Discussion
Congenital hypothyroidism is the most common neonatal disorder (Feuchtbaum, Carter, Dowray, Currier, & Lorey, 2012). Prompt diagnosis and treatment help prevent patient intellectual disability (Cherella & Wassner, 2017). The newborn screening program for congenital hypothyroidism with detection of blood spot thyroid stimulating hormone (TSH) or thyroxine (T4) was implemented between 1970 and 1980 worldwide, especially in developed countries. This public health program has nearly eradicated the profound physical and cognitive impairments due to severe congenital hypothyroidism. Recent studies raised an issue that current screening criteria miss borderline or subclinical congenital hypothyroidism (Lain et al., 2016; Leonardi et al., 2008).
Primary congenital hypothyroidism is broadly caused by thyroid dysgenesis (including agenesis, hypoplasia, or abnormal location) or dyshormogenesis (when a normal thyroid gland produces abnormal amounts of thyroid hormone). Historically, the most common cause (approximately 85%) of primary hypothyroidism is thyroid dysgenesis (Cherella & Wassner, 2017; Deladoey, Ruel, Giguere, & Van Vliet, 2011; Olivieri, Fazzini, Medda, & Italian Study Group for Congenital, 2015; Wassner & Brown, 2015), with an incidence of about 1:4,000 births. However, thyroid dysgenesis occurs sporadically, and fewer than 5% of thyroid dysgenesis cases are attributable to genetic variations in the known genes. Dyshormogenesis accounts for approximately 15% of primary hypothyroidism and is mainly caused by a genetic defect. The proportion of dyshormogenesis cases within congenital hypothyroidism has been increasing up to over 30% (Cherella & Wassner, 2017; Wassner & Brown, 2015).
In this study, the carrier frequency and predicted genetic prevalence of primary congenital hypothyroidism were analyzed based on the general population database. Most of the general population is regarded to include individuals without severe hypothyroid conditions; therefore, only genes associated with primary congenital hypothyroidism (excluding central congenital hypothyroidism) inherited in an autosomal recessive pattern were included. To date, there are 6 genes (SLC5A5 ,TPO , TG , IYD , DUOXA2 , DUOX2 ) associated with thyroid dyshormonogenesis and 8 genes (TSHR, PAX8, TSHB, NKX2-5, THRA, TRHR, TBL1X, IRS4 ) associated with nongoitrous congenital hypothyroidism in the Online Mendelian Inheritance in Man database. All thyroid dyshormonogenesis genes are inherited in an autosomal recessive pattern, while three nongoitrous congenital hypothyroidism genes (TSHR, TSHB, TRHR ) are inherited in an autosomal recessive pattern, three genes (PAX8, NKX2-5, THRA ) are autosomal dominant, and two (TBL1X, IRS4 ) are X-linked. Other genes associated with thyroid dysgenesis include NKX2-1, CDCA8, JAG1, and NTN1 and their related conditions are autosomal dominant (Peters, van Trotsenburg, & Schoenmakers, 2018). Other genes,FOXE1 or GLIS3 , are inherited in an autosomal recessive manner. Even though a higher proportion of genes associated with dyshormonogenesis compared with thyroid dysgenesis genes were included in this study, the CF of all genes associated with dyshormonogenesis was approximately 90%.
Differences in the prevalence of congenital hypothyroidism by ethnicity have been reported (Feuchtbaum et al., 2012; Stoppa-Vaucher, Van Vliet, & Deladoey, 2011). The Asian and Latino (Hispanic) groups showed higher rates while the African population had a lower rate compared with the prevalence of congenital hypothyroidism in the European group. In this study, the pGP of congenital hypothyroidism in East Asians (1:2,240) was notably higher than other populations and consistent with the prevalence of congenital hypothyroidism calculated based on number of patients in Asians (1:918–1:4,464). However, in contrast to the previous studies, the Latino population in this study showed the lowest rate of pGP for congenital hypothyroidism among all populations except Ashkenazi Jewish. In addition, there was a difference between the pGP and real prevalence of congenital hypothyroidism in other populations except the East Asian group.
The difference between the pGP based on the population database and the real prevalence might be determined by how many genes following autosomal recessive inheritance patterns were associated with their diseases by ethnic group, because the pGP in this study was calculated not considering autosomal dominant inheritance: a larger proportion of genes that follow an autosomal recessive inheritance pattern within the entire genetic portion, the gap between the pGP and real prevalence is narrowing. There are differences between the proportions of thyroid dysgenesis and dyshormonogenesis between ethnic groups (Stoppa-Vaucher et al., 2011; Sun et al., 2018). Since all pathogenic variations associated with dyshormonogenesis are inherited in an autosomal recessive manner, if the proportion of dyshormonogenesis is higher in the specific population, the pGP would be more consistent with the real prevalence. Recent studies using NGS have reported that more than 50% of congenital hypothyroidism in East Asians was caused by thyroid dyshormonogenesis (Park et al., 2016; Sun et al., 2018; Yu et al., 2018). These results may indicate why the pGP of the East Asian group in this study was consistent with the real prevalence. Interestingly, the pGP of the sum of DUOX and DUOXA2 was 43.2 per 100,000 births (1:2317) and 96.7% of total pGP in the East Asian group. In contrast, if the proportion of dyshormonogenesis in a population is lower, the difference between pGP and real prevalence would be bigger because the genetic cause from thyroid dysgenesis would be underestimated; many of the thyroid dysgenesis genes are inherited in an autosomal dominant manner.
Most of the studies on the genetic epidemiology of congenital hypothyroidism were based on European populations. Generally, if the specific variant is submitted to ClinVar as PLPV, it means that clinical patients with those PLPVs are present as well as those PLPVs are the main cause of their disease development. In this study, the results showed that whether the presumed PLPV was detected in a European group (specifically Non-Finnish European) significantly affected the submission to ClinVar. Therefore, the CF and pGP might be underestimated in the population that showed the biggest difference between the pGP and real prevalence, because many variants would be classified as variants of uncertain significance and not as PLPVs due to insufficiency of genetic and clinical information.
Additionally, unknown genetic factors (including causative variants in unknown genes or unrecognized variants in known genes) and epidemiologic or environmental factors (Hinton et al., 2010; Medda et al., 2005) also are attributable to the difference between pGP and prevalence.
In conclusion, this is the first study that assessed congenital hypothyroidism based on general population data and estimated CF and pGP by ethnicity. The feasibility of genetic screening for congenital hypothyroidism may be determined by ethnicity. In particular, in comparing the pGP with the real prevalence of congenital hypothyroidism, genetic screening in East Asian populations may be feasible in the future; this may be caused by a higher proportion of thyroid dyshormonogenesis due the contribution ofDUOX2 and DUOXA2 compared with other populations. The approach to obtain genomic information of a general population would allow an additional and helpful direction for preventive medicine. However, when using genomic information from the general population, the pathogenesis of particular diseases should be considered by ethnic group.