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.