Supplemental Table 1: References used for evidence criteria per patient

Gene Candidate Gene Evidence Categories

ABCA51 A1 (Sun, 20091), C1 (Allikments, 19962; Dassa, 20013; Petry, 20034) , C2 (Kubo, 20055)

ACTG2 B1 (Olson, 19986; Riviere, 20126; Guo, 20077; Milewicz, 20107; Nowak, 19998; Zhu, 20039; Procaccio, 200610), B3 (Qian, 199611; Sun 2009), C1 (Lehtonen, 201212), C6 (Kumar, 199713)

ACTG2 A2 (Ambry internal patient, Oct 2012), B1 (Olson, 19986; Riviere, 20126; Guo, 20077; Milewicz, 20107; Nowak, 19998; Zhu, 20039; Procaccio, 200610), B3 (Qian, 199611; Sun 2009), C1 (Lehtonen, 201212), C6 (Kumar, 199713)

ACTG2 A2 (Ambry internal patients, Oct 2012 and May 2013), B1 (Olson, 19986; Riviere, 20126; Guo, 20077; Milewicz, 20107; Nowak, 19998; Zhu, 20039; Procaccio, 200610), B3 (Qian, 199611; Sun 2009), C1 (Lehtonen, 201212), C6 (Kumar, 199713)

AIMP22 B1 (Feinstein, 201014; Park, 200815), C1 (Park, 201016; Kim, 200217), C6 (Corti, 200318)

ARHGAP11A3 B5 (Kandpal, 200619), C1 (Xu, 201320), C5 (Xu, 201320)

ARV1 A1 (Alazami, 201521), C1 (Ikeda, 201622; Fujita and Kinashita, 201223; Tinkelenberg, 200024; Kajiwara, 2008; Swain, 2002; Tong, 2010), C5 (OMIM # 300868; OMIM# 614080; OMIM# 615398)

BASP1 B1 (Caroni, 199725; Maekawa,200326; Allen,200727), B2 (Frey, 200028), C1 (Odagaki, 200929; Kropotova,201330), C5 (OMIM #614583)

BPTF B1 (Tsurausaki, 201231; Tzeng, 201432; VanHoudt, 201233), B3 (Landry, 200834), C1 (Barak, 200335; Xiao,200136), C2 (Badenhorst, 200237; Badenhorst,200538)

BRD4 B1 (Rodriguez, 201239), B2 (Houzelstein, 200240), C1 (Floyd, 201341; Dey, 200042)

CACNA1E B1 (Lacinova, 200543) B2 (Weiergraber, 200644; Zaman, 201145) B3 (Williams, 199446) C1 (Breustedt, 200347; Deitrich, 200348)

CDC42 B3 (Kang,200849; Wirth, 201350), C1 (Cotteret, 200251; Urbanska, 200852), C2 (Chen,200653), C4 (Heilstedt, 200354), C5 (Endris, 200255)

CDC42 A1 (Ambry internal patient, Oct 2013), B3 (Kang,200849; Wirth, 201350), C1 (Cotteret, 200251; Urbanska, 200852), C2 (Chen,200653), C4 (Heilstedt, 200354), C5 (Endris, 200255)

CLTC C1 (Sudhof, 200456), C2 (Miesenbock, 199857; Kasprowicz, 200858), C4 (Ballif, 201059), C5 (Chahrour, 201260)

COQ4 B1 (Doimo, 201461), C1 (Trevisson, 201162; Quinzii, 2007), C2 (MGI: 4441729), C5 (Doimo, 200761)

DAP3 C1 (Cavdar Koc, 200163; Morgan, 200164), C2 (Kim, 200765), C3 (Kissil, 199966) C5 (OMIM # 613070)

DGKZ1 B1 (Hofmann, 199967; Okada, 199968; Nilius, 200769), B2 (Rodriguez, 200170), C1 (Leach, 200771; vanBlitterswijk, 200072; Bordi, 199973; Pacheco, 199674), C5 (Leach, 200771)

DLL4 B1 (McDaniell, 200675; Stittrich, 201476; Markus, 200277), C1 (Shutter, 200078), C2 (Duarte, 200479; Yan, 201080)

DNMT3A C1 (Feng, 2005; Vire, 2006), C2 (Okano, 1999; Feng, 2010), C5 (Chedin, 2011), C6 (Jiang, 2013)

DNM1 B1 (Fassio, 201181; Greengard, 199382; Saitsu, 200883), B2 (Boumil, 201084; Ford, 201185), B3 (Ferguson, 201286; Nakata, 199187), C1 (Ferguson, 201286), C3 (Ford, 201185)

DPYSL24 B3 (Inagaki, 200088; Charrier, 200389), B5 (Chu, 201090), C1 (Hensley, 201191; Goshima, 199592; Chae, 200993; Khanna, 201294; Chi, 200995; Brittain, 200996; Bretin, 200697), C2 (Brittain, 201198)

EMILIN1 B3 (Doliana, 200199; Zacchigna, 2006100; Colombati, 2000101), C1 (Colombatti, 2000101; Colombatti, 2011102), C2 (Zanetti, 2004103; Zacchigna, 2006100; Danussi, 2008104), C5 (Jobsis, 1996105)

ETV63 B4 (Hock, 2004106; Schindler, 2009107), C1 (Ciau-Uitz, 2010108; Peker, 2013109; Stegmaier, 1995110), C4 (Raimondi, 1993111; Stegmaier, 1995110), C6 (Van Vlierberghe, 2011112)

FGR5 B3 (Inoue, 1990113), C1 (Eiseman & Bolen, 1992114; Drazen, 1996115; Lee, 2011116; Vicentini, 2002117), C2 (Vicentini, 2002117), C5 (Han, 2009118; Gourh, 2010119; Schreiner, 2002120; Banin, 1996121; Finan, 1996122; Rivero-Lezcano, 1995123)

GNB1 C1 (Smrcka, 2008124; Arshavsky, 2002125; Okae, 2010), C2 (Kitamura, 2006126; Lobanova, 2013127), C5 (Pierce,2001128; Mylvaganam, 2006129; Okae & Iwakura, 2010130; Niswender, 2010131; Ruano, 2010132), C6 (DECIPHER 250604)

H3F3A A2 (Deciphering Developmental Disorders; decipher.sanger.ac.uk), B1 (Najmabadi, 2015133; Bartholdi, 2007134), C1 (Ederveen, 2011135; Bhasin, 2006136; Maze, 2015137)

HDAC1 C1 (Hildmann, 2007138; Saha & Pahan, 2006139; Abel, 2008140), C4 (Levy, 2011141; Sanders, 2011142), C5 (Qui, 2012143), C6 (LeBlanc, 2011144; Phiel, 2001145; Williams, 2001146)

HDAC36B1 (Williams, 2010147; Ambry patient with HDAC1 de novo missense; O’Roak, 2012148; Saitsu, 2014149; Pons, 2015150; Gregoire, 2007151; Ebert, 2013152), B3

(Mahlknecht, 1999153; Broide, 2007153; Takami, 2000154; Shen, 2005155; Debacker, 2012156), C1 (Haggarty & Tsai, 2011157; Borrelli, 2008158; Li, 2000159; Wen, 2000160; Guenther, 2001161; Codina, 2005162; Watson, 2012163), C2 (Montgomery, 2008164; Norwood, 2014165)

HNRNPK B2 (Charroux, 1999166), C1(Fukuda, 2009167; Thyagarajan, 2008168), C5 (Kim, 2013169; Thierry, 2012170)

HNRNPK A2 (Ambry internal patient, Feb 2014; Au, 2015171), B2 (Charroux, 1999166), C1 (Fukuda, 2009167; Thyagarajan, 2008), C3 (Proepper, 2011172; Folci, 2014173), C5 (Kim, 2013169; Thierry, 2012170)

HNRNPR B2 (Glinka, 2010174), B3 (Glinka, 2010174; Rossoll, 2003175), C1 (Rossoll, 2002176), C5 (Dombert, 2014177)

HTR2C B1 (Maze, 2015137), B5 (Firth, 2009178), C1 (Everreen, 2011135), C2 (Couldrey, 1999179), X5 (Najmabadi, 2015133; Bartholdi, 2007134)

IL21R C1 (Spolski, 2008180; Hamming, 2012181), C2 (Ozaki, 2002182; Jin, 2009183), C5 (Leonard, 2000184; Spolski, 2008180; OMIM# 600802; OMIM# 614162; OMIM# 613796; OMIM# 209950; OMIM# 147060)

ITGA11 B3 (Lehnert, 1999185; Tiger, 2001186), C1 (Lehnert, 1999185; Velling, 1999187; Lu, 2010188), C2 (Popova, 2004189; Popova, 2007190), C5 (Lu, 2010188),

ITSN14 B3 (Guipponi, 1998191; Sengar, 1999192; Pucharcos, 2001193), B4 (Koh, 2004194; Marie, 2004195; Koh, 2007196), C1 (Pechstein, 2010197), C2 (Yu, 2008198; Sengar, 2013199), C6 (Pucharcos, 1999200; Cataldo, 2000201; van der Crabben, 2010202)

JAK15 B1 (Macchi, 1995203; Russell, 1995204; Kouro, 2009205; Hambleton, 2013206; Minegishi, 2007207), C1 (Yamaoka, 2004208), C2 (Rodig, 1998209; Sabrautzki, 2013210)

KCNA2 A2 (Pena, 2015211), B3 (Sheng, 1994212; Wang, 1994213; Lu, 2002214), C1 (Salkoff, 1992215; Yellen, 2002216; Grizel, 2014217), C2 (Brew, 2007218; Xie, 2010219), C5 (OMIM# 160120; Browne, 1994220)

LAS1L B3 (Castle, 2010221), C1 (Castle, 2010221), C5 (Castle, 2012222), C6 (Narla, 2010223; Freed, 2010224)

LPHN16 B1 (Arcos-Burgos, 2010225; Domene, 2011226; Fromer, 2014227), B3 (Kreienkamp, 2000228; Silva, 2009229; Boucard, 2014230; Meza-Aguilar, 2014231), C1 (Fredriksson, 2003232; Capogna, 2003233; Deak, 2009234; Lelyanova, 2009235; Meza-Aguilar, 2014231), C2 (Kellendonk, 2009236; Silva, 2010237)

LRFN22 B3 (Wang, 2006238; Morimura, 2006239), C1 (Nam, 2011240), C5 (Mikhail, 2011241)

LRFN5 B3 (Ko, 2006242; Morimura, 2006239; Wang, 2008243; Mah, 2010244), B5 (De Bruijn, 2010245), C1 (Morimura, 2006239; Mah, 2010244), C4 (Mikhail, 2011241)

MADD B1 (Wada 1997246; Des Portes 1997247), C1 (Schievella 1997248; Efimova 2004249; Figueiredo 2008250; Pavlos 2010251; Okada 1995252; Niwa 2008253), C2 (Tanaka 2001254; Iwasaki 1997255)

MAP1B B2 (Edelmann 1996256; Takei 1997257; Gonzalez-Billaut 2000258; Meixner 2000259), C1 (Meixner 2000259; Gonzalez-Billault 2001258; Montenegro-Venegas 2010260; Goold 2003261), C5 (Goold 2003261; Carvalho 2011262)

MAPK1 C2 (Yao 2003263; Satoh 2011264; Krenz 2008265; Tartaglia 2011266), C4 (Torres-Juan 2007267; Ryan 1997268), C5 (Bromberg-White 2012269; Roskoski 2012270)

MN1 B1 (Sutton 2005271; Braybrook 2001272; Srour 2013273; van Wely 2003274), C1 (Zhang 2009275), C2 (Meester-Smoor 2005276; Liu 2008277), C4 (Davidson 2012278)

MSMO1 A2 (He 2011133; He 2014279), C1 (Agrawal 2015280), C5 (Porter and Herman 2011281; Jira 2013282; Aldahmesh 2012283; Gillespie 2014284)

MTIF2 B1 (Tucker 2011285; Neeve 2013286; Haack 2014287), C1 (Ma 1995288; Smits 2007289; Bonnefond 2005290; Spencer 2004291), C3 (Luchin 1999292; Laalami 1994293)

MTOR B1 (Butler 2005294; Herman 2007295; Theoharides 2013296), C1 (Hay 2004297; Inoki 2005298; Andrade 1995299; Chiu 1994300; Halova 2012301; Shang 2011302; Smrz 2011303), C3 (Hoeffer & Klann 2010304; Murakami 2004305; Clipperton-Allen & Page 2014306; Theoharides, 2013296)

MYH10 B1 (Althaus 2011307), B2 (Ma 2006308; Tullio 1997309; Tullio 2001310; Takeda 2003311), C1 (Ma 2006308; Svitina 1997; Svitina 1997312; Vicente-Manzanares 2009313; Bao, 2007314; Tullio 2001310; Uren 2000315)

NFASC B1 (Mathey 2007247; Iqbal 2013316; Compton 2008317; Laquerriere 2014318; Ratcliffe 2001319), B3 (Ango 2004320; Nagase 1998321; Davis 1993322), C1 (Kriebel 2012323; Howell 2006324; Zhang 2015325), C2 (Sherman 2005326)

NMNAT2 B1 (Perrault 2012327; Magen 2015328), B2 (Hicks 2012329), C1 (Raffaelli 2002330; Zhang 2003331; Yalowitz 2004332; Milde 2013333; Conforti 2014334; Berger 2005335; Mayer 2010336)

NTF4C1 (Gao 1995337; Morison 1998338; Wiedemann 2006339; Walker 1998340), C2 (Belluardo 2001341; Conover 1995342; Harada 2005343; Endres 2000344; Kulakowski 2011345; Kong 1999346; Sakuma 2002347), C5 (Gupta 2013348; Correia 2010349; Louhivuori 2011350; Johnson 2009351; Cao 2013352; Schwartz 1997353), C6 (Pasutto

2009354; Vithana 2010355)

OGDHL B1 (Bonnefont 1992356; Guffon 1993357; and Kohlschutter 1982358), C1 (Bunik 2008359; Bunik & Degtyarev 2008360; Szabo 1994361), C6 (Dunckelmann 2000362; Gibson 2005363)

OGTB1 (Capotosti 2011364; Lazarus 2013365; Yu 2013366; Cole and Hart 1999367), B3 (Kreppel 1997368; Lubas 1997369; Cole and Hart 2001370; Akimoto 2003371), C1 (Shafi

2000372; Shin 2011373; Love 2003374; Kreppel and Hart 1999375; Clarke 2008376; Ma and Hart 2014377; Fujiki 2011378; Akimoto 2003371; Tallent 2009379), C2 (Shafi 2000372; O’Donnell 2004380; Howerton 2013381; Howerton and Bale 2014382)

PCBP1 B1 (Ambry internal patient, Feb 2014; Chakarova, 2002383; Dauber, 2013384; Gamundi, 2008385; Maubaret, 2011386; McKie, 2001387; OMIM #600124, #607300, #607301; Towns, 2010388), B5 (Ghanem, 2014389), C1 (Choi, 2009390; Ghanem, 2014389; Unigene:131305-Hs.2853), C4 (DECIPHER ID 257771178; Los, 1994391)

PIGQB5 (Alazami, 201521; Martin, 2014392); C1 (Fujita, 201223; Tiede, 1998393; Watanabe, 1998394); C3 (Tiede, 2001395); C5 (Belet, 2014396; Brady, 2014397; Johnston,

2012398; Kato, 2014399); Kvarnung, 2013400; Ohba, 2014401; OMIM #300868; OMIIM *311770; OMIM *606097; OMIM *610272; OMIM #614080; OMIM #615398; Maydan, 2011402; Nakashima, 2014403; Swoboda, 2014404)

PLD1 C1 (Chernomordik, 2005405; Gomez-Cambronero, 2010406; Peng, 2012407; Vitale, 2010408; Zeniou-Meyer, 2007409), C2 (Sethu, 2010410, C5 (Delaunoy, 2006411; OMIM #303600; Nishimoto, 2012412; Trivier, 1996413; Zeniou-Meyer, 2009414)

POU3F3

C1 (Castro, 2006415; Hara, 1992416; Kim, 2008417; Kuhlbrodt, 1998418), C2 (McEvilly, 2002419; Nakai, 2003420; Sugitani, 2002421), C4 (Dheedene, 2014422), C5 (Aarskog, 1998423; de Zegher, 1995424; Hashimoto, 2003425; Hendriks-Stegeman, 2001426; Irie, 1995427; Ohta, 1992428; Okamoto, 1994429; OMIM #613038; OMIM #615866;

Miyata, 2006430; Pelligrini-Bouiller, 1996431; Pernasetti, 1998432; Pfaffle, 1992433; Radovik, 1992434; Rogol, 1976435; Sun, 2006436; Tatsumi, 1992437; Tsurusaki, 2014438; Turton, 2005439), C6 (DECIPHER DDD Research Variant178)

PURA B1 (Jin, 2007440), B2 (Khalili, 2003441), B5 (Brown, 2013442), C1 (Gallia, 2000443; Hokkanen, 2012444; Johnson, 2003445; Mishra, 2013446)

PURA A2 (Ambry internal patient, Jan 2013; Lalani, 2014447), B1 (Jin, 2007440), B2 (Khalili, 2003441), B5 (Brown, 2013442), C1 (Gallia, 2000443; Hokkanen, 2012444; Johnson, 2003445; Mishra, 2013446)

RAD54L B1 (Mazin, 2010448), B5 (Matsuda, 1999449), C1 (Ceballos, 2011450), C2 (Essers, 1997451; Rousseau, 2012452)

RAD54L B1 (Mazin, 2010448), B5 (Ambry internal patient presenting with paraganglioma, pheochromocytoma, papillary thyroid cancer, café au lait spots, and brittle hair syndrome, Matsuda, 1999449), C1 (Ceballos, 2011450), C2 (Essers, 1997451; Rousseau, 2012452)

RORB A1 (Baglietto, 2014453; Bartnik, 2012454; Boudry-Labis, 2013455; Lal, 2015456), C1 (Evans, 1988457; Jabaudon, 2012458; Lopes da Silva, 1995459; OMIM 601972), C5 (Hu, 2009460; Nguyen, 2010461; Sarachana, 2013462)

RYR3 B3 (Hakamata, 1992463; Leeb, 1998464; Matsuo, 2009465; Nakashima, 1997466; OMIM *180903), C1 (Ooashi, 2005; Uniprot Q15413; Van Petegem, 2012467), C2 (Balschun, 1999468; Matsuo, 2009465), C5 (Ambry internal patient, Dec 2013; Fromer, 2014227; O’Roak, 2012148; Purcell, 2014469; Splawski, 2006470)

SETD5 A2 (Rauch, 2012471; Neale, 2012472), C1 (Volkel, 2007473; Visel, 2004474; Tachibana, 2005475), C4 (Gunnarsson, 2010476; Kellogg, 2013477; Riess, 2012478)

SIN3A B1 (Nan, 1998479; Kadamb, 2013480); C1 (Kadamb, 2013480; Dannenberg, 2005481; Grimes, 2000482); C4 (Samuelsson, 2015483), C5 (Firth, 2009178)

SLIT2 B3 (Radeke, 2007484; Niclou, 2000485); C1 (Brose, 1999486; Thompson, 2006487; Down, 2013488; Fish, 2011489; Grieshammer, 2004490; Kramer,2001491); C2 (Jones, 2008492; Down, 2013488)

SLC9A1 A2 (Zhu, 2015493; Guissart, 2014494); C1 (Ruffin, 2014495; Fliegel, 2005496); C2 (Cox, 1997497; Bell, 1999498); C5 (Morrow, 2008499; Kondapalli, 2013500)

SNAP25 B1 (Corradini, 2009501), B2 (Wilson, 1996502; Kataoka, 2011503; Jeans, 2007504); B5 (Firth, 2009178); C1 (Sudhof, 2011505; Sudhof, 200456; Turner, 1999506; Corradini, 2009501)

SON B1 (Zhang, 2003507; Zhao, 2010508; Sharma, 2011509; Ahn, 2011510; Poirier, 2013511; Cederquist, 2012512), B3 (McKee, 2005513; Dillman, 2013514), C1 (Wynn, 2000515; Sun, 2001516; Chumakov, 1991517; Greenhalf, 1999518; Ahn, 2011510; Huen, 2010519; Lu, 2013520), C6 (de Ligt, 2012521; Gilissen, 2014522).

SONA2 (Ambry internal patient, May 2015), B1 (Zhang, 2003507; Zhao, 2010508; Sharma, 2011509; Ahn, 2011510; Poirier, 2013511; Cederquist, 2012512), B3 (McKee,

2005513; Dillman, 2013514), C1 (Wynn, 2000515; Sun, 2001516; Chumakov, 1991517; Greenhalf, 1999518; Ahn, 2011510; Huen, 2010519; Lu, 2013520), C6 (de Ligt, 2012521; Gilissen, 2014522).

STAT2 B1 (Cayado-Gutiérrez, 2012523; Sosonkina, 2014524), C1 (Miklossy, 2013525; Yan, 1995526; Bromberg, 2000527), C2 (Park 2000528; Bromberg, 2000527) C5 (Kaplan, 1998529; Clifford, 2003530)

SV2A B2 (Janz, 1999531; Crowder, 1999532; Kaminski, 2009533), B3 (Bajjalieh, 1993534 & 1994535), B5 (Lynch, 2004536; Kinrys, 2007537; Enggaard, 2006538), C1 (Yao, 2010539; Nowack, 2010540; Chang, 2009541)

TIMM50 B1 (Richman, 2014542; Davey, 2006543; Xu, 2005544); C1 (Geissler, 2002545; Yamamoto, 2002546; Guo, 2004547; Jensen, 2002548); C3 (Mokranjac, 2003549; Guo, 2004547)

UNC45B B2 (Etard, 2007550); B5 (Hansen, 2014551); C1 (Price, 2002552; Geer, 2010553; Hansen, 2014551); C5 (Peterson, 1985554)

ZBTB18 A1 (Ballif, 2012555; Boland, 2007556; Caliebe, 2010557; Nagamani, 2012558; Thierry, 2012170), B3 (Becker, 1997559; Okado, 2009560; Xiang, 2012561), C2 (Xiang, 2012561; Yokoyama, 2009562); C5 (Johnston, 2010563; Sztriha, 2003564)

ZBTB20 A1 (Molin, 2012565; Wiśniowiecka-Kowalnik, 2013566), C1 (Xie, 2010567; Molin, 2012565); C2 (Sutherland, 2009568)

ZFHX3 B3 (Ishii 2003569; Watanabe 1996570; Qi, 2008571), C1 (Morinaga, 1991572; Miura, 1995573; Berry, 2001574; Ishii 2003569; Sun 2012575), C4 (Firth, 2009178), C5 (Aarskog, 1997423)

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