{"text_format":"3","workbook":"xls","n_sheets":1,"sheets":["DSD_Track_040315forRedCap"],"not_rendered":{"external_links":1,"defined_names":1},"read":"whole","date_system":"1900","formulas":"cached_only"}

{"sheet":"DSD_Track_040315forRedCap","index":0,"n_rows":47,"n_cols":3,"rows_kept":47,"flags":["formulas_cached_only"]}
["Supplementary Table 22. Some DSD Genes with Previously Described Small CNVs and Other Disorders in OMIM"]
["Gene (OMIM #)","Reported CNVs (from OMIM)","Associated DSD and Other Phenotype (OMIM Phenotype)"]
["AHRR (ambiguous genitalia)","polymorphisms (e.g. Pro185Ala on exon 5 ) in micropenis (Fujita 2002 Soneda 2005), poor semen quality (Watanabe 2004), and adverse effects on male reproductive functions (Brokken 2014)"]
["ANOS1/ KAL1 (300836) (cryptorchidism)","3.3 Kb deletion (Bick et al. 1992) - men with hypogonadotropic hypogonadism; exons 3-5 deletion/coding region for fibronectin type III-like repeat; exon 5 deletion (Soderlund et al. 2002); exons 3-13 deletion - men with Kallman syndrome with hypogonadotropic hypogonadism and delayed puberty, unilateral renal aplasia,  (Massin et al. 2003) ","Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) "]
["AR (313700)","familial 5-kb deletion of exon E/introns 4,5 (MacLean et al. 1993) sisters, mother, aunt, grandmother, and affected (XY) aunt - abnormal receptors, lacking steroid binding domain, unresponsive to androgens","Androgen insensitivity, 46,XY with female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, with or without breast cancer; spinal and bulbar muscular atrophy of Kennedy - gynecomastia, symmetrical muscle weakness and atrophy; PAIS - hypospadias, hypogonadism, gynecomastia, genital ambiguity, azoospermia or severe oligospermia; Hypospadias 1, X-linked"]
["ARX","1.5 Kb deletion of intron 4-exon 5resulting in an alternative carboxy-terminal (Stromme et al. 2002) - 2 males with epileptic encephalopathy; exons 1-2 (Kitamura et al. 2002)","Lissencephaly, X-linked 2, ambiguous or underdeveloped genitalia; mental retardation and seizures, limb contractures, scoliosis, tapered fingers with hyperconvex nails, a characteristic facies; urologic anomalies include renal dysplasia, cryptorchidism, and hypospadias"]
["AXIN1 (603816)","CNVs, indels, SVs  in hepatocellular carcinoma (Taniguchi 2002); medulloblastomas (Dahmen 2001); exons 5-10 in alpha-thalassemia (Joly 2010)"]
["BNC2","point mutations in distal hypospadias (Bhoj 2011)"]
["CFTR (602421)","OMIM Rowntree 2001 intron 1 DHS is tissue-specific and is required for normal CFTR expression levels in the intestinal epithelium in vivo; Dork et al. (2000) deletion frequently observed in Central and Eastern Europe CF. The mutation deletes 21.1 Kb (intron 1 to intron 3), loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. ","Congenital bilateral absence of vas deferens"]
["CHD7","2.3-Mb de novo deletion in CHARGE individuals (some with microphallus) (OMIM; Vissers et al. 2004) ","Hypogonadotropic hypogonadism 5 with or without anosmia (HH5) "]
["CTNNA3 (607667) ","60 Kb exon 11 in ASD; exons 6-13 of varying lengths (Bacchelli 2014)"]
["CTNNB1 ","mice exon 3 deletion (OMIM; Harada et al. 1999) - serine/threonine dysphosphorylation resulting in adenomatous intestinal polyps; deletion (Lickert et al. 2002) resulted in formation of multiple and ectopic hearts"]
["DMD (300377) ","deletion of one or more exons (Xp21.2) in patients with syndromic DMD phenotype - glycerol kinase deficiency, congenital adrenal hypoplasia, and severe mental retardation (Furst et al. 1987; Pernelle et al. 1988; McCabe et al. 1989; Rininsland et al. 1992);  intron 44 is one of the hotspots in DMD deletions, common deletions in exons 2-22 and 45-54, while duplications are common in exons 3-11, 21-37, 45-55 (Yang 2013, Greer 2014 White 2006)"]
["EP300 (602700) "," exons 1-8 deletion in renal and genitourinary congenital anomalies, Rubinstein-Taybi syndrome 2, somatic colorectal cancer (OMIM; Foley et al. 2009; Roelfsema et al. 2005; Solomon 2015)"]
["ESR1","deletions of exons 2, 4, 5, and 7 (OMIM;  Shupnik et al. 1998); exons 3, 5, or 7 (McGuire et al. 1991); duplication of exon 6 in human breast cancer (Murphy et al. 1996) ","Estrogen resistance - absence of the pubertal growth spurt, delayed bone maturation, very tall adult stature, glucose intolerance, hyperinsulinemia"]
["ESR2 (601663)","exon 5 deletion (290 bp) (OMIM; Vladusic in Speirs 2000); CA repeat polymorphisms influence serum levels of testosterone ie individuals with longer repeats display decreased androgen levels, increased risks for hypospadias (Beleza 2007, Ban 2008); SNPs rs4986938 and rs928554 are in 3' UTR and could affect mRNA stability and/or translatability (exons 8-9) (Haldosen 2014); polymorphisms (e.g. intron 6) in hypospadias, decreased androgen levels (Westberg 2001; Beleza 2007; Zanden 2010; Choudhry 2015)","hypospadias (Choudhry 2015)"]
["FGFR2 (hypospadias)","deletion in mice testis; essential role in testis determination (OMIM; Kim et al. 2007) ","Lacrimo-auriculo-dento-digital syndrome (LADDS) - malformations of the kidney and respiratory system, abnormal genitalia, aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb segments anomalies, facial dysmorphism); Beare-Stevenson cutis gyrata syndrome - anogenital anomalies, craniofacial anomalies"]
["FRAS1 (607830) ","64 Kb deletion in Fraser syndrome (Hoefele 2013)","Fraser syndrome; unilateral renal agenesis"]
["GRIP1 (604597)","deletion of exons 2-11; 3.22−5.38 Kb (Takamiya 2004) in animal model of Fraser syndrome","Fraser syndrome"]
["INSR (147670)","1.2 Kb deletion of exon 14) (OMIM; Shimada 1990; Ardon 2014); Donohue syndrome (OMIM; Wertheimer 1993) ","Rabson-Mendenhall syndrome (phallic enlargement) (OMIM)"]
["KANK1  ","225-kb deletion in individuals with cerebral palsy CPSQ2 (OMIM; Lerer et al. 2005) "]
["KRAS (190070) (cryptorchidism)","mutations in exons 3 or 4 Cardiofaciocutaneous syndrome 2, Noonan syndrome 3, Schimmelpenning-Feuerstein-Mims syndrome, and several cancers (OMIM; Schubbert 2006)","Noonan syndrome 3 - cryptorchidism; short stature, facial dysmorphic features, congenital heart defects, short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, and bleeding diathesis"]
["MAMLD1 (300120)","240-kb deletion in myotubular myopathy with normal genital development; included CXORF6, MTM1, MTMR1; chimeric intron 4 of CXORF6-intron 2; exon 3 of CXORF6 encodes over 80% of the protein - is essential for the development of male genitalia (Tsai et al. 2005)","Hypospadias 2, X-linked"]
["MID1 (300552)","duplication of exon 1 in Opitz syndrome - anal atresia, a rectourethral fistula, bifid scrotum, CHD, tracheoesophageal cleft, facial abnormalities (Winter et al. 2003) ","Opitz GBBB syndrome, type I - genital-urinary defects such as hypospadias in males and splayed labia in females; hypertelorism, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay and congenital heart defects"]
["MOV10L1 (605794) ","deletions of exons 18-21 in mice lack helicase domain resulting meiotic arrest before pachytene and testes size decline (Zheng 2010); loss of DNA methylation at Line1 and Iap retrotransposons and depressed Line1 and Iap expression; global deletion silencing retrotransposons (Frost 2010)"]
["NLGN4X (300427)","maternal 757 Kb hemizygous deletion of exons 4, 5, 6 of NLGN4X in Tourette syndrome, ADHD (Lawson-Yuen et al. 2008) "]
["NOTCH1 ","85 Kb deletion 5' region in AOS5 (OMIM; Stittrich 2014); deletion of the promoter region in T-ALL (Jeannet 2010)"]
["NOTCH2","last coding exonmay escape nonsense-mediated decay and truncated proteins act in a gain-of-function manner","Hajdu-Cheney syndrome - genital anomalies and polycystic kidney disease; facial anomalies, skeletal defects, periodontal disease, cleft palate, congenital heart defects "]
["NOTCH3 (600276)","truncating mutations in exon 33 in lateral meningocele syndrome (Gripp 2015) ; small  (bp) deletionand duplication have been reported by sequencing in CADASIL patients (Lee 2011; Weiming 2012) "]
["NR0B1 (300473)","duplication of part of the short arm of the X chromosome and an intact SRY gene show male-to-female sex reversal (OMIM; Swain et al., 1998); 2.2-kb deletion of exon 2 and a 27-bp insertion in a patient with adrenal failure, hypogonadotropic hypogonadism (Salvi et al. 2002), some XY with deletion develop as males","46XY DSD, adrenal hypoplasia, congenital, with hypogonadotropic hypogonadism/X-linked adrenal hypoplasia congenital (XL-AHC) - absence of the permanent zone of the adrenal cortex and by a structural disorganization of the glands, hypogonadotropic hypogonadism (HHG) - decreased gonadal function, with retardation of growth and sexual development"]
["NR5A2 (LRH1)","deletion in mice is embryonic lethal, results in dysmaturation of ovarian follicles and for ovulation (OMIM; Dugghavati 2008)"]
["OCA2 (611409) ","deletion of last exon/poly(A) tail in a patient with OCA2 and Prader-Willi syndrome (OMIM; Rinchik et al. 1993); 2.7-kb exon deletion of P gene (Durham-Pierre et al. 1994; Manga 1997; Aquaron et al. 2007);  LINE-mediated 122.5-kb deletion of exons 10-20, and 184 Kb deletion of exons 3-20 in OCA2 (Yi et al. 2003; Rooryck et al. 2011) "]
["PBX1 (176310) ","mutations result in undifferentiated mesonephros and kidney, and absence of Mullerian structures as seen in MRKH22 (Burel 2006); polymorphisms in MRKH (Ma 2015)"]
["PCSK1 (162150)","Proprotein convertase 1 deficiency (PC1 deficiency) - hypogonadism and obesity, hypoadrenalism due to impaired processing of prohormones"]
["PDGFRA ","interstitial deletion resulting in PDGFRA-FIP1L1 fusion in idiopathic hypereosinophilic syndrome (OMIM; Cools et al. 2003); deletion in mice Pdgfra linked to Kit oncogene resulting in 'Patched' (Ptch) mutation/spotted phenotype (OMIM; Stephenson et al., 1991; Smith et al., 1991); sequence mutations in exons 12, 14 and 18 in gonablastoma/DSD cases (Hersmus 2012) ","mediates testis cord organization and fetal Leydig cell development in the mice XY gonad (Brennan 2003) "]
["PIP5K1B ","duplicated last four exons in DSD (Norling 2013)"]
["PTCH1  (aka PTC)","maternal 360-kb duplication in microcephaly, mild developmental delay, and mild dysmorphic features (OMIM; Derwinska et al. 2009) "]
["PTPN11 (176876) (cryptorchidism)","15 Kb deletion of exon 7 in metachondromatosis (OMIM; Brown 2011); deletion of exon 4 (Shp2 domain) in cardiomyopathy (OMIM; Princen 2009); larger duplications in NS with urogenital anomalies (Lissewski 2015; Shchelochkov; 2008 Doco 2006) and RASopathies (Chen 2014, Graham 2009)","LEOPARD syndrome 1 - genital anomalies (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, retardation of growth, and sensorineural deafness); Noonan syndrome 1 - cryptorchidism, short stature, facial dysmorphic features, congenital heart defects and hypertrophic cardiomyopathy, short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, bleeding diathesis"]
["RAF1 (164760) (cryptorchidism)","duplication fusion of exons 1-12 of SRGAP3-exons 10-17 of RAF1 in pilocytic astrocytoma (OMIM; Jones et al. 2009) ","Noonan syndrome 5 - cryptorchidims, short stature, facial dysmorphic features, congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, and bleeding diathesis, risk of juvenile myelomonocytic leukemia; LEOPARD syndrome 2 - genital anomalies, lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, retardation of growth, and sensorineural deafness"]
["SHOX (400020)","45,X/46,X,dup(X) in female with primary amenorrhea, tall stature, complete gonadal dysgenesis (Ogata et al. 2000); homozygous deletion of exon 6b extending 1.1 Mb downstream (enhancers) in Langer mesomelic dysplasia (Bertorelli et al. 2007) "]
["SNRPN (182279) (or PWCR) (hypospadias)","paternal 4.8-kb deletion caused partial or mosaic imprinting defect and perinatal lethality (Bressler et al. 2001); 900 bp deletion of exon 1 of mouse Snrpn did not disrupt imprinting or result in aberrant phenotype but allowed detection of previously unknown upstream exons; in mice, maternal duplication causes an imprinting effect that may correspond to PWS and paternal duplication, Angelman syndrome (Cattanach et al. 1992)"]
["SOX3 (313430)","123 kb and 85 kb duplications (Sutton 2011; UniProt); 343 kb deletion upstream is probably responsible of altered regulation (and not increased dosage); ~6 Mb duplication with proximal breakpoint  within SOX3 regulatory region was found in a patient with XX male reversal, scrotal hypoplasia, microcephaly, developmental delay, and growth retardation; 685.6 kb duplication in 2 male maternal half sibs with X-linked panhypopituitarism (Woods et al. 2005) ","46,XX sex reversal 3 (SRXX3) - male gonads develop in a genetic female (female to male sex reversal); Mental retardation, X-linked, with isolated growth hormone deficiency - delayed pubertal development, panhypopituitarism,short stature"]
["SRD5A2","deletion of SRD5A2 in pseudovaginal perineoscrotal hypospadias (Andersson et al. 1991) ","Pseudovaginal perineoscrotal hypospadias (OMIM) 46,XY DSD males show ambiguous genitalia at birth, severely hypospadiac penis"]
["SUPT3H","217-kb duplication of exons 5-12 in 46,XY gonadal dysgenesis (Norling et al. 2013)"]
["TAF7L (300314) (aka TAF2Q) ","OMIM Winter et al. (2003) identified a duplication of the first exon of the MID1 gene. The diagnosis of Opitz syndrome was made soon after birth on the basis of a combination of characteristic symptoms. Anal atresia, a rectourethral fistula, and a bifid scrotum were found. In addition, he had a complex heart defect (coarctation of the aorta, patent ductus arteriosus and atrial septal defect secundum type, and abnormal venous return) and a tracheoesophageal cleft. Facial abnormalities comprised hypertelorism, mild downslanting of palpebral fissures, and posteriorly rotated ears. The mother was heterozygous for the duplication and showed mild hypertelorism, a tracheoesophageal cleft, and esophageal stenosis, which was surgically corrected","Opitz GBBB syndrome, type I"]
["TP63 (603273)","terminal deletion (3q27-qter) in genital anomalies (Chitayat 2006) and in Limb-Mammary syndrome (OMIM); exons 5-10 duplications (Kouwenhoven 2015) (Mikkola 2010); in pyschomotor and growth delay, tricuspid valve dysplasia, bifid thumb (Pollazon 2009); exon deletions in mice (Vanbokhoven 2011); 2-bp deletion on exon 13 SAM domain resulting in frameshift mutation and PTC in severe dysgenesis of internal genitalia (no uterus or ovaries), absence of mammary gland and nipple tissue, isolated CP, primary amenorrhea with advanced adrenarche, hypergonadotrpic hypogonadism, low plasma estrogen (Guazzaroti 2008)","urogenital abnormalities including micropenis, hypospadias, vaginal septum, external female genitalia hypoplasia (Guazzarotti 2008)"]
["WWOX","exons 6-8 deletion in 46,XY DSD (White 2012); critical homozygous deletions (Ried 2000); frequent hetero/homozygous deletions or alternative splicing of exons 5-8 in cancer (Aldaz 2014; Richards 2015); or exons 4-9 (Abdeen 2011 in Masson 2014); familial (with EIEE28) compound heterozygous 131-Kb deletion of exons 1-5 and 82-kb deletion of exons 6-8 (Mignot et al. 2015) resulting in an in-frame deletion and complete absence of the normal WWOX protein; Loss of Wwox expression by deletions, ROH, translocations, epigenetic silencing by hypermethylation of promoter (Iliopoulos 2005 in Aarhus 2008) "]