MODY Probability Calculator Is Suitable for MODY Screening in China: A Population-based Study.

Context: Selecting appropriate individuals for genetic testing is essential due to the optimal treatment for maturity-onset diabetes of the young (MODY). However, how to effectively screen for MODY in China remains unclear. Objective: To validate the performance of current screening strategies in selecting patients with MODY based on a nationwide type 2 diabetes cohort. Methods: A panel of 14 MODY genes was analyzed from 1911 type 2 diabetes patients who were ages 15 to 35 years. Variants were evaluated according to the American College of Medical Genetics and Genomics guidelines. Based on this cohort, we simulated the 2 most frequently used screening strategies, including the traditional MODY criteria and the MODY probability calculator (MPC), to assess their ability to select patients with MODY. Results: From a total of 1911 participants, 42 participants harbored pathogenic/likely pathogenic variants. The performance of the traditional criteria was sensitivity: 19.0%, specificity: 72.9%, positive predictive value (PPV): 1.6%, and missing rate: 81.0%. The optimal cut-off for MPC was 40.7%. Based on this cut-off value, the performance was sensitivity: 54.8%, specificity: 81.0%, PPV: 6.1%, and missing rate: 45.2%. Moreover, hemoglobin A1c, insulin treatment, and family history of diabetes have poor discrimination between MODY and young-onset type 2 diabetes. Conclusion: The MPC is better than traditional criteria in terms of both sensitivity and PPV. To ensure more MODY patients benefit from optimal treatment, we therefore suggest that routine genetic testing be performed on all type 2 diabetes patients who are between the ages of 15 and35 years and have MPC probability value over 40.7%.

Pathogenicity of Congenital Adrenal Hyperplasia Induced by the p.P377L Mutation of CYP11B1.

CYP11B1 encodes an 11ß-hydroxylase that is involved in the catalysis of adrenal glucocorticoids and the production of cortisol. Mutations in CYP11B1 can result in congenital adrenal hyperplasia. We discovered a proband with a CYP11B1 gene mutation. Gene sequencing revealed a homozygous missense mutation of c.1130C > T in the 7th exon of the CYP11B1 gene that resulted in the change from Pro377 to leucine in the encoded protein. Based on the proband's clinical symptoms and the prognosis according to the database, this mutation may be harmful. However, the pathogenicity has not yet been reported. Thus, we created an expression vector for the mutation in vitro, transfected cells, observed the changes in gene expression, and determined its pathogenicity. To determine the pathogenicity of the CYP11B1 p.P377L mutation site through in vitro verification. The eukaryotic expression vector of the CYP11B1 mutation site was constructed in vitro, and the success of the construct was confirmed by sequencing. Fluorescence microscopy was used to determine the transfection effectiveness, GFP fluorescent tag labeling was used to detect changes in protein localization, and qRT‒PCR and Western blotting were used to detect CYP11B1 mRNA and protein expression. Sequencing revealed that the proband harbored a homozygous missense mutation of CYP11B1 (p.P377L). The expression of the protein decreased but the localization did not change when cells were transfected with the CYP11B1 mutation vector compared to the wild-type vector. The p.P377L mutation of CYP11B1 could affect protein expression and enzymatic activity and may be pathogenic.

[Analysis of a patient with Kallmann syndrome and a 45,X/46,XY karyotype].

OBJECTIVE: To explore the etiology of a patient with Kallmann syndrome (congenital hypogonadism and anosmia) and a 45,X/46,XY karyotype. METHODS: Peripheral venous blood samples were collected from the proband and his parents and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: The proband was found to harbor compound heterozygous variants of the PROKR2 gene, namely c.533G>C (p.W178S) and c.308C>T (p.A103V), which were inherited from his father and mother, respectively. The two variants were respectively predicted to be likely pathogenic and variant of unknown significance, respectively. CONCLUSION: The reduced chromosomal mosaicism might have caused no particular clinical manifestations in this patient. For patients with features of Kallmann syndrome, genetic testing is conducive to early diagnosis and can provide a basis for genetic counseling and clinical treatment.

Impact of Abdominal Obesity on Thyroid Auto-Antibody Positivity: Abdominal Obesity Can Enhance the Risk of Thyroid Autoimmunity in Men.

BACKGROUND: The interrelation between obesity and autoimmune thyroid diseases is complex and has not been confirmed. The aim of the present study was to observe the relationship between thyroid autoimmunity and obesity, especially abdominal obesity, in a large population. METHODS: A total of 2253 residents who had lived in Xinjiang for more than 3 years were enrolled. Serum thyroid hormone concentration, thyroid autoantibodies, lipid parameters, Weight, height, and waist and hip circumference were measured. RESULTS: The prevalence of thyroid peroxidase antibody (TPOAb) and/or thyroglobulin antibody (TgAb) positive was 32.1% (21.2% in men and 37% in women, P < 0.01). Compared with women, men had significantly higher TG levels, waist circumference, and hip circumference levels (P < 0.01), while women showed higher TSH, TPOAb, and TgAb levels (P < 0.01). The prevalence of overweight and obesity was 71.1% in men and 63.5% in women. Men had a higher prevalence of abdominal obesity than women (56.6% in men and 47.6% in women, P < 0.01). TPOAb correlates positively with waist circumference (r = 0.100, P < 0.05) in men. Binary logistic analysis showed that TPOAb positivity had increased risks of abdominal obesity in men, and the OR was 1.1044 (95% CI 1.035, 1.151, P < 0.05). CONCLUSION: Our results indicate that men had higher lipid levels, thicker waist circumference, and higher prevalence of overweight, obesity, and abdominal obesity. Abdominal obesity is a risk factor for TPOAb positivity in men, suggesting that abdominal obesity can enhance the risk of thyroid autoimmunity in men.

[Changes of thyroid function, thyroid antibodies and urinary iodine among permanent residents of Urumqi in Xinjiang].

OBJECTIVE: To understand the rates of diagnosis on thyroid disease and the differences in the distribution of age groups among those permanent residents, to analyze the relationships among thyroid function, thyroid antibodies and urinary iodine. METHODS: A cross-sectional survey was performed in 1 995 permanent residents in Urumqi, Xinjiang in May, 2013, Among them, 1 906 were healthy adults aged 18-84 age, with mean age as (46.3 ± 14.2) years and 30.4% of them were men. One time 10 ml random urine and blood samples were drown to examine urinary iodine (UI) thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), anti-thyroglobulin (TgAb) and anti-thyroid peroxidase (TPOAb). RESULTS: 1) 213 residents were newly diagnosed as having thyroid dysfunction (11.2%, including 78.4% women), hyperthyroidism (clinical and subclinical hyperthyroidism) that accounted for 2.7%, hypothyroidism (clinical and subclinical hypothyroidism) was accounted for 8.5%. Positive rates of TgAb (23.2%), TPOAb (16.6%) were noticed. The median urinary iodine was 134.5 µg/L, with 32% of the subjects were having iodine deficiency, 58% having adequate iodine and another 10% as under excessive iodine. No differences were observed on urine iodine between thyroid dysfunction and euthyroidism or between subjects with positive and negative antibodies. 2) TSH appeared different among age-groups of 18-, 45- and over 60. TSH showed higher in women than in men, with P value as < 0.001. For people with euthyroidism, TSH level in the antibody positive group was significantly higher than the antibody negative group (P < 0.000 1). 3) For people over 60 of age, morbidity of hypothyroidism was significantly higher than those under 60 but with no differences related to hyperthyroidism or the antibody positive rate. CONCLUSION: UI levels were not significantly related with thyroid function and thyroid antibodies among residents of Urumqi, women showed higher on thyroid dysfunction or the rate of positive antibody. In the antibody positive group, TSH levels were significantly higher than in the antibody negative group. Hypothyroidism was seen higher in the over 60-years-of-age population. Monitoring programs on thyroid function, thyroid antibodies and urinary iodine among people over 60-years-of-age, should be strengthened.