Recurring and isolated intronic FGFR1 variants as an underdiagnosed cause of congenital hypogonadotropic hypogonadism

Abstract Background Congenital hypogonadotropic hypogonadism (CHH) is a genetically heterogeneous disorder characterized by absent or delayed puberty and infertility due to gonadotropin-releasing hormone deficiency. While loss-of-function variants in FGFR1 are the most commonly known genetic cause of CHH, diagnostic screening typically focuses on coding exons, potentially overlooking pathogenic variants in non-coding regions. Methods We investigated four unrelated families with CHH. Family 1 included a mother and three daughters presenting with variable reproductive phenotypes and incomplete penetrance of anosmia; Family 3 consisted of a girl with CHH and anosmia; and Families 2 and 4 consisted of male patients who presented with CHH and anosmia. Genetic investigations were done using either exome or genome sequencing (ES/GS). Experimental characterization of the identified intronic variants was conducted using RNA extracted from peripheral blood mononuclear cells. ES/GS-based haplotyping was performed for the recurring variant. Results In Families 1-3, we identified a recurring heterozygous intronic variant in FGFR1: c.92-19G > A. RNA analysis confirmed that this variant generates a cryptic splice acceptor site, leading to the inclusion of 17 intronic nucleotides, resulting in a premature stop codon. Haplotype analysis revealed the variant occurred independently in each family. In Family 4, a distinct heterozygous intronic variant was identified in FGFR1 which was shown to cause intron 15 retention with premature termination. Conclusion Our findings demonstrate that intronic variants in FGFR1 are a possible cause of CHH and can lead to diverse clinical phenotypes ranging from normosmic CHH to severe Kallmann syndrome, including significant presentation in female patients.