The Pathogenicity Analysis of a Hypogonadotropic Hypogonadism Patient With the Novel Variant in the Deep Intronic Region of the PROK2 Gene

ABSTRACT Background Isolated hypogonadotropic hypogonadism (IHH) is a rare endocrine disorder caused by genes such as ANOSI (OMIM*300836), FGFR1 (OMIM*136350), PROK2 (OMIM*607002) and PROKR2 (OMIM*607123) (etc.), leading to downstream dysfunction of pituitary gonadotropin secretion and subsequent impairment of gonadal function. Clinical manifestations include incomplete or partial puberty and infertility. Methods and Results In this study, whole‐genome sequencing of a female patient with HH identified a novel 5′ splice site variant c.285 + 772 T>G in the deep intron of PROK2 (NM_001126128.2). In vitro minigene validation revealed abnormal splicing of this variant, with 69 base pairs retained in intron 3, ultimately leading to changes in protein length, which may lead to changes in protein structure. According to the American College of Medical Genetics and Genomics (ACMG) pathogenicity classification, this variant is rated as likely pathogenic variant (LP). Conclusion PROK2 variants can lead to HH and we report a case with a novel splice site variant that has been confirmed to lead to the retention of 69 base pairs in intron 3 during RNA splicing.