Abstract
STUDY QUESTION: What is the clinical and genetic overlap across subtypes of congenital gonadotropin (Gn) deficiency? SUMMARY ANSWER: This study reveals substantial clinical and genetic overlap among Gn deficiency disorders, with shared genetic and developmental features across congenital hypogonadotropic hypogonadism (CHH), combined pituitary hormone deficiency (CPHD), and syndromic forms of Gn deficiency. WHAT IS KNOWN ALREADY: Congenital Gn deficiency includes a subset of hypogonadotropic hypogonadism (HH) and can result from defects at the level of the hypothalamus or the pituitary. It includes (i) CHH, further classified into normosmic CHH (nCHH) and Kallmann syndrome (KS); (ii) CPHD; and (iii) syndromic forms such as CHARGE syndrome and septo-optic dysplasia (SOD). STUDY DESIGN SIZE DURATION: The study included all probands with Gn deficiency recruited at a tertiary care center between 2011 and 2024 (n = 568), including 276 KS, 247 nCHH, 29 CPHD, and 16 syndromic Gn deficiency cases. All individuals underwent detailed clinical phenotyping followed by DNA sequencing. PARTICIPANTS/MATERIALS SETTING METHODS: Genetic analysis focused on pathogenic (P) and likely pathogenic (LP) variants and variants of uncertain significance (VUS) within established CHH and CPHD genes. Oligogenicity was assessed in the CHH/syndromic HH cohort (n = 523) compared with controls from 1000 Genomes (n = 601). Genetic overlap among CHH, CPHD, and syndromic Gn deficiency was systematically investigated. MAIN RESULTS AND THE ROLE OF CHANCE: Cleft lip/palate, dental agenesis, and ear abnormalities were recurrent across all Gn-deficient groups. Notably, some CPHD and SOD patients exhibited anosmia and a preserved Gn response to LH-releasing hormone (LHRH) stimulation, indicating a hypothalamic component to their HH. Rare variants in CHH genes were identified in 53% of KS probands (40% P/LP, 13% VUS) and 33% of nCHH probands (23% P/LP, 10% VUS). FGFR1, ANOS1, and PROKR2 were most frequently mutated in KS, while GNRHR, FGFR1, and KISS1R predominated in nCHH. Oligogenic inheritance was detected in 15% of CHH cases, with variants in FGFR1 being most commonly involved. Importantly, a substantial proportion (14%) of CHH patients without a molecular diagnosis carried rare variants predicted to be P or LP in genes typically associated with CPHD (e.g. ROBO1, BRAF, FAT2, and DCHS2). Conversely, several CHH-associated genes such as FGFR1 and FGF8, already implicated in CPHD, were also identified in patients with CPHD and syndromic GN deficiency, further supporting a shared genetic architecture between CHH and CPHD. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: Non-coding and copy number variants were not studied. Functional studies of the new candidate genes for CHH were not undertaken. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the importance of comprehensive clinical evaluation and broadened genetic testing in patients with Gn deficiency. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Swiss National Foundation (NP) (Grant No. 310030B_201275 to N.P.) and the Natural Science Foundation of Beijing (Grant No. 7244338 to Y.W.). The authors declare no competing interests.