Table 2.
KS patients with genetic defects in hypothalamic/pituitary development and signaling.
| Patient No. | Stage | Variant HGVS | MAF | ACMG Classification | Anosmia/Hyposmia | Cryptorchidism | Associated Defects |
|---|---|---|---|---|---|---|---|
| 24 | Pituitary dev. and signalling | GNRHR p.C114* (c342C>A) | NR | Pathogenic | Hyposmia | No | NA |
| Pituitary dev. and signalling | GNRHR p.R262Q (c.785G>A) | 0.00179 | Likely pathogenic | ||||
| Pituitary dev. and signalling | PCSK1 intronic (c.544-43T>G) | NR | Uncertain significance | ||||
| 25 | Pituitary dev. and signalling | GNRHR p.R139H (c.416G>A) | 0.000144 | Pathogenic | Hyposmia | No | NA |
| Pituitary dev. and signalling | GNRHR p.N10_Q11delinsKK (c.30_31delinsAA) | NR | Likely pathogenic | ||||
| GnRH neuron migration | CHD7 p.K683_T684insAK (c.2053_2058dupGCAAAA) | 0.00623 | Uncertain significance | ||||
| 26 | Pituitary dev. and signalling | GNRHR p.P146S (c.436C>T) | 0.00127 | Pathogenic | Anosmia | ND | Incomplete rotation of the right kidney |
| 27 | Hypothalamic signalling | GNRH1 p.C21Lfs*23 (c.60_61insC) | 0.00000401 | Pathogenic | Anosmia | ND | NA |
| GnRH neuron development | WDR11 p.P475= (c.1425G>A) | 0.00275 | Benign | ||||
| 28 | Hypothalamic signalling | GNRH1 p.E47D (c.141G>C) | 0.00153 | Uncertain significance | Anosmia | No | Micropenis |
| Hypothalamic signalling | GNRH1 p.F65= (c.183C>T) | 0.00524 | Uncertain significance | ||||
| 29 | Hypothalamic signalling | GNRH1 p.F65= (c.183C>T) | 0.00524 | Uncertain significance | Hyposmia | ND | NA |
| 30 | Pituitary dev. and signalling | GLI2 p.G185C (c.553G>T) | NR | Likely pathogenic | Anosmia | No | Micropenis |
| GnRH neuron migration | PROKR2 p.R85H (c.254G>A) | 0.000712 | Likely pathogenic | ||||
| 31 | Pituitary dev. and signalling | GLI2 p.L1488F (c.4464G>T) | 0.0000676 | Uncertain significance | Hyposmia | No | NA |
| Pituitary dev. and signalling | PITX2 p.T38= (c.114G>T) | 0.000032 | Likely benign | ||||
| 32 | Pituitary dev. and signalling | GLI2 p.G1006= (c.3018C>T) | 0.00429 | Benign | Anosmia | ND | Strabismus; oligodontia; ptosis; VSD |
| 33 | Pituitary dev. and signalling | GLI2 p.G1006= (c.3018C>T) | 0.00429 | Benign | Anosmia | ND | Strabismus; oligodontia; ptosis; VSD |
| 34 | Pituitary dev. and signalling | SOX3 p.R155Afs*26 (c.462_462delG) | NR | Pathogenic | Hyposmia | No | NA |
| 35 | Pituitary dev. and signalling | POLR3B p.T682A (c.2044A>G) | NR | Uncertain significance | Anosmia | No | NA |
| 36 | Pituitary dev. and signalling | NR0B1 p.S148N (c.443G>A) | NR | Uncertain significance | Anosmia | No | Abdominal hernia |
| GnRH neuron migration | PROKR2 p.S130= (c.390C>T) | 0.000529 | Uncertain significance | ||||
| 37 | Pituitary dev. and signalling | LRRIQ3 p.R227C (c.679C>T) | 0.000748 | Uncertain significance | Hyposmia | No | NA |
| 38 | Pituitary dev. and signalling | LHX4 p.D128= (c.384C>T) | 0.00864 | Benign | Anosmia | Bilateral | NA |
| 39 | Pituitary dev. and signalling | LHX4 p.D128= (c.384C>T) | 0.00864 | Benign | Anosmia | No | NA |
| GnRH neuron migration | CHD7p.S103T (c.307T>A) | 0.0123 | Benign | ||||
| 40 | Pituitary dev. and signalling | LHX3 p.Q41= (c.123G>A) | 0.0111 | Benign | Anosmia | Bilateral | NA |
MAF: minor allele frequency; *: STOP codon; NR: not reported; ND: no data (neither results from the past nor information from the patient); NA: no abnormalities; variant frequency unclear because it falls within a segmental duplication region with inbreeding coefficient suspicion according to GnomAD; pathogenic/likely pathogenic variants are in bold.