Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.

While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.

Phenotypic and genotypic characterization of familial hypercholesterolemia in French adult and pediatric populations.

BACKGROUND: Familial hypercholesterolemia (FH) is the most common genetic disorder associated with a high risk for premature atherosclerotic cardiovascular disease attributable to increased levels of LDL-cholesterol (LDL-C) from birth. FH is both underdiagnosed and undertreated. OBJECTIVE: We describe the clinical, biological, and genetic characteristics of 147 patients in France with clinical FH (including a group of 26 subjects aged < 20 years); we explore how best to detect patients with monogenic FH. METHODS: We retrospectively reviewed all available data on patients undergoing genetic tests for FH from 2009 to 2019. FH diagnoses were based on the Dutch Lipid Clinics Network (DLCN) scores of adults, and elevated LDL-C levels in subjects < 20 years of age. We evaluated LDLR, APOB, and PCSK9 status. RESULTS: The mutations of adults (in 25.6% of all adults) were associated with DLCN scores indicating "possible FH," "probable FH, and "definitive FH" at rates of 4%, 16%, and 53%, respectively. The areas under the ROC curves of the DLCN score and the maximum LDL-C level did not differ (p = 0.32). We found that the pediatric group evidenced more monogenic etiologies (77%, increasing to 91% when an elevated LDL-C level was combined with a family history of hypercholesterolemia and/or premature coronary artery disease). CONCLUSION: Diagnosis of monogenic FH may be optimized by screening children in terms of their LDL-C levels, associated with reverse-cascade screening of relatives when the children serve as index cases.