scholarly journals Association between monoallelic TSHR mutations and congenital hypothyroidism: a statistical approach

2018 ◽  
Vol 178 (2) ◽  
pp. 137-144 ◽  
Author(s):  
Kiyomi Abe ◽  
Satoshi Narumi ◽  
Ayuko S. Suwanai ◽  
Masanori Adachi ◽  
Koji Muroya ◽  
...  
Keyword(s):  
General Population ◽  
Congenital Hypothyroidism ◽  
Posterior Probability ◽  
Statistical Approach ◽  
Bayes Theorem ◽  
Mutation Carriers ◽  
Japanese General Population ◽  
Monoallelic Mutation ◽  
Serum Tsh

Objective Biallelic TSHR mutations cause congenital hypothyroidism (CH). Serum TSH levels of monoallelic mutation carriers range from normal to mildly elevated, and thus the size of its effect remains unclear. The objectives were to examine the association between monoallelic TSHR mutations and positivity at newborn screening (NBS) for CH, and to test whether the association was modified by another genetic factor. Subjects and methods We enrolled 395 patients that had a positive result in NBS and sequenced TSHR. Monoallelic TSHR mutation carriers were further sequenced for DUOX2. Molecular functions of the mutations were verified in vitro. The frequency of the mutations in the study subjects was compared with a theoretical value in the Japanese general population. Odds ratio (OR) for NBS positivity associated with the mutation was calculated. Using Bayes’ theorem, we estimated a posterior probability of NBS positivity given the mutation. Results Twenty-six monoallelic TSHR mutation carriers were found. Four out of the 26 also had a monoallelic DUOX2 mutation (double heterozygotes). The frequencies of monoallelic TSHR mutation carriers (6.6%) and double heterozygotes (1.0%) were significantly higher than those in the general population (0.58% and 0.0087%, respectively). OR for NBS positivity of having a monoallelic TSHR mutation or being a double heterozygote was 12.0 or 117.9, respectively. Posterior probability of NBS positivity was 0.38% in monoallelic TSHR mutation carriers and 3.8% in double heterozygotes. Conclusions Monoallelic TSHR mutations are significantly associated with NBS positivity, and the association is further strengthened by the coexistence of monoallelic DUOX2 mutations.

scholarly journals Functional characterization of four novel PAX8 mutations causing congenital hypothyroidism: new evidence for haploinsufficiency as a disease mechanism

2012 ◽  
Vol 167 (5) ◽  
pp. 625-632 ◽  
Author(s):  
Satoshi Narumi ◽  
Shunsuke Araki ◽  
Naoaki Hori ◽  
Koji Muroya ◽  
Yukiyo Yamamoto ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Functional Characterization ◽  
High Serum ◽  
Dominant Negative ◽  
Mutation Carriers ◽  
Target Dna ◽  
History Of ◽  
Protein Instability ◽  
New Evidence

Background Individuals carrying a heterozygous inactivating PAX8 mutation are affected by congenital hypothyroidism (CH), although heterozygous Pax8 knockout mice are not. It has remained unclear whether CH in PAX8 mutation carriers is caused by haploinsufficiency or a dominant negative mechanism. Objective To report clinical and molecular findings of four novel PAX8 mutations, including one early-truncating frameshift mutation. Subjects and methods Four probands were CH patients. Two had family history of congenital or childhood hypothyroidism. Three probands were diagnosed in the frame of newborn screening for CH, while one had a negative result in screening but was diagnosed subsequently. Three had thyroid hypoplasia and one had a slightly small thyroid with low echogenicity. For these probands and their family members, we sequenced PAX8 using a standard PCR-based method. Pathogenicity of identified mutations was verified in vitro. Results We found four novel heterozygous PAX8 mutations in the four probands: L16P, F20S, D46SfsX24, and R133Q. Family studies showed four additional mutation carriers, who were confirmed to have high serum TSH levels. Expression experiments revealed that three mutations (L16P, F20S, and R133Q) had defects in target DNA binding, while D46fs had protein instability that was rescued by the proteasome inhibitor MG132. All four mutations had reduced transactivation on the thyroglobulin promoter, supporting that they were inactivating mutations. Conclusion D46fs is the first PAX8 mutation with confirmed protein instability. Our clinical and in vitro findings together suggest that pure PAX8 haploinsufficiency can cause CH in humans.

Determinants of serum adiponectin levels: a cross-sectional study

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Azar Sattarinezhad ◽  
Akbar Rasekhi Kazerouni ◽  
Gholamhossein Ranjbar Omrani ◽  
Mesbah Shams
Keyword(s):  
Ovarian Cancer ◽  
Germ Line ◽  
Brca Mutation ◽  
Bilateral Mastectomy ◽  
Ovarian Cancer Risk ◽  
Breast And Ovarian Cancer ◽  
Double Blind ◽  
Cross Sectional ◽  
Mutation Carriers

Abstract Objectives To review non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes. Content Women with a gBRCA1 or 2 mutations face a high cumulative breast and ovarian cancer risk. While bilateral mastectomy (PBM) and bilateral salpingo-oophrectomy (PBSO) profoundly reduce the respective cancer risks, they are also associated with considerable side effects. There is therefore an urgent need for alternative and non-surgical risk reduction options. Tamoxifen and aromatase inhibitors have both been evaluated in secondary prevention, but their benefit in primary prevention is currently unknown in BRCA mutation carriers. In addition, their use is compromised by their side effect profile which makes them less appealing for a use in chemoprevention. Summary and outlook Denosumab is a well-tolerated osteoprotective drug, which has been demonstrated to have a potential preventive effect particularly in BRCA1-deficient models in vitro. The prospectively randomized double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germ line mutation carriers.

scholarly journals A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Juliette Coignard ◽  
◽  
Michael Lush ◽  
Jonathan Beesley ◽  
Tracy A. O’Mara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
General Population ◽  
Genome Wide Association Study ◽  
Brca2 Mutation ◽  
Risk Scores ◽  
Genetic Modifiers ◽  
Mutation Carriers ◽  
Genotype Frequencies ◽  
Genome Wide ◽  
Brca1 Brca2

AbstractBreast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

scholarly journals A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population

2010 ◽  
Vol 42 (10) ◽  
pp. 885-892 ◽  
Author(s):  
Antonis C Antoniou ◽  
◽  
Xianshu Wang ◽  
Zachary S Fredericksen ◽  
Lesley McGuffog ◽  
...  
Keyword(s):  
Breast Cancer ◽  
General Population ◽  
Hormone Receptor ◽  
Brca1 Mutation ◽  
Mutation Carriers

Urinary iodine and thyroglobulin are useful markers in infants suspected of congenital hypothyroidism based on newborn screening

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Makiko Tachibana ◽  
Yoko Miyoshi ◽  
Miho Fukui ◽  
Shinsuke Onuma ◽  
Tomoya Fukuoka ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Congenital Hypothyroidism ◽  
Clinical Course ◽  
Urinary Iodine ◽  
Iodine Status ◽  
Need For Treatment ◽  
Urine Creatinine ◽  
Few Data ◽  
The Relationship ◽  
Serum Tsh

Abstract Objectives Iodine deficiency and excess both cause thyroid dysfunction. Few data describe the relationship between iodine status and outcomes of congenital hypothyroidism (CH) in iodine-sufficient areas. We investigated urinary iodine (UI) concentration and its relationship with the clinical course of CH. Methods We reviewed and retrospectively analyzed patients with positive newborn screening (NBS) for CH from January 2012 to June 2019 in Japan, obtaining UI and UI-urine creatinine ratio (UI/Cr), serum TSH, free T4, free T3 and thyroglobulin (Tg) at the first visit, TSH at NBS, levothyroxine (LT4) dose, and subsequent doses. A UI value of 100–299 μg/L was considered adequate. Results Forty-eight patients were included. Median UI and UI/Cr were 325 μg/L and 3,930 µg/gCr, respectively. UI was high (≥300 μg/L) in 26 (54%) and low (≤99 μg/L) in 11 (23%). LT4 was administered to 34 patients. Iodine status was not related to the need for treatment. We found a U-shaped relationship between Tg and UI/Cr. Patients with high Tg (≥400 ng/mL) and abnormal UI levels required significantly lower LT4 doses (≤20 µg/day) at three years of age. Even if they showed severe hypothyroidism initially, they did not need subsequent dose increments. Conclusions Abnormal UI levels with Tg elevation were associated with lower LT4 dose requirements. The evaluation of iodine status and Tg concentrations were considered useful in patients suspected of CH.

Sign in / Sign up

Export Citation Format

Share Document