ESPE Abstracts

The proband is a 12 yr old Caucasian European girl with grade 3 obesity, developmental delay and hyperphagia. She was born at term via an uncomplicated pregnancy and exhibited neonatal hypotonia, difficulty feeding, failure to thrive and delayed attenuation of milestones. At the age of 2 years she started developing hyperphagia and rapid excessive weight gain. Molecular analysis for Prader Willi syndrome and array CGH were negative. At the age of 10 yrs she was diagnosed with autoimmune hypothyroidism and was started on L-T4 replacement therapy. First menstrual period was at the age of 11 yrs however on ultrasound imaging ovarian size is small despite normal pubertal uterine size. She developed insulin resistance and was started on metformin for one year, recently transitioned to daily GLP-1 analog. She exhibits dysmorphic features, mild intellectual delay, autism spectrum disorder and depressive symptoms. Family history is unremarkable for other similarly affected individuals. WES performed by 3billion, Seoul, South Korea, revealed a novel heterozygous likely pathogenic variant in GNB1 (NM_002074.5:c.93_94del, p.Gln32AspfsTer46). This is a frameshift mutation predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. This variant is not observed in the gnomAD_v2.1.1 dataset. GNB-1 is associated with autosomal dominant 'Intellectual developmental disorder, autosomal dominant 42 (OMIM: 616973)'. It encodes a subunit of a heterotrimeric G‐protein complex that transduces intracellular signaling cascades. Disruptions to the gene have previously been shown to be embryonic lethal in knockout mice and to cause complex neurodevelopmental disorders in humans. Recently two patients with novel LoF variants in GNB1 and neurodevelopmental phenotypes including intellectual disability, hypotonia, psychiatric symptoms and obesity were described. We propose that GNB-1 could be considered a candidate gene associated with severe early onset obesity, hyperphagia and neurodevelopmental delay. Functional analysis of our proband's mutation can provide additional insights on how perturbation in heterotrimeric G protein function contributes to the phenotype of the disease.