Rare sequence variants in gonadotropin-releasing hormone–associated genes identified in women with hypothalamic amenorrhea
| Gene . | Chrom . | Position . | Ref . | Alt . | RefSeq ID . | Protein consequence . | No. of HA participants with RSV . | No. of control participants with RSV . |
|---|---|---|---|---|---|---|---|---|
| RAB3GAP2 | 1 | 220327339 | C | A | NM_012414.4 | Asp1206Tyr | 1 | 0 |
| RAB3GAP2 | 1 | 220363770 | G | A | NM_012414.4 | Pro527Leu | 1 | 0 |
| RAB3GAP2 | 1 | 220366594 | G | A | NM_012414.4 | Arg420Cys | 1c | 0 |
| RAB3GAP1 | 2 | 135887597 | C | T | NM_001172435.2 | Arg336Cys | 3c | 0 |
| RAB3GAP1 | 2 | 135926245 | G | A | NM_001172435.2 | Arg954His | 1c | 0 |
| HESX1 | 3 | 57232493 | C | T | NM_003865.3 | Val129Ile | 1c | 0 |
| PROK2 | 3 | 71830659 | T | C | NM_001126128.2 | Met61Val | 1 | 0 |
| SOX2 | 3 | 181430212 | G | A | NM_003106.4 | Gly22Ser | 1c | 0 |
| KLB | 4 | 39409074 | G | A | NM_175737.4 | Ala169Thr | 1 | 0 |
| KLB | 4 | 39449069 | G | T | NM_175737.4 | Gly908Val | 1c | 0 |
| GNRHR b | 4 | 68606400 | C | T | NM_000406.3 | Arg262Gln | 1 | 0 |
| GNRHR | 4 | 68619550 | A | T | NM_000406.3 | Ser168Agr | 1c | 0 |
| TACR3 | 4 | 104577496 | T | C | NM_001059.3 | His248Arg | 1c | 0 |
| OTUD4 | 4 | 146058934 | G | C | NM_001102653.1 | Pro933Arg | 1 | 0 |
| SRA1 | 5 | 139931626 | TCA | T | NM_001035235.3 | 110AspfsTer25 | 1 | 0 |
| SPRY4 | 5 | 141694021 | G | T | NM_030964.4 | Ser241Tyr | 2 | 0 |
| SPRY4 | 5 | 141694468 | C | A | NM_030964.4 | Gly92Val | 1 | 0 |
| PROP1 | 5 | 177419966 | G | A | NM_006261.4 | Ala142Val | 1c | 0 |
| SEMA3E | 7 | 83047745 | G | A | NM_012431.3 | Pro171Ser | 1c | 0 |
| SEMA3A | 7 | 83689870 | T | C | NM_006080.3 | Asn153Ser | 1c | 0 |
| FEZF1 | 7 | 121942136 | T | G | NM_001024613.4 | Gln448Pro | 1 | 0 |
| GNRH1 | 8 | 25279183 | A | C | NM_000825.3 | Ile48Arg | 1 | 0 |
| FGFR1 | 8 | 38282184 | C | T | NM_001174067.1 | Gly291Glu | 1 | 0 |
| CHD7 | 8 | 61654723 | C | G | NM_017780.4 | Ser244Arg | 1 | 0 |
| CHD7 | 8 | 61655366 | C | T | NM_017780.4 | Arg459Cys | 1c | 0 |
| CHD7 | 8 | 61707630 | G | C | NM_017780.4 | Asp728His | 1c | 0 |
| CHD7 | 8 | 61757872 | C | A | NM_017780.4 | Pro1705Gln | 1c | 0 |
| CHD7 | 8 | 61764736 | C | T | NM_017780.4 | Arg1942Trp | 1d | 0 |
| CHD7 | 8 | 61769418 | A | C | NM_017780.4 | Met2527Leu | 1c | 0 |
| LHX3 | 9 | 139089431 | C | T | NM_014564.5 | Gly317Ser | 1 | 0 |
| WDR11 | 10 | 122610948 | G | A | NM_018117.12 | Val6Met | 1 | 0 |
| POLR3B | 12 | 106821117 | T | C | NM_018082.6 | Met415Thr | 1c | 0 |
| POLR3B | 12 | 106848357 | A | T | NM_018082.6 | Lys721e | 1 | 0 |
| POLR3B | 12 | 106890644 | C | T | NM_018082.6 | Arg978Cys | 1d | 0 |
| KL | 13 | 33635467 | A | G | NM_004795.4 | Arg751Gly | 1c | 0 |
| KL | 13 | 33635750 | T | G | NM_004795.4 | Val845Gly | 1c | 0 |
| DMXL2 | 15 | 51828990 | T | C | NM_001174116.2 | Met563Val | 1 | 0 |
| DMXL2 | 15 | 51829875 | G | C | NM_001174116.2 | Thr476Ser | 1 | 0 |
| DCC | 18 | 50683873 | G | A | NM_005215.4 | Gly470Asp | 2c | 0 |
| DCC | 18 | 50912508 | G | A | NM_005215.4 | Asp819Asn | 1 | 0 |
| DCC | 18 | 50918216 | G | A | NM_005215.4 | Val883Ile | 1c | 0 |
| PNPLA6 | 19 | 7626135 | G | A | NM_001166111.2 | Gly1329Arg | 1 | 0 |
| AXL | 19 | 41743932 | G | GC | NM_021913.5 | His292ProfsTer47 | 1 | 0 |
| AXL | 19 | 41754430 | G | A | NM_021913.5 | Gly517Ser | 1c | 0 |
| PROKR2 | 20 | 5282822 | G | C | NM_144773.3 | Thr340Ser | 1 | 0 |
| PROKR2 | 20 | 5294684 | A | C | NM_144773.3 | Met111Arg | 1 | 0 |
| PROKR2 b | 20 | 5294762 | C | T | NM_144773.3 | Arg85His | 1 | 0 |
| FLRT3 | 20 | 14306951 | T | A | NM_013281.3 | Gln401Leu | 1c | 0 |
| ANOS1 | X | 8501064 | T | C | NM_000216.4 | His672Arg | 1 | 0 |
| ANOS1 | X | 8503715 | C | A | NM_000216.4 | Val587Leu | 2 | 0 |
| ANOS1 b | X | 8536369 | C | T | NM_000216.4 | Val371Ile | 1 | 0 |
| NR0B1 | X | 30322875 | T | C | NM_000475.5 | Ser412Gly | 1c | 0 |
| RAB3GAP2 | 1 | 220324983 | G | T | NM_012414.4 | Leu1331Ile | 1 | 1 |
| SEMA3E | 7 | 83014747 | C | T | NM_012431.3 | Asp580Asn | 1c | 1 |
| CHD7 | 8 | 61655179 | G | T | NM_017780.4 | Met396Ile | 1c | 1 |
| CHD7 | 8 | 61655388 | C | T | NM_017780.4 | Ser466Leu | 1c | 1 |
| CHD7 | 8 | 61778448 | C | T | NM_017780.4 | Leu2984Phe | 2 | 1 |
| LHX3 | 9 | 139089436 | C | G | NM_014564.5 | Arg315Pro | 1c | 1 |
| DMXL2 | 15 | 51756963 | T | C | NM_001174116.2 | Ile2573Val | 1 | 1 |
| DMXL2 | 15 | 51791472 | T | C | NM_001174116.2 | Ile1317Val | 1c | 1 |
| AXL | 19 | 41743930 | G | A | NM_021913.5 | Val289Met | 1c | 1 |
| ANOS1 | X | 8504901 | G | T | NM_000216.4 | Ser511Tyr | 1 | 1 |
| LEPR | 1 | 66083694 | G | A | NM_002303.5 | Val754Met | 1 | 2 |
| CCDC141 | 2 | 179730592 | C | T | NM_173648.4 | Glu876Lys | 1 | 2 |
| KLB | 4 | 39448789 | A | G | NM_175737.4 | Lys815Glu | 1 | 2 |
| KLB | 4 | 39450295 | G | A | NM_175737.4 | Val1042Ile | 1c | 2 |
| GNRHR | 4 | 68619737 | T | C | NM_000406.3 | Gln106Arg | 2c | 2 |
| PCSK1 | 5 | 95729049 | T | C | NM_000439.5 | Thr640Ala | 1c | 2 |
| DCC | 18 | 50741960 | A | G | NM_005215.4 | Asn635Ser | 1c | 2 |
| SPRY4 | 5 | 141694117 | C | T | NM_030964.4 | Cys209Tyr | 1 | 3 |
| CHD7 | 8 | 61655009 | A | G | NM_017780.4 | Met340Val | 1 | 3 |
| Gene . | Chrom . | Position . | Ref . | Alt . | RefSeq ID . | Protein consequence . | No. of HA participants with RSV . | No. of control participants with RSV . |
|---|---|---|---|---|---|---|---|---|
| RAB3GAP2 | 1 | 220327339 | C | A | NM_012414.4 | Asp1206Tyr | 1 | 0 |
| RAB3GAP2 | 1 | 220363770 | G | A | NM_012414.4 | Pro527Leu | 1 | 0 |
| RAB3GAP2 | 1 | 220366594 | G | A | NM_012414.4 | Arg420Cys | 1c | 0 |
| RAB3GAP1 | 2 | 135887597 | C | T | NM_001172435.2 | Arg336Cys | 3c | 0 |
| RAB3GAP1 | 2 | 135926245 | G | A | NM_001172435.2 | Arg954His | 1c | 0 |
| HESX1 | 3 | 57232493 | C | T | NM_003865.3 | Val129Ile | 1c | 0 |
| PROK2 | 3 | 71830659 | T | C | NM_001126128.2 | Met61Val | 1 | 0 |
| SOX2 | 3 | 181430212 | G | A | NM_003106.4 | Gly22Ser | 1c | 0 |
| KLB | 4 | 39409074 | G | A | NM_175737.4 | Ala169Thr | 1 | 0 |
| KLB | 4 | 39449069 | G | T | NM_175737.4 | Gly908Val | 1c | 0 |
| GNRHR b | 4 | 68606400 | C | T | NM_000406.3 | Arg262Gln | 1 | 0 |
| GNRHR | 4 | 68619550 | A | T | NM_000406.3 | Ser168Agr | 1c | 0 |
| TACR3 | 4 | 104577496 | T | C | NM_001059.3 | His248Arg | 1c | 0 |
| OTUD4 | 4 | 146058934 | G | C | NM_001102653.1 | Pro933Arg | 1 | 0 |
| SRA1 | 5 | 139931626 | TCA | T | NM_001035235.3 | 110AspfsTer25 | 1 | 0 |
| SPRY4 | 5 | 141694021 | G | T | NM_030964.4 | Ser241Tyr | 2 | 0 |
| SPRY4 | 5 | 141694468 | C | A | NM_030964.4 | Gly92Val | 1 | 0 |
| PROP1 | 5 | 177419966 | G | A | NM_006261.4 | Ala142Val | 1c | 0 |
| SEMA3E | 7 | 83047745 | G | A | NM_012431.3 | Pro171Ser | 1c | 0 |
| SEMA3A | 7 | 83689870 | T | C | NM_006080.3 | Asn153Ser | 1c | 0 |
| FEZF1 | 7 | 121942136 | T | G | NM_001024613.4 | Gln448Pro | 1 | 0 |
| GNRH1 | 8 | 25279183 | A | C | NM_000825.3 | Ile48Arg | 1 | 0 |
| FGFR1 | 8 | 38282184 | C | T | NM_001174067.1 | Gly291Glu | 1 | 0 |
| CHD7 | 8 | 61654723 | C | G | NM_017780.4 | Ser244Arg | 1 | 0 |
| CHD7 | 8 | 61655366 | C | T | NM_017780.4 | Arg459Cys | 1c | 0 |
| CHD7 | 8 | 61707630 | G | C | NM_017780.4 | Asp728His | 1c | 0 |
| CHD7 | 8 | 61757872 | C | A | NM_017780.4 | Pro1705Gln | 1c | 0 |
| CHD7 | 8 | 61764736 | C | T | NM_017780.4 | Arg1942Trp | 1d | 0 |
| CHD7 | 8 | 61769418 | A | C | NM_017780.4 | Met2527Leu | 1c | 0 |
| LHX3 | 9 | 139089431 | C | T | NM_014564.5 | Gly317Ser | 1 | 0 |
| WDR11 | 10 | 122610948 | G | A | NM_018117.12 | Val6Met | 1 | 0 |
| POLR3B | 12 | 106821117 | T | C | NM_018082.6 | Met415Thr | 1c | 0 |
| POLR3B | 12 | 106848357 | A | T | NM_018082.6 | Lys721e | 1 | 0 |
| POLR3B | 12 | 106890644 | C | T | NM_018082.6 | Arg978Cys | 1d | 0 |
| KL | 13 | 33635467 | A | G | NM_004795.4 | Arg751Gly | 1c | 0 |
| KL | 13 | 33635750 | T | G | NM_004795.4 | Val845Gly | 1c | 0 |
| DMXL2 | 15 | 51828990 | T | C | NM_001174116.2 | Met563Val | 1 | 0 |
| DMXL2 | 15 | 51829875 | G | C | NM_001174116.2 | Thr476Ser | 1 | 0 |
| DCC | 18 | 50683873 | G | A | NM_005215.4 | Gly470Asp | 2c | 0 |
| DCC | 18 | 50912508 | G | A | NM_005215.4 | Asp819Asn | 1 | 0 |
| DCC | 18 | 50918216 | G | A | NM_005215.4 | Val883Ile | 1c | 0 |
| PNPLA6 | 19 | 7626135 | G | A | NM_001166111.2 | Gly1329Arg | 1 | 0 |
| AXL | 19 | 41743932 | G | GC | NM_021913.5 | His292ProfsTer47 | 1 | 0 |
| AXL | 19 | 41754430 | G | A | NM_021913.5 | Gly517Ser | 1c | 0 |
| PROKR2 | 20 | 5282822 | G | C | NM_144773.3 | Thr340Ser | 1 | 0 |
| PROKR2 | 20 | 5294684 | A | C | NM_144773.3 | Met111Arg | 1 | 0 |
| PROKR2 b | 20 | 5294762 | C | T | NM_144773.3 | Arg85His | 1 | 0 |
| FLRT3 | 20 | 14306951 | T | A | NM_013281.3 | Gln401Leu | 1c | 0 |
| ANOS1 | X | 8501064 | T | C | NM_000216.4 | His672Arg | 1 | 0 |
| ANOS1 | X | 8503715 | C | A | NM_000216.4 | Val587Leu | 2 | 0 |
| ANOS1 b | X | 8536369 | C | T | NM_000216.4 | Val371Ile | 1 | 0 |
| NR0B1 | X | 30322875 | T | C | NM_000475.5 | Ser412Gly | 1c | 0 |
| RAB3GAP2 | 1 | 220324983 | G | T | NM_012414.4 | Leu1331Ile | 1 | 1 |
| SEMA3E | 7 | 83014747 | C | T | NM_012431.3 | Asp580Asn | 1c | 1 |
| CHD7 | 8 | 61655179 | G | T | NM_017780.4 | Met396Ile | 1c | 1 |
| CHD7 | 8 | 61655388 | C | T | NM_017780.4 | Ser466Leu | 1c | 1 |
| CHD7 | 8 | 61778448 | C | T | NM_017780.4 | Leu2984Phe | 2 | 1 |
| LHX3 | 9 | 139089436 | C | G | NM_014564.5 | Arg315Pro | 1c | 1 |
| DMXL2 | 15 | 51756963 | T | C | NM_001174116.2 | Ile2573Val | 1 | 1 |
| DMXL2 | 15 | 51791472 | T | C | NM_001174116.2 | Ile1317Val | 1c | 1 |
| AXL | 19 | 41743930 | G | A | NM_021913.5 | Val289Met | 1c | 1 |
| ANOS1 | X | 8504901 | G | T | NM_000216.4 | Ser511Tyr | 1 | 1 |
| LEPR | 1 | 66083694 | G | A | NM_002303.5 | Val754Met | 1 | 2 |
| CCDC141 | 2 | 179730592 | C | T | NM_173648.4 | Glu876Lys | 1 | 2 |
| KLB | 4 | 39448789 | A | G | NM_175737.4 | Lys815Glu | 1 | 2 |
| KLB | 4 | 39450295 | G | A | NM_175737.4 | Val1042Ile | 1c | 2 |
| GNRHR | 4 | 68619737 | T | C | NM_000406.3 | Gln106Arg | 2c | 2 |
| PCSK1 | 5 | 95729049 | T | C | NM_000439.5 | Thr640Ala | 1c | 2 |
| DCC | 18 | 50741960 | A | G | NM_005215.4 | Asn635Ser | 1c | 2 |
| SPRY4 | 5 | 141694117 | C | T | NM_030964.4 | Cys209Tyr | 1 | 3 |
| CHD7 | 8 | 61655009 | A | G | NM_017780.4 | Met340Val | 1 | 3 |
Abbreviations: Alt, alternate allele; Chrom, chromosome; HA, hypothalamic amenorrhea; ID, identification; Low conf, low confidence; Ref, reference allele; RSV, rare sequence variant.
aSee Supplemental References.
bParticipant and mutation previously reported.
cVariant identified in a participant previously reported as mutation negative.
dVariant identified in a participant previously reported with a heterozygous ANOS1 RSV (23).
eDenotes stop codon.
Rare sequence variants in gonadotropin-releasing hormone–associated genes identified in women with hypothalamic amenorrhea
| Gene . | Chrom . | Position . | Ref . | Alt . | RefSeq ID . | Protein consequence . | No. of HA participants with RSV . | No. of control participants with RSV . |
|---|---|---|---|---|---|---|---|---|
| RAB3GAP2 | 1 | 220327339 | C | A | NM_012414.4 | Asp1206Tyr | 1 | 0 |
| RAB3GAP2 | 1 | 220363770 | G | A | NM_012414.4 | Pro527Leu | 1 | 0 |
| RAB3GAP2 | 1 | 220366594 | G | A | NM_012414.4 | Arg420Cys | 1c | 0 |
| RAB3GAP1 | 2 | 135887597 | C | T | NM_001172435.2 | Arg336Cys | 3c | 0 |
| RAB3GAP1 | 2 | 135926245 | G | A | NM_001172435.2 | Arg954His | 1c | 0 |
| HESX1 | 3 | 57232493 | C | T | NM_003865.3 | Val129Ile | 1c | 0 |
| PROK2 | 3 | 71830659 | T | C | NM_001126128.2 | Met61Val | 1 | 0 |
| SOX2 | 3 | 181430212 | G | A | NM_003106.4 | Gly22Ser | 1c | 0 |
| KLB | 4 | 39409074 | G | A | NM_175737.4 | Ala169Thr | 1 | 0 |
| KLB | 4 | 39449069 | G | T | NM_175737.4 | Gly908Val | 1c | 0 |
| GNRHR b | 4 | 68606400 | C | T | NM_000406.3 | Arg262Gln | 1 | 0 |
| GNRHR | 4 | 68619550 | A | T | NM_000406.3 | Ser168Agr | 1c | 0 |
| TACR3 | 4 | 104577496 | T | C | NM_001059.3 | His248Arg | 1c | 0 |
| OTUD4 | 4 | 146058934 | G | C | NM_001102653.1 | Pro933Arg | 1 | 0 |
| SRA1 | 5 | 139931626 | TCA | T | NM_001035235.3 | 110AspfsTer25 | 1 | 0 |
| SPRY4 | 5 | 141694021 | G | T | NM_030964.4 | Ser241Tyr | 2 | 0 |
| SPRY4 | 5 | 141694468 | C | A | NM_030964.4 | Gly92Val | 1 | 0 |
| PROP1 | 5 | 177419966 | G | A | NM_006261.4 | Ala142Val | 1c | 0 |
| SEMA3E | 7 | 83047745 | G | A | NM_012431.3 | Pro171Ser | 1c | 0 |
| SEMA3A | 7 | 83689870 | T | C | NM_006080.3 | Asn153Ser | 1c | 0 |
| FEZF1 | 7 | 121942136 | T | G | NM_001024613.4 | Gln448Pro | 1 | 0 |
| GNRH1 | 8 | 25279183 | A | C | NM_000825.3 | Ile48Arg | 1 | 0 |
| FGFR1 | 8 | 38282184 | C | T | NM_001174067.1 | Gly291Glu | 1 | 0 |
| CHD7 | 8 | 61654723 | C | G | NM_017780.4 | Ser244Arg | 1 | 0 |
| CHD7 | 8 | 61655366 | C | T | NM_017780.4 | Arg459Cys | 1c | 0 |
| CHD7 | 8 | 61707630 | G | C | NM_017780.4 | Asp728His | 1c | 0 |
| CHD7 | 8 | 61757872 | C | A | NM_017780.4 | Pro1705Gln | 1c | 0 |
| CHD7 | 8 | 61764736 | C | T | NM_017780.4 | Arg1942Trp | 1d | 0 |
| CHD7 | 8 | 61769418 | A | C | NM_017780.4 | Met2527Leu | 1c | 0 |
| LHX3 | 9 | 139089431 | C | T | NM_014564.5 | Gly317Ser | 1 | 0 |
| WDR11 | 10 | 122610948 | G | A | NM_018117.12 | Val6Met | 1 | 0 |
| POLR3B | 12 | 106821117 | T | C | NM_018082.6 | Met415Thr | 1c | 0 |
| POLR3B | 12 | 106848357 | A | T | NM_018082.6 | Lys721e | 1 | 0 |
| POLR3B | 12 | 106890644 | C | T | NM_018082.6 | Arg978Cys | 1d | 0 |
| KL | 13 | 33635467 | A | G | NM_004795.4 | Arg751Gly | 1c | 0 |
| KL | 13 | 33635750 | T | G | NM_004795.4 | Val845Gly | 1c | 0 |
| DMXL2 | 15 | 51828990 | T | C | NM_001174116.2 | Met563Val | 1 | 0 |
| DMXL2 | 15 | 51829875 | G | C | NM_001174116.2 | Thr476Ser | 1 | 0 |
| DCC | 18 | 50683873 | G | A | NM_005215.4 | Gly470Asp | 2c | 0 |
| DCC | 18 | 50912508 | G | A | NM_005215.4 | Asp819Asn | 1 | 0 |
| DCC | 18 | 50918216 | G | A | NM_005215.4 | Val883Ile | 1c | 0 |
| PNPLA6 | 19 | 7626135 | G | A | NM_001166111.2 | Gly1329Arg | 1 | 0 |
| AXL | 19 | 41743932 | G | GC | NM_021913.5 | His292ProfsTer47 | 1 | 0 |
| AXL | 19 | 41754430 | G | A | NM_021913.5 | Gly517Ser | 1c | 0 |
| PROKR2 | 20 | 5282822 | G | C | NM_144773.3 | Thr340Ser | 1 | 0 |
| PROKR2 | 20 | 5294684 | A | C | NM_144773.3 | Met111Arg | 1 | 0 |
| PROKR2 b | 20 | 5294762 | C | T | NM_144773.3 | Arg85His | 1 | 0 |
| FLRT3 | 20 | 14306951 | T | A | NM_013281.3 | Gln401Leu | 1c | 0 |
| ANOS1 | X | 8501064 | T | C | NM_000216.4 | His672Arg | 1 | 0 |
| ANOS1 | X | 8503715 | C | A | NM_000216.4 | Val587Leu | 2 | 0 |
| ANOS1 b | X | 8536369 | C | T | NM_000216.4 | Val371Ile | 1 | 0 |
| NR0B1 | X | 30322875 | T | C | NM_000475.5 | Ser412Gly | 1c | 0 |
| RAB3GAP2 | 1 | 220324983 | G | T | NM_012414.4 | Leu1331Ile | 1 | 1 |
| SEMA3E | 7 | 83014747 | C | T | NM_012431.3 | Asp580Asn | 1c | 1 |
| CHD7 | 8 | 61655179 | G | T | NM_017780.4 | Met396Ile | 1c | 1 |
| CHD7 | 8 | 61655388 | C | T | NM_017780.4 | Ser466Leu | 1c | 1 |
| CHD7 | 8 | 61778448 | C | T | NM_017780.4 | Leu2984Phe | 2 | 1 |
| LHX3 | 9 | 139089436 | C | G | NM_014564.5 | Arg315Pro | 1c | 1 |
| DMXL2 | 15 | 51756963 | T | C | NM_001174116.2 | Ile2573Val | 1 | 1 |
| DMXL2 | 15 | 51791472 | T | C | NM_001174116.2 | Ile1317Val | 1c | 1 |
| AXL | 19 | 41743930 | G | A | NM_021913.5 | Val289Met | 1c | 1 |
| ANOS1 | X | 8504901 | G | T | NM_000216.4 | Ser511Tyr | 1 | 1 |
| LEPR | 1 | 66083694 | G | A | NM_002303.5 | Val754Met | 1 | 2 |
| CCDC141 | 2 | 179730592 | C | T | NM_173648.4 | Glu876Lys | 1 | 2 |
| KLB | 4 | 39448789 | A | G | NM_175737.4 | Lys815Glu | 1 | 2 |
| KLB | 4 | 39450295 | G | A | NM_175737.4 | Val1042Ile | 1c | 2 |
| GNRHR | 4 | 68619737 | T | C | NM_000406.3 | Gln106Arg | 2c | 2 |
| PCSK1 | 5 | 95729049 | T | C | NM_000439.5 | Thr640Ala | 1c | 2 |
| DCC | 18 | 50741960 | A | G | NM_005215.4 | Asn635Ser | 1c | 2 |
| SPRY4 | 5 | 141694117 | C | T | NM_030964.4 | Cys209Tyr | 1 | 3 |
| CHD7 | 8 | 61655009 | A | G | NM_017780.4 | Met340Val | 1 | 3 |
| Gene . | Chrom . | Position . | Ref . | Alt . | RefSeq ID . | Protein consequence . | No. of HA participants with RSV . | No. of control participants with RSV . |
|---|---|---|---|---|---|---|---|---|
| RAB3GAP2 | 1 | 220327339 | C | A | NM_012414.4 | Asp1206Tyr | 1 | 0 |
| RAB3GAP2 | 1 | 220363770 | G | A | NM_012414.4 | Pro527Leu | 1 | 0 |
| RAB3GAP2 | 1 | 220366594 | G | A | NM_012414.4 | Arg420Cys | 1c | 0 |
| RAB3GAP1 | 2 | 135887597 | C | T | NM_001172435.2 | Arg336Cys | 3c | 0 |
| RAB3GAP1 | 2 | 135926245 | G | A | NM_001172435.2 | Arg954His | 1c | 0 |
| HESX1 | 3 | 57232493 | C | T | NM_003865.3 | Val129Ile | 1c | 0 |
| PROK2 | 3 | 71830659 | T | C | NM_001126128.2 | Met61Val | 1 | 0 |
| SOX2 | 3 | 181430212 | G | A | NM_003106.4 | Gly22Ser | 1c | 0 |
| KLB | 4 | 39409074 | G | A | NM_175737.4 | Ala169Thr | 1 | 0 |
| KLB | 4 | 39449069 | G | T | NM_175737.4 | Gly908Val | 1c | 0 |
| GNRHR b | 4 | 68606400 | C | T | NM_000406.3 | Arg262Gln | 1 | 0 |
| GNRHR | 4 | 68619550 | A | T | NM_000406.3 | Ser168Agr | 1c | 0 |
| TACR3 | 4 | 104577496 | T | C | NM_001059.3 | His248Arg | 1c | 0 |
| OTUD4 | 4 | 146058934 | G | C | NM_001102653.1 | Pro933Arg | 1 | 0 |
| SRA1 | 5 | 139931626 | TCA | T | NM_001035235.3 | 110AspfsTer25 | 1 | 0 |
| SPRY4 | 5 | 141694021 | G | T | NM_030964.4 | Ser241Tyr | 2 | 0 |
| SPRY4 | 5 | 141694468 | C | A | NM_030964.4 | Gly92Val | 1 | 0 |
| PROP1 | 5 | 177419966 | G | A | NM_006261.4 | Ala142Val | 1c | 0 |
| SEMA3E | 7 | 83047745 | G | A | NM_012431.3 | Pro171Ser | 1c | 0 |
| SEMA3A | 7 | 83689870 | T | C | NM_006080.3 | Asn153Ser | 1c | 0 |
| FEZF1 | 7 | 121942136 | T | G | NM_001024613.4 | Gln448Pro | 1 | 0 |
| GNRH1 | 8 | 25279183 | A | C | NM_000825.3 | Ile48Arg | 1 | 0 |
| FGFR1 | 8 | 38282184 | C | T | NM_001174067.1 | Gly291Glu | 1 | 0 |
| CHD7 | 8 | 61654723 | C | G | NM_017780.4 | Ser244Arg | 1 | 0 |
| CHD7 | 8 | 61655366 | C | T | NM_017780.4 | Arg459Cys | 1c | 0 |
| CHD7 | 8 | 61707630 | G | C | NM_017780.4 | Asp728His | 1c | 0 |
| CHD7 | 8 | 61757872 | C | A | NM_017780.4 | Pro1705Gln | 1c | 0 |
| CHD7 | 8 | 61764736 | C | T | NM_017780.4 | Arg1942Trp | 1d | 0 |
| CHD7 | 8 | 61769418 | A | C | NM_017780.4 | Met2527Leu | 1c | 0 |
| LHX3 | 9 | 139089431 | C | T | NM_014564.5 | Gly317Ser | 1 | 0 |
| WDR11 | 10 | 122610948 | G | A | NM_018117.12 | Val6Met | 1 | 0 |
| POLR3B | 12 | 106821117 | T | C | NM_018082.6 | Met415Thr | 1c | 0 |
| POLR3B | 12 | 106848357 | A | T | NM_018082.6 | Lys721e | 1 | 0 |
| POLR3B | 12 | 106890644 | C | T | NM_018082.6 | Arg978Cys | 1d | 0 |
| KL | 13 | 33635467 | A | G | NM_004795.4 | Arg751Gly | 1c | 0 |
| KL | 13 | 33635750 | T | G | NM_004795.4 | Val845Gly | 1c | 0 |
| DMXL2 | 15 | 51828990 | T | C | NM_001174116.2 | Met563Val | 1 | 0 |
| DMXL2 | 15 | 51829875 | G | C | NM_001174116.2 | Thr476Ser | 1 | 0 |
| DCC | 18 | 50683873 | G | A | NM_005215.4 | Gly470Asp | 2c | 0 |
| DCC | 18 | 50912508 | G | A | NM_005215.4 | Asp819Asn | 1 | 0 |
| DCC | 18 | 50918216 | G | A | NM_005215.4 | Val883Ile | 1c | 0 |
| PNPLA6 | 19 | 7626135 | G | A | NM_001166111.2 | Gly1329Arg | 1 | 0 |
| AXL | 19 | 41743932 | G | GC | NM_021913.5 | His292ProfsTer47 | 1 | 0 |
| AXL | 19 | 41754430 | G | A | NM_021913.5 | Gly517Ser | 1c | 0 |
| PROKR2 | 20 | 5282822 | G | C | NM_144773.3 | Thr340Ser | 1 | 0 |
| PROKR2 | 20 | 5294684 | A | C | NM_144773.3 | Met111Arg | 1 | 0 |
| PROKR2 b | 20 | 5294762 | C | T | NM_144773.3 | Arg85His | 1 | 0 |
| FLRT3 | 20 | 14306951 | T | A | NM_013281.3 | Gln401Leu | 1c | 0 |
| ANOS1 | X | 8501064 | T | C | NM_000216.4 | His672Arg | 1 | 0 |
| ANOS1 | X | 8503715 | C | A | NM_000216.4 | Val587Leu | 2 | 0 |
| ANOS1 b | X | 8536369 | C | T | NM_000216.4 | Val371Ile | 1 | 0 |
| NR0B1 | X | 30322875 | T | C | NM_000475.5 | Ser412Gly | 1c | 0 |
| RAB3GAP2 | 1 | 220324983 | G | T | NM_012414.4 | Leu1331Ile | 1 | 1 |
| SEMA3E | 7 | 83014747 | C | T | NM_012431.3 | Asp580Asn | 1c | 1 |
| CHD7 | 8 | 61655179 | G | T | NM_017780.4 | Met396Ile | 1c | 1 |
| CHD7 | 8 | 61655388 | C | T | NM_017780.4 | Ser466Leu | 1c | 1 |
| CHD7 | 8 | 61778448 | C | T | NM_017780.4 | Leu2984Phe | 2 | 1 |
| LHX3 | 9 | 139089436 | C | G | NM_014564.5 | Arg315Pro | 1c | 1 |
| DMXL2 | 15 | 51756963 | T | C | NM_001174116.2 | Ile2573Val | 1 | 1 |
| DMXL2 | 15 | 51791472 | T | C | NM_001174116.2 | Ile1317Val | 1c | 1 |
| AXL | 19 | 41743930 | G | A | NM_021913.5 | Val289Met | 1c | 1 |
| ANOS1 | X | 8504901 | G | T | NM_000216.4 | Ser511Tyr | 1 | 1 |
| LEPR | 1 | 66083694 | G | A | NM_002303.5 | Val754Met | 1 | 2 |
| CCDC141 | 2 | 179730592 | C | T | NM_173648.4 | Glu876Lys | 1 | 2 |
| KLB | 4 | 39448789 | A | G | NM_175737.4 | Lys815Glu | 1 | 2 |
| KLB | 4 | 39450295 | G | A | NM_175737.4 | Val1042Ile | 1c | 2 |
| GNRHR | 4 | 68619737 | T | C | NM_000406.3 | Gln106Arg | 2c | 2 |
| PCSK1 | 5 | 95729049 | T | C | NM_000439.5 | Thr640Ala | 1c | 2 |
| DCC | 18 | 50741960 | A | G | NM_005215.4 | Asn635Ser | 1c | 2 |
| SPRY4 | 5 | 141694117 | C | T | NM_030964.4 | Cys209Tyr | 1 | 3 |
| CHD7 | 8 | 61655009 | A | G | NM_017780.4 | Met340Val | 1 | 3 |
Abbreviations: Alt, alternate allele; Chrom, chromosome; HA, hypothalamic amenorrhea; ID, identification; Low conf, low confidence; Ref, reference allele; RSV, rare sequence variant.
aSee Supplemental References.
bParticipant and mutation previously reported.
cVariant identified in a participant previously reported as mutation negative.
dVariant identified in a participant previously reported with a heterozygous ANOS1 RSV (23).
eDenotes stop codon.
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