisons to other population may aid in determine the prevalence gap of a number of disorders that exist between the Chinese and world populations. Not surprisingly, the ATTRv prevalence was 57.4 per 100,000 persons estimated by the genomic sequencing projects approach. It was equal to or even higher than that in epidemic regions such as Portugal, Sweden, and Japan, whose prevalence were calculated by case reports, epidemiological surveys and patient registries. A recent study using a national population-based exome sequence database reported the prevalence of 21.5 per 100,000 persons in Saudi (Abouelhoda et al., 2021), an Asian country that was not reported as an ATTRv epidemic region. This further supported that the true prevalence of ATTRv was much higher than that reported in previous studies.

There are four plausible explanations for the unexpected high prevalence: 1) the pathogenic variants in the ChinaMAP and Amcarelab databases differ from those found in ATTRv in reality and variants were not pathogenic but were polymorphisms, 2) all of the individuals with a TTR pathogenic variant in the ChinaMAP and Amcarelab databases have an undiagnosed or unreported classical TTR variant; 3) a late onset, mild TTR phenotype which was less readily diagnosed, may be much more prevalent than recognized to date. However, it is highly unlikely that any of the 15 disease-causing amyloidogenic TTR variants found in ChinaMAP and Amcarelab databases were polymorphisms as most the 15 pathogenic variants have been previously reported in TTR pedigrees. Taking the results from the gnomAD and Saudi databases into consideration, low prevalence estimation from previous traditional methods may be from penetrance TTR variability, misdiagnosis or missed diagnosis, delayed diagnosis and/or for other reasons (Rapezzi et al., 2010).

A high prevalence highlights the importance of diagnosing ATTRv clinically at an early stage. Recent years have seen the description of a series of novel and effective therapies for ATTRv. Tafamidis, patisiran, inotersen as well as the most promising NTLA-2001 have shown great benefits for patients with ATTRv. Specifically, these benefits are better received when ATTRv is diagnosed at an early stage of disease (Benson et al., 2018; Lamb and Deeks, 2019; Adams et al., 2021b; Gillmore et al., 2021). It challenges and encourage clinical practitioners to raise awareness and have a deeper and broader understanding of ATTRv because early diagnosis of amyloidosis remains an elusive goal that requires education of both physicians and patients (Wechalekar et al., 2016). Further examinations or even gene sequencing must be performed when there is any suspicion of hereditary amyloidosis with initial signs and symptoms, to enter the screening process for amyloidosis and improve early diagnosis (Conceicao et al., 2019).

Our study has several limitations. First, in the present study, only “pathogenic” and “likely pathogenic” variants were defined as disease-causing variants. In fact, some variants in the “uncertain significance” group may also be disease-causing. Thus, the prevalence of ATTRv may be even higher. Secondly, penetrance analysis of the TTR gene could not be determined. Lastly, the characteristics of the Chinese variants and the relationship between variants and clinical characteristics were not analyzed.

In conclusion, we confirmed the high prevalence of ATTRv in the Chinese mainland population, demonstrating that the previous prevalence was greatly underestimated obtained using traditional methods. Therefore, raising awareness of the disease is essential for recognizing ATTRv in its early stage.