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

FGFR1

Heterozygous intronic FGFR1 variants: cryptic splice acceptor (c.92-19G>A, inclusion of 17 intronic nucleotides) or intron 15 retention, with a premature stop codon

Loss-of-function FGFR1 variants are the most common known genetic cause of congenital hypogonadotropic hypogonadism (CHH), but diagnostic analysis usually focuses on coding exons. In four unrelated families studied by exome or genome sequencing, the authors found the same heterozygous intronic variant, c.92-19G>A, in three families, arising independently according to haplotyping; RNA analysis from peripheral blood mononuclear cells showed that it creates a cryptic splice acceptor site, with inclusion of 17 intronic nucleotides and a premature stop codon. In the fourth family, a different intronic variant caused intron 15 retention with premature termination. Phenotypes ranged from normosmic CHH to severe Kallmann syndrome, with incomplete penetrance of anosmia and significant presentations in women.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A direct message for exome and genome interpretation: in unresolved CHH, FGFR1 intronic regions should be examined, and c.92-19G>A specifically sought since it is recurrent. Validation on blood RNA is an approach within reach of a diagnostic laboratory. With four families, the true frequency of these variants among unresolved CHH cases remains to be measured.

Analysis by Dr Thibaut Benquey