Table 1: Pathogenic and likely pathogenic variants in 69 DSD genes listed in the ClinVar database:
The variants in 69 human DSD genes (column 1) deposited in the NIH-maintained ClinVar database and classified as pathogenic or likely pathogenic for a DSD condition were compiled. The total number (column 2) and type (column 3) of variants are shown (FS Del/Ins: deletion/insertion resulting in frameshift). Copy number variants that included multiple genes were not included, as pathogenicity could not be easily attributed to the single gene. If the genes were involved in several phenotypes, only the variants relevant to DSD were included. Variants for which phenotypic information was not available were not included. Selected references cited as evidence in the database are shown in column 4 (the complete list for each gene entry can be found at https://www.ncbi.nlm.nih.gov/clinvar/).
| Gene name | Number of variants | Type of variants | Example references |
|---|---|---|---|
| Sex Determination | |||
| BMP15 (POF4) | 3 | Missense, nonsense | (Di Pasquale et al., 2004; Dixit et al., 2006; Rossetti et al., 2009) |
| CBX2 | 2 | Missense | (Biason-Lauber et al., 2009) |
| DHH | 9 | FS Del, nonsense, missense | (Canto et al., 2008; Tajouri et al., 2018; Umehara et al., 2000; Werner et al., 2015) |
| DMRT1 | 1 | Missense | - |
| DMRT2 | 0 | - | - |
| FSHR | 17 | Missense | (Aittomäki et al., 1995; Beau et al., 1998; De Leener et al., 2008, 2006; Di Carlo et al., 1997; Doherty et al., 2002; Gromoll et al., 1996; Kuechler et al., 2010; Meduri et al., 2003; Montanelli et al., 2004; Smits et al., 2003; Vasseur et al., 2003) |
| GATA4 | 1 | Missense | (Lourenco et al., 2011) |
| HHAT | 0 | - | - |
| MAP3K1 | 9 | Missense, Splice site | (Baxter et al., 2015; Granados et al., 2017; Loke and Ostrer, 2012; Pearlman et al., 2010) |
| NR0B1 (DAX1) | 75 | FS del/ins, rearrangement, gene deletion, gene duplication, missense, nonsense, splice site | (Barbaro et al., 2007; Muscatelli et al., 1994; Jun Nakae et al., 1997; Schwartz et al., 1997; Yanase et al., 1996) |
| NR5A1 (SF1) | 26 | Missense, nonsense, in-frame deletion, FS del | (Achermann et al., 1999; Baetens et al., 2017; Bashamboo et al., 2010; Colson et al., 2017; Correa et al., 2004; Igarashi et al., 2017; Lin et al., 2007; Lourenço et al., 2009) |
| RSPO1 | 3 | Exon deletion, FS ins, Splice site | (Parma et al., 2006; Tomaselli et al., 2008) |
| SOX3 | 3 | Gene duplication, missense, in-frame duplication | (Karaca et al., 2015; Woods et al., 2005) |
| SOX9 | 14 | Promoter Del, Promoter Dup/Triplication, FS ins, FS del, missense, nonsense | (Benko et al., 2011; Cox et al., 2011; Foster et al., 1994; Kim et al., 2015; Kwok et al., 1995; Pop et al., 2005; Vetro et al., 2011) |
| SRY | 27 | Missense, FS del, in-frame del, nonsense | (Berta et al., 1990; Hawkins et al., 1992; Jäger et al., 1990; McElreavey et al., 1992; Nykamp et al., 2017a; Vilain et al., 1992) |
| STAG3 (POF8) | 4 | FS del, FS dup, Splice site, nonsense | (Caburet et al., 2014; He et al., 2018; Le Quesne Stabej et al., 2016) |
| WNT4 | 4 | Missense | (Biason-Lauber et al., 2007, 2004; Mandel et al., 2008; Philibert et al., 2008) |
| WT1 | 23 | Splice site, missense, nonsense, FS del, FS dup | (Barbaux et al., 1997; Barrera et al., 2016; Bruening et al., 1992; Little and Wells, 1997; Royer-Pokora et al., 2004; F. Wang et al., 2017) |
| WWOX | 0 | - | - |
| ZFPM2 | 3 | Missense | (Bashamboo et al., 2014; Royer-Pokora et al., 2004) |
| Sex differentiation | |||
| AKR1C2 | 4 | Missense | (Christa E. Flück et al., 2011) |
| AKR1C4 | 0 | - | - |
| AMH | 4 | FS Del, FS Ins, nonsense | (Carré-Eusèbe et al., 1992; Knebelmann et al., 1991; Lang-Muritano et al., 2001) |
| AMHR2 | 4 | FS Del, in-frame del, Splice site, missense | (Belville et al., 2009; Imbeaud et al., 1995, 1996; Messika-Zeitoun et al., 2001) |
| AR | 109 | Splice site, missense, FS Ins/del, nonsense, multi exon deletion | (Brown et al., 1988; Brüggenwirth et al., 1997; Choong et al., 1996; MacLean et al., 1993; Sammarco et al., 2000; Vilchis et al., 2003; Zhu et al., 1999; Zoppi et al., 1993) |
| ARX | 2 | Nonsense, FS Del | (Kato et al., 2004; Kitamura et al., 2002) |
| ATRX | 24 | Splice site, Nonsense, FS Del, missense | (Gibbons et al., 1995; Mitson et al., 2011a; Stevenson, 1993) |
| CYP11A1 | 10 | FS Del, FS Ins, in-frame insertion, missense | (Hiort et al., 2005; Katsumata et al., 2002; C. J. Kim et al., 2008; Tajima et al., 2001) |
| CYP17A1 | 35 | Splice site, in-frame deletion, FS del, FS Dup, rearrangement, missense, nonsense | (Ahlgren et al., 1992; Imai et al., 1992; Kagimoto et al., 1988; Oshiro et al., 1995; Schwab et al., 2005; van den Akker et al., 2002; Yamaguchi et al., 1997; Yanase et al., 1990; Yang et al., 2006) |
| CYP19A1 | 13 | fusion, insertion, deletion, missense SNV, intron SNV, missense SNV, nonsense SNV | (Deladoëy et al., 1999; Herrmann et al., 2002; Ito et al., 1993; Shozu et al., 2003; Tiulpakov et al., 2005) |
| CYP21A2 | 49 | Deletion, duplication, SNVs, insertion, intron SNV, missense SNV | (Billerbeck et al., 2002; Hayashi et al., 2013; Kaupert et al., 2016; Kirac et al., 2014; Livadas et al., 2015; C. Wang et al., 2017; Wang et al., 2016; Welzel et al., 2010; Yoo et al., 2013) |
| DHCR7 | 90 | Missense, FS Ins, in-frame deletion, nonsense, Splice site | (Lanthaler et al., 2015; Sparks et al., 2014; Wassif et al., 1998; Waterham and Hennekam, 2012; Waye et al., 2002; Yu et al., 2000) |
| FGFR2 | 3 | Intragenic deletion, missense | (Bagheri-Fam et al., 2015; Fonseca et al., 2008; Przylepa et al., 1996; Slavotinek et al., 2009) |
| FOXL2 (POF 3) | 5 | FS Del, FS Ins, in-frame deletion, missense | (Harris et al., 2002; Yang et al., 2018) |
| HSD17B3 | 23 | Missense, Splice site, FS Del, SNV deleting a stop codon | (Castro et al., 2012; Geissler et al., 1994; Lindqvist et al., 2001; Phelan et al., 2015) |
| HSD3B2 | 11 | FS ins, FS del, nonsense, missense | (Rhéaume et al., 1992; Simard et al., 1994; Welzel et al., 2008) |
| KDM5D | 0 | - | - |
| LHCGR | 32 | FS del, in-frame deletion, in-frame insertion, missense, nonsense, Splice site | (Boot et al., 2011; Gromoll et al., 2000; Laue et al., 1995; Misrahi et al., 1997; S. M. Wu et al., 1998) |
| MAMLD1 | 4 | Nonsense | (Fukami et al., 2006) |
| POR | 14 | Splice site, missense, FS Ins, FS Dup, deletion | (Arlt et al., 2004; Flück et al., 2004; Fukami et al., 2005; Huang et al., 2005; Oh et al., 2017) |
| SRD5A2 | 41 | FS Del, missense, nonsense, Splice site, exon loss deletion, in-frame deletion | (Bertelloni et al., 2016; Cai et al., 1996; Can et al., 1998; Eggers et al., 2016; Ko et al., 2010; Thigpen et al., 1992) |
| STAR | 33 | FS Del, FS Ins, Splice site, missense, nonsense | (Abdulhadi-Atwan et al., 2007; Bose et al., 1996; Christa E. Flück et al., 2011; Huang et al., 2016; J Nakae et al., 1997; Okuyama et al., 1997; Tee et al., 1995) |
| VAMP7 | 0 | - | - |
|
Central causes of hypogonadism | |||
| ARL6 (BBS3) | 10 | Missense, nonsense, gene deletion, FS Del, Splice site | (Chiang et al., 2004; Fan et al., 2004; Lindstrand et al., 2016) |
| CHD7 | 187 | Multi-exon deletion, FS Del, FS Ins, nonsense, Splice site, rearrangement, a few missense | (Jongmans et al., 2008; H.-G. Kim et al., 2008; Moccia et al., 2018; Udaka et al., 2007) |
| FGF8 | 7 | FS Del, Missense, 5’UTR SNV | (Costa-Barbosa et al., 2013; Falardeau et al., 2008) |
| FGFR1 | 27 | Missense, nonsense, FS Del, Splice site | (Dodé et al., 2003; Pitteloud et al., 2006; Trarbach et al., 2006; Xu et al., 2007) |
| FRAS1 | 17 | FS Ins, FS Del, nonsense splice site, in-frame deletion | (Cavalcanti et al., 2007; McGregor et al., 2003; Slavotinek et al., 2006) |
| FREM2 | 6 | Missense, FS Del, FS Ins, nonsense, Splice site | (Jadeja et al., 2005; Shafeghati et al., 2008; van Haelst et al., 2008) |
| GNRH1 | 1 | FS Ins | (Bouligand et al., 2009) |
| GNRHR | 20 | Missense, nonsense, Splice site | (Caron et al., 1999; Gianetti et al., 2012; Kottler et al., 2000; Layman et al., 1998; Meysing et al., 2004) |
| GRIP1 | 2 | Splice site, FS Del | (Vogel et al., 2012) |
| HESX1 | 14 | FS Del, FS Ins, missense, splice site, nonsense | (Brickman et al., 2001; Cohen et al., 2003; Dattani et al., 1998; Sobrier et al., 2006; Tajima et al., 2003; Thomas et al., 2001) |
| HFE | 11 | Missense, nonsense, FS Del | (Beutler et al., 2002; de Villiers et al., 1999; Gochee et al., 2002; Piperno et al., 2000) |
| KAL1/ANOS1 | 25 | Multi-exon deletion, FS Dup, FS Del, missense, nonsense, splice site | (Albuisson et al., 2005; Canto et al., 2008; Massin et al., 2003; Söderlund et al., 2002; Trarbach et al., 2006) |
| KISS1R | 7 | Intragenic deletion, missense, nonsense, FS SNV | (Brioude et al., 2013; Seminara et al., 2003; Tenenbaum-Rakover et al., 2007) |
| LEP | 4 | FS Del, missense | (Gibson et al., 2004; Strobel et al., 1998; Wabitsch et al., 2015) |
| LEPR | 2 | Splice site, FS Ins | (Clément et al., 1998) |
| LHX3 | 9 | Gene deletion, intragenic deletion, FS del, nonsense, missense | (Netchine et al., 2000; Pfaeffle et al., 2007; Rajab et al., 2008) |
| PCSK1 | 5 | Splice site, missense, nonsense, in-frame deletion | (Farooqi et al., 2007; Jackson et al., 2003, 1997) |
| PROK2 | 6 | FS Ins, FS Del, missense | (Cole et al., 2008; Dodé et al., 2006; Leroy et al., 2008; Pitteloud et al., 2007) |
| PROKR2 | 12 | Missense, FS Del | (Lindsay W. Cole et al., 2008a; Dodé et al., 2006b; Dodé and Rondard, 2013; McCabe et al., 2013; Monnier et al., 2009; Reynaud et al., 2012; Ruiz-Ferrer et al., 2011; Sarfati et al., 2013, 2010) |
| PROP1 | 31 | Nonsense, missense, FS Ins, FS Del, Splice site | (Lindsay W Cole et al., 2008; Johnny Deladoëy et al., 1999; Fofanova et al., 1998; Kelberman et al., 2009; Lemos et al., 2006; Reynaud et al., 2005; Sarfati et al., 2010; W. Wu et al., 1998) |
| PTPN11 | 80 | Missense, in-frame deletion | (Sobreira et al., 2010; Tartaglia et al., 2006; Thiel et al., 2009; Yoshida et al., 2004; Zenker et al., 2004) |
| SOS1 | 27 | Missense | (Lepri et al., 2011; Li et al., n.d.; Roberts et al., 2007) |
| TAC3 | 4 | Missense, FS Del | (Gianetti et al., 2010; Topaloglu et al., 2009) |
| TACR3 | 7 | Missense, nonsense | (Francou et al., 2011; Gianetti et al., 2010; Topaloglu et al., 2009) |
| TRIM32 | 6 | Missense, FS Del | (Chiang et al., 2006; Locke et al., 2009; Van Goor et al., 2014) |
| TTC8 | 4 | In-frame deletion, Splice site, 5’UTR deletion | (Ansley et al., 2003; Stoetzel et al., 2006) |