311 - Correlation of genotype-phenotype of congenital hypothyroidism cohort diagnosed by newborn screening: a long-term observational study

Publication Number: 311.4221

Li Long, Xinjiang Hospital of Beijing Children’s Hospital Children’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China (People's Republic); Yajie Su, Children’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China (People's Republic); Lei Xifeng, Xinjiang Medical University, Urumqi, Xinjiang, China (People's Republic); he jinfeng, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China (People's Republic); Ayijiamali Muhetaer, Children’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China (People's Republic)

Background: Congenital hypothyroidism (CH) is the most prevalent endocrine disorder in newborns. However, existing genetic research cannot fully explain its molecular basis, and the relationship between various genotypes and phenotypes remains unclear.

Objective: To identify the genetic mutation spectrum in the cohort, and examine the correlation between several genes and clinical phenotypes, especially the maintenance dose of L-thyroxine (L-T4) at 6, 12, 18, and 24 months, as well as the clinical outcomes after 2– 3 years.

Design/Methods: Data were collected between January 2011 and March 2024 in the Neonatal Disease Screening Center at our hospital. We analyzed the genotype-phenotype relationship based on different types of congenital hypothyroidism (CH). Written informed consent was obtained from the parents of all infants for the collection of samples and publication of medical data.

Results: Overall, pathogenic mutations in CH-related genes were identified in 96 cases of 138 patients, while resulting in a genetic diagnosis rate of 63.8% (88/138). The DUOX2 mutation was present in 45.8% (44/96) of these patients, with the most frequent variant being p.K530X (16.5%). The correlation analysis between various genes and phenotypes showed that the TSH levels at newborn screening (NBS) for the DUOX2 mutation group were lower than those for the TPO mutation group (118.13 ± 82.22 vs 177.13 ± 76.88, p=0.017). The L-T4 dose for the DUOX2 mutation group was lower than that for the TPO mutation group at 6, 12, 18, and 24 months, the differences were statistically significant at 6 months (3.67 ± 1.89 vs 5.80 ± 2.23, p=0.027). No significant differences were identified in biochemical data, maintenance L-T4 dosages, and clinical outcomes between the monoallelic and biallelic mutation groups with the DUOX2, nor between the negative, monogenic and oligogenic mutation groups.

Conclusion(s): The cohort showed a high positive rate of genetic diagnosis for neonatal CH, with DUOX2 being the most frequently mutated gene. Mutations in different genes or genotypes were associated with clinical phenotype and thyroid ultrasound findings, but no significant difference was observed in clinical outcomes.

Genotype-Phenotype of Different Gene and Allelic in CH Cohort.
A-C. Differences in the biochemical data between DUOX2, TG, TPO, and TSHR gene mutations groups. D-F. Differences in the biochemical data between “DUOX2 monoallelic mutations” and “DUOX2 biallelic mutations” groups. H-G. Differences in the biochemical data between “Negative”, “monogenic mutations” and “oligogenic mutations” groups.

Drug Maintenance Dosages for Different Groups in Infants Aged 6–24 Months.
A. L-T4 dose by age for DUOX2, TG, TPO, and TSHR mutations groups. B. L-T4 dose by age for “DUOX2 monoallelic mutations” and “DUOX2 biallelic mutations” groups. C. L-T4 dose by age between “Negative”, “Monogenic mutations” and “Oligogenic mutations” groups.