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

Abstract

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 noncoding regions. Methods We investigated 4 unrelated families with CHH. Family 1 included a mother and 3 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. Experimental characterization of the identified intronic variants was conducted using RNA extracted from peripheral blood mononuclear cells. Exome or genome sequencing–based haplotyping was performed for the recurring variant. Results In Families 1 to 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.