Novel SIM1 Variants Expanding the Spectrum of SIM1-Related Obesity

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Monogenic obesity often results from genetic defects in the hypothalamic leptin-melanocortin pathway.
• SIM1 gene variants are a known cause of Prader-Willi-like syndrome, presenting with hyperphagia, severe obesity, and developmental delay.

Purpose of the Study:

• To identify genetic variants in the SIM1 gene associated with severe early-onset obesity in pediatric patients.
• To analyze the functional impact of identified SIM1 variants using protein domain modeling and bioinformatic tools.

Main Methods:

• Targeted next-generation sequencing of 52 obesity-associated genes in pediatric patients with severe early-onset obesity.
• Analysis of variant population frequency and predicted pathogenicity using in silico tools.
• Protein domain modeling with AlphaFold3 to assess the structural impact of novel missense variants.

Main Results:

• Five rare SIM1 variants were identified in eleven pediatric patients.
• Four heterozygous nonsynonymous variants (one frameshift, two missense) and one synonymous variant (c.1173G>A, p.(Ser391Ser)) were found.
• Structural modeling indicated that missense variants likely disrupt protein-protein interactions and SIM1 function; the synonymous variant may affect splicing.

Conclusions:

• This study expands the known spectrum of SIM1 mutations causing monogenic obesity, including novel frameshift and missense variants, and a recurrent synonymous variant.
• The findings reinforce the critical role of the SIM1 gene in hypothalamic development and energy homeostasis.
• Inclusion of the SIM1 gene in genetic testing panels for severe obesity and hyperphagia is recommended for precise diagnosis and personalized management.