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Review
. 2024 Nov 25.
doi: 10.1007/s42000-024-00615-1. Online ahead of print.

The possible association of two novel heterozygous GNB1 variants with obesity and metabolic disorders

Maria Karantza  1 , Hane Lee  2 , Sophia Kitsiou  3 , Lina Michala  3 , Bessie E Spiliotis  4 , Gabriel Dimitriou  4 , Eirini Kostopoulou  5   6
Affiliations
Review

The possible association of two novel heterozygous GNB1 variants with obesity and metabolic disorders

Maria Karantza et al. Hormones (Athens). .

Abstract

Purpose: Variants in the GNB1 gene, which encodes for the beta-1 subunit of G proteins, have been associated with intellectual development disorder (OMIM: 616973), characterized by developmental delay, infantile hypotonia, seizures, and psychiatric problems. GNB1 variants may also cause a multisystem disorder, with symptoms such as hearing and vision impairment, gastrointestinal disorders, genitourinary abnormalities, and growth delay.

Case presentations: We present two pediatric patients with two novel GNB1 variants. The first patient is a 12-year old Caucasian European female with a history of neonatal hypotonia, feeding difficulties, and failure to thrive for the first 2 years of life. Subsequently, she developed grade 3 obesity, hyperphagia, and autoimmune thyroiditis. Whole Exome Sequencing (WES) revealed a novel likely pathogenic variant in the GNB1 gene (NM_002074.5:c.93_94del, p.Gln32AspfsTer46), which is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. The second patient is a 2-year old Roma female with severe failure to thrive during infancy, congenital hypothyroidism, and transient hyperoxaluria. No developmental delay was identified. Genetic testing excluded primary hyperoxaluria and WES revealed to be a novel likely pathogenic variant {NM_002074.5:c.183G > T (NP_002065.1:p.Met61Ile), which is predicted to have a damaging effect on the gene or gene product.

Conclusion: We present two rare pediatric cases with novel GNB1 variants which highlight the phenotypic variability associated with disrupted GNB1 expression. GNB1 may serve as a candidate gene for severe early onset obesity, hyperphagia, neurodevelopmental delay, and other metabolic and endocrine disorders.

Keywords: GNB1; Developmental delay; Intellectual disability; Obesity; Thyroid disorders.

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Conflict of interest statement

Declarations. Ethical approval: The study was in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments and it was approved by the Research Ethics Committee of the University Hospital of Patras, Greece. No animal studies were carried out by the authors for this article. Informed consent: The current research involves the participation of human subjects. To partake in the study, the parents of the patients gave their informed consent in a written format and the patient their informed assent, while participation was voluntary and anonymity was assured. Conflict of interest: The authors have no conflict of interest to disclose.

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