A Novel FGFR1 Missense Mutation in a Portuguese Family with Congenital Hypogonadotropic Hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive endocrine disorder characterized by complete or partial failure of pubertal development and infertility due to deficiency of the gonadotropin-releasing hormone (GnRH). CHH has a significant clinical heterogeneity and can be caused by mutations in over 30 genes. The aim of this study was to investigate the genetic defect in two siblings with CHH. A woman with CHH associated with anosmia and her brother with normosmic CHH were investigated by whole exome sequencing. The genetic studies revealed a novel heterozygous missense mutation in the Fibroblast Growth Factor Receptor 1 (FGFR1) gene (NM_023110.3: c.242T>C, p.Ile81Thr) in the affected siblings and in their unaffected father. The mutation affected a conserved amino acid within the first Ig-like domain (D1) of the protein, was predicted to be pathogenic by structure and sequence-based prediction methods, and was absent in ethnically matched controls. These were consistent with a critical role for the identified missense mutation in the activity of the FGFR1 protein. In conclusion, our identification of a novel missense mutation of the FGFR1 gene associated with a variable expression and incomplete penetrance of CHH extends the known mutational spectrum of this gene and may contribute to the understanding of the pathogenesis of CHH.

Short-term consumption of highly processed diets varying in macronutrient content impair the sense of smell and brain metabolism in mice.

OBJECTIVE: Food processing greatly contributed to increased food safety, diversity, and accessibility. However, the prevalence of highly palatable and highly processed food in our modern diet has exacerbated obesity rates and contributed to a global health crisis. While accumulating evidence suggests that chronic consumption of such foods is detrimental to sensory and neural physiology, it is unclear whether its short-term intake has adverse effects. Here, we assessed how short-term consumption (<2 months) of three diets varying in composition and macronutrient content influence olfaction and brain metabolism in mice. METHODS: The diets tested included a grain-based standard chow diet (CHOW; 54% carbohydrate, 32% protein, 14% fat; #8604 Teklad Rodent diet , Envigo Inc.), a highly processed control diet (hpCTR; 70% carbohydrate, 20% protein, 10% fat; #D12450B, Research Diets Inc.), and a highly processed high-fat diet (hpHFD; 20% carbohydrate, 20% protein, 60% fat; #D12492, Research Diets Inc.). We performed behavioral and metabolic phenotyping, electro-olfactogram (EOG) recordings, brain glucose metabolism imaging, and mitochondrial respirometry in different brain regions. We also performed RNA-sequencing (RNA-seq) in the nose and across several brain regions, and conducted differential expression analysis, gene ontology, and network analysis. RESULTS: We show that short-term consumption of the two highly processed diets, but not the grain-based diet, regardless of macronutrient content, adversely affects odor-guided behaviors, physiological responses to odorants, transcriptional profiles in the olfactory mucosa and brain regions, and brain glucose metabolism and mitochondrial respiration. CONCLUSIONS: Even short periods of highly processed food consumption are sufficient to cause early olfactory and brain abnormalities, which has the potential to alter food choices and influence the risk of developing metabolic disease.

Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort.

STUDY QUESTION: What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. WHAT IS KNOWN ALREADY: CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. STUDY DESIGN SIZE DURATION: Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. PARTICIPANTS/MATERIALS SETTING METHODS: The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). MAIN RESULTS AND THE ROLE OF CHANCE: A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH. STUDY FUNDING/COMPETING INTERESTS: This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests.