Abstract: Objective To report a central hypothyroidium(CeH) family with a novel immanoglobulin super family member 1(IGSF1) mutation and elucidates its clinical heterogeneity through a systematic review. Methods Clinical data of the family were collected and The level of thyroid and pituitary hormone was evaluated. Genetic diagnosis was performed using whole-exome sequencing and Sanger sequencing, and AlphaFold2 was used to predict the impact of the mutation on protein conformation. A systematic search of Plumbed/MEDLINE was conducted, 137 male patients and 104 female carriers were included for comprehensive analysis. Results A novel mis-sense mutation(c.1948T＞C, p.F650L) in IGSF1 was identified and validated by family co-segregation analysis. Three male patients in the family presented with CeH: The proband exhibited severe neonatal jaundice, macrosomia (birth weight 4.8 kg), and markedly elevated alpha-fetoprotein; The other two patients presented with mild hypothyroidism accompanied by obesity and neuro-developmental delay. Female carriers showed normal thyroid function. AlphaFold2 predicted that this mutation alters the spatial structure of the IGSF1 protein. Literature synthesis revealed that growth retardation (82.3%) and neonatal jaundice (67.1%) were the most common presenting symptoms. Conclusions Phenotypic heterogeneity in the families exists in IGSF1 mutation-related CeH. Neonatal jaundice, macrosomia, and metabolic abnormalities are important clinical manifestations of this condition. This result expands the IGSF1 mutation database, and the structural biology evidence provides a molecular basis for interpreting genotype-phenotype correlations.

Key words: central hypothyroidism, immanoglobulin super family member 1(IGSF1), obesity, macrosomia, AlphaFold