Table 1.

KS patients with genetic defects in primary GnRH neuron development/migration.

Patient No.	Stage	Variant HGVS	MAF	ACMG Classification	Anosmia/Hyposmia	Cryptorchidism	Associated Defects
1	GnRH neuron migration	ANOS1 p.R631* (c.1891C>T)	NR	Pathogenic	Anosmia	Bilateral	Bimanual synkinesis; left kidney agenesis
2	GnRH neuron migration	ANOS1 p.R631* (c.1891C>T)	NR	Pathogenic	Anosmia	Right testis	Bimanual synkinesis; right kidney agenesis
3	GnRH neuron development	FGFR1 p.W99* (c.297G>A)	NR	Pathogenic	Anosmia	Bilateral	Bilateral duplex pelvicalyceal system
4	GnRH neuron development	FGFR1 p.V135I (c.403G>A)	0.00042	Likely pathogenic	Hyposmia	No	NA
5	GnRH neuron development	FGFR1 p. R281W (c.841C>T)	NR	Pathogenic	Anosmia	Bilateral	Cleft lip and palate
	Pituitary dev. and signalling	GLI2 p.D1520N (c.4558G>A)	0.00935	Benign
6	GnRH neuron development	FGFR1 p.K649R (c.1946A>G)	NR	Likely pathogenic	Hyposmia	Bilateral	NA
7	GnRH neuron migration	CHD7 p.V567Afs*8 (c.1699_1700insC)	NR	Pathogenic	Hyposmia	Bilateral	Double pyelum in the left kidney; myopia (8 dptr)
	GnRH neuron migration	CHD7 p.E1478= (c.4434A>G)	NR	Likely benign
8	GnRH neuron migration	CHD7 p.K850Q (c.2548A>C)	NR	Likely pathogenic	Anosmia	No	Dental agenesis (lateral jaw’s incisors)
	Pituitary dev. and signalling	LHX4 p.G305W (c.913G>T)	0.00000796	Likely pathogenic
9	GnRH neuron migration	CHD7 p.N1030H (c.3088A>C)	NR	Pathogenic	Anosmia	No	Sandal gap deformity
	GnRH neuron development	FGFR1 p.R285W (c.853C>T)	NR	Likely pathogenic
10	GnRH neuron migration	CHD7 p.N1030H (c.3088A>C)	NR	Pathogenic	Anosmia	No	NA
	GnRH neuron development	FGFR1 p.R285W (c.853C>T)	NR	Likely pathogenic
11	GnRH neuron migration	CHD7 p.N1030H (c.3088A>C)	NR	Pathogenic	Anosmia	No	Left kidney agenesis; splenomegaly
	GnRH neuron development	HS6ST1 p.K67* (c.199A>T)	0.00624	Benign
	Pituitary dev. and signalling	LHX4 p.D128= (c.384C>T)	0.00864	Benign
12	GnRH neuron migration	CHD7 p.E1195A (c.3584A>C)	NR	Likely pathogenic	Hyposmia	No	Syndactyly of the toes
13	GnRH neuron migration	CHD7 p.D2838Tfs*51 (c.8512delG)	NR	Pathogenic	Hyposmia	Right testis	Choanal atresia; clinodactyly; spina bifida (L5)
	Pituitary dev. and signalling	LHX4 p.D128= (c.384C>T)	0.00864	Benign
14	GnRH neuron migration	CHD7 p.R947Q (c.2840G>A)	0.0000763	Uncertain significance	Anosmia	Bilateral	Micropenis; pre-auricular fistula; discoloration of the hair on the temple; brachydactyly
15	GnRH neuron migration	CHD7 p.M340V (c.1018A>G)	0.00462	Benign	Hyposmia	No	NA
16	GnRH neuron development	WDR11 p.M769V (c.2305A>G)	0.000565	Uncertain significance	Anosmia	Right testis	NA
	GnRH neuron migration	PROKR2 p.R268C (c.802C>T)	0.00391	Benign
17	GnRH neuron development	FGF8 intronic (c.445-62G>T)	0.0000957	Uncertain significance	Anosmia	Migrating testis	NA
18	GnRH neuron development	FGF8 intronic (c.445-62G>T)	0.0000957	Uncertain significance	Anosmia	No	Intellectual disability
19	GnRH neuron development	FGF8 p.P26L (c.77C>T)	0.00115	Uncertain significance	Hyposmia	No	Bimanual synkinesis
20	GnRH neuron development	HS6ST1 p.R249S (c.745C>A)	0.0074	Uncertain significance	Anosmia	Right testis	NA
	GnRH neuron development	HS6ST1 p.D87E (c.261C>A)	0.01’	Uncertain significance
21	GnRH neuron development	HS6ST1 p.R249S (c.745C>A)	0.0074	Uncertain significance	Anosmia	Right testis	Micropenis; syndactyly of toes
	GnRH neuron development	HS6ST1 p.D87E (c.261C>A)	0.01’	Uncertain significance
22	GnRH neuron development	WDR11 p.I716V (c.2146A>G)	NR	Likely pathogenic	Anosmia	Right testis	Bimanual synkinesis
	Pituitary dev. and signalling	GNRHR p.Q106R (c.317A>G)	0.00284	Likely pathogenic
	Pituitary dev. and signalling	GNRHR p.Ser151 = (c.453C>T)	0.0755	Uncertain significance
23	GnRH neuron development	WDR11 p.M769V (c.2305A>G)	0.000565	Uncertain significance	Anosmia	No	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.