Supplementary Table 1 Patients with developmental delay as the referral reason for diagnostic cytogenetics: 217 cases with CNVs from 752 referrals____________________________________________________________________________________________________________Case Age Sex CNV(s) CNV size(s) Genes involved† Overlapping Family (years) Start End (bp) [Oligos*] FISH probe(s) HGNC OMIM phenotypes‡ study§

____________________________________________________________________________________________________________Established pathogenic microdeletion/microduplication/aneuploidy syndromes (28 cases)1 2 M dup(X)(p22.33-q28) 47,XXY║ Klinefelter DD DN2 8 M dup(X)(p22.33-q28) 47,XXY║ Klinefelter DD DN3 10 F dup(X)(p22.33-q28) 47,XXX║ Triple X DD DN4 1 M dup(X)(p22.33-q28) 47,XXY║ Klinefelter DD DN5 9 M dup(X)(p22.33-q28) 47,XXY║ Klinefelter DD a,b,c DN6 1 F dup(X)(p22.33-q28) 47,XXX║ Triple X DD DN

del(8)(q24.3) 2.19 Mb Likely pathogenic DN142,377,506-144,756,649 [31] BAC RP11-120B22

7 2 F del(2)(q37.3) 2.24 Mb MIM 600430 DD DN239,396,186-241,889,404 [95] BAC RP11-766M07/RP11-603E16dup(2)(q37.2-q37.3) 1.8 Mb Likely pathogenic DN236,798,288-238,736,733 BAC RP11-205L13

8 8 M del(4)(p16.3) 1.18 Mb Wolf Hirschhorn DD DN554,564-1,845,084 [43] BAC RP11-241P10

9 4 F del(7)(q11.23) 1.36 Mb Williams DD DN72,404,279-73,771,239 [70] Vysis Williamsdel(8)(q21.13) 176 kb Likely benign Fam(M)83,435,539-83,612,457 [4] BAC RP11-181O19

10 1 F del(7)(q11.23) 1.37 Mb Williams DD DN72,404,279-73,771,239 [70] Vysis Williams

11 7 M del(7)(q11.23) 1.54 Mb Williams DD DN72,283,799-73,832,309 [76]dup(X)(p22.3) 1.28 Mb Benign; Furrow et al.1 ?

6,638,294-7,920,089 [66]12 3 F del(7)(q11.23) 1.54 Mb Williams DD ?

72,283,799-73,832,309 [76]13 9 M del(7)(q11.23) 1.48 Mb Williams DD ?

72,284,913-73,831,310 [71]14 2 F del(10)(p13-p14) 2.2 Mb MIM 601362 DD ?

10,278,416-12,460,002 [34] BAC RP11-48A1315 5 M del(15)(q11.2-q13.1) 7.86 Mb Angelman DD DN

18,946,233-26,829,529 [646] BAC RP11-790O16 (on M allele)16 4 F dup(15)(q11.2-q13.1) 5.6 Mb MIM 608636 DD DN

20,637,722-26,232,968 [571] BAC RP11-790O16 (on M allele)17 1 F del(17)(p13.3) 3.6 Mb Miller Dieker DD DN

29,196-3,393,883 [179] Mosaic║

18 4 M del(17)(q11.2) 1.2 Mb Type II NF1 DDd,e ?26,108,488-27,351,042 [93]

19 24 F del(17)(q21.31) 432 kb MIM 610443 DDf DN41,011,560-41,563,784 [61] BAC RP11-656O14

20 5 M del(22)(q11.21) 2.56 Mb Di George DDf,g ?17,274,864-19,835,388 [114] Vysis TUPLEI/22q11.2

21 2 M del(22)(q11.21) 2.56 Mb Di George DDf ?17,274,865-19, 835,388 [147]MLPA P064B MRI

22 3 M dup(22)(q11.21) 2.49 Mb MIM 608363 DD Fam (M)17,274,854-19,770,485 [146] Vysis TUPLEI/22q11.2

23 1 M dup(22)(q11.21) 2.45 Mb MIM 608363 DD Fam (M)17,227,965-19,770,485 [147] Vysis TUPLEI/22q11.2

24 2 F del(22)(q11.21) 2.67 Mb Di George DD ?17,198,399-19,870,318 [150]

25 1 M del(22)(q11.21-q11.22) 1.3 Mb MIM 611867 DDh DN19,870,318-21,342,043 [19] BAC RP11-47L18

26 3 M dup(22)(q11.21) 1.9 Mb MIM 608363 DD ?16,899,586-18,989,576 [117]

27 2 M del(22)(q11.21) 2.6 Mb Di George DDi,j ?17,198,399-19,870,318 [148]

28 2 F del(22)(q11.21) 2.6 Mb Di George DD ?17,227,965-19,870,318 [147]del(13)(q21.31) 467 kb Benign?63,280,418-63,892,109 [9]

Predicted pathogenic CNVs (42 cases)29 6 M dup(X)(p22.33) 3.9 Mb 22 25 DDi,k DN

pter-4,010,612 [673] BAC arraydel(1)(q44) 4.58 Mb 76 7 DN 242,518,639-qter [99] BAC array

30 2 M dup(X)(p22.33) 1.54 Mb 11 13 DD1,659,100-3,196,290 [177] BAC RP11-457M07del(X)(q12) 205 kb OPHN1 ?67,318,451-67,523,112 [36] BAC RP11-126L06dup(20)(p12.3-p13) 722 kb 7 4 ?4,877,458-5,599,153 [11] BAC RP11-480P15

31 4 F del(X)(p21.2) 37.8 kb IL1RAPL1 DDf Fam(P), S29,883,423-29,845,598 [5] Array repeated

32 3 M dup(X)(p11.23) 61.3 kb FTSJ1 DD Fam(M)48,089,074-48,263,671 [92] Confirmed in mother (array)del(15)(q11.2) 519 kb Cooper et al.2 DD Fam(M)20,203,447-20,811,125 [83] Confirmed in mother (array)

33 12 F dup(X)(p11.22-11.23) 4.41 Mb FTSJ1, PQBP1 DD DN48,219,769-52,629,721 [189] BAC RP11-753E19 108 69

34 4 M dup(X)(p11.22) 211 kb SHROOM4 DD Fam(M)50,413,746-50,625,037 [33] BAC RP11-753E19

35 4 M dup(X)(p11.22) 477 kb IQSEC2 DD Fam(M)52,854,902-53,332,238 [36] PAC 2165E13 8 4

36 8 M del(X)(q26.3) 6.3 kb ARHGEF6 DD ?135,575,771-135.582,134 [3] Array repeated

37 5 M dup(X)(q26.3) 77 kb SLC9A6 DD ?134,737,774-134,908,684 [6] Array repeated

38 2 M dup(1)(p36.11-p36.12) 4.81 Mb 76 51 DD ?21,672,748-26,486,906 [72] BAC RP11-57F20

39 2 M dup(1)(q21.1) 380 kb 16 7 DD ?144,130,209-144,510,930 [42] BAC RP11-293J20del(17)(q12) 1.4 Mb 14 9 ?31,930,198-33,323,002 [45] BAC RP11-483B12

40 1 F dup(1)(q21.2-q21.3) 929 kb 33 24 DDf ?148,758,360-149,687,369 [16] RP11-115I07

41 5 F del(1)(q42.3-q43) 6.2 Mb 27 18 DDl DN232,960,130-239,360,177 [113] BAC RP11-470L20

42 7 F del(2)(p15) 111 kb XPO1 DDd DN61,500,050-61,702,320 [6] BAC RP11-564K18

43 3 F del(2)(p11.2) 3.63 Mb 42 26 DDf ?85,196,711-88,831,533 [89] BAC RP11-490F05

44 6 M del(2)(q22.2-q23.1) 4.9 Mb 7 6 DD DN, T143,504,447-148,408,498 [92] BAC RP11-107E05║

del(10)(p15.1) 212 kb 3 2 DN, T5,080,344-5,292,365 [4] BAC RP11-603H04║

45 7 F dup(2)(q13) 1.28 Mb 8 3 DD Fam(M),S109,879,012-111,158,631 [45] BAC RP11-528G9del(11)(p14.3) 328 kb 1 1 DD Fam(P)24,388,087-24,716,206 [7] BAC RP11-267C11

46 1 F del(2)(q23.3-q24.2) 9.87 Mb 35 25 DD ?153,235,451-163,221,342 [204] Magri et al.3

47 7 M dup(2)(q32.2) 1.7 Mb 15 10 DDm,n Fam(P)189,294,168-191,073,955 [26] RP11-622E16

48 4 F del(3)(q22.1-q22.3) 5.2 Mb 28 15 DDf DN133,617,951-138,806,582 [77] BAC RP11-248P16

49 37 M del(3)(q26.2-q26.31) 2.9 Mb 23 13 DD DN

170,887,025-173,885,117 [40] BAC RP11-158I1850 1 M dup(4)(p13-p14) 3.3 Mb 26 15 DDo DN

38,570,940-41,869,790 [46] BAC RP11-38M1651 25 M del(5)(q23.1) 1.6 Mb PRR16 DDf Fam(M), S

118,949,528-120,675,225 [19] BAC RP11-122N1552 7 M del(6)(p25.3) 445 kb GMDSA DD Fam(P)

1,636,806-2,253,487 [8] BAC RP11-707D0153 14 F dup(6)(q27) 395 kb 5 5 DD DN

170,316,535-qter [39] PAC CTD-2024J17del(12)(p13.33) 896 kb 7 4 DD Fam (M)1,966,408-2,940,582 [145] RP11-391L19

54 27 M del(6)(p25.3) 756 kb 4 2 DD DN108,113-864,205 [46] Mosaic ring 6║

del(6)(q27) 155 kb 3 3 DN170,607,994-170,762,985 [36] Mosaic Ring 6║

55 5 F dup(7)(q36.3) 582 kb SHH DD DN154,886,656-155,589,580 [54] BAC RP11-252I21

56 8 F del(9)(p24.3) 875 kb 7 5 DDp DNpter-1,167,173[93] PAC 43N6 Ravnan et al.4

57 3 F del(12)(q24.21) 1.6 kb TBX3 DDq ?113,602,476-113,604,094 [4] Array repeated Bamshad et al.5

58 11 F del(14)(q31.1-q32.2) 16.78 Mb 84 57 DD ?80,688,418-97,474,757 [268] Confirmed║

59 1 M dup(14)(q32.32-q32.33) 3.7 Mb 137 31 DDr T102,601,484-106,358,520 [97] PAC CTC-820M16del(17)(p13.3) 263 kb 3 11,715-264,580 [39] PAC CTD-2326F01/PAC CTD-2573J08

60 10 F dup(17)(p13.3) 177 kb YWHAE DD ?1,308,211-1,131,255 [25] BAC RP11-294J05 Bruno et al.6

61 7 M del(17)(q12) 1.4 Mb 14 9 DD ?31,635,490-33,708,908 [45] BAC RP11-383B12 Nagamani et al.7

62 4 M dup(18)(q12.1-q12.3) 10.6 Mb 39 21 DD Fam(M)26,261,005-36,919,697 [153] Confirmed║

63 10 M del(18)(q22.1) 347 kb DSEL DDs Fam(P), S63,243,475-63,590,823 [5] BAC RP11-26L13

64 5 M dup(19)(p13.3) 52 kb PPAP2C DD Fam, S, ITpter-265,486 [13] ST-MLPA

65 1 F dup(20)(p12.2-p13) 11.3 Mb 121 62 DD Fam(M), T8,770-11,322,239 [221] BAC RP11-238D15dup(10)(q25.1) 695 kb 0 0 Fam(M)110,167,433-110,863,117 [9] Confirmed in mother (array)

66 12 M del(20)(q13.33) 0.9 Mb 44 20 DD Fam(M)61,478,030-62,379,088 [45] BAC RP11-1021O15

67 8 F dup(22)(q11.21-q11.22) 1.1 Mb 58 8 DD Fam(P)20,138,980-21,235,039 [18] BAC RP11-47L18 Ou et al.8

68 17 F dup(22)(q11.21-q11.22) 1.1 Mb 58 8 DD ?19,891,492-21,342,042 [18] Ou et al.8

69 4 F dup(22)(q11.21-q11.23) 1.8 Mb 110 15 DDr ?20,138,980-21,984,193 [54] RP11-47L18

70 1 M del(22)(q13.2) 648 kb 19 12 DDt DN40,247,542-41,041,009 [15] BAC RP11-420C16

Established pathogenic disease susceptibility CNVs (27 cases)71 4 M del(1)(q21.1) 484 kb Cooper et al.2 DDf,u Fam(M)

144,126,574-144,610,725 [44] BAC RP11-293J2072 5 F del(1)(q21.1) 1.42 Mb Cooper et al.2 DDf ?

144,610,726-146,290,802 [65] BAC RP11-772D10del(2)(p16.3) 248 kb Winniowiecka-Kowalnik et al.9 ?50,763,299-51,011,775 [31] BAC RP11-463P12 NRXN1dup(16)(p11.2) 1.87 Mb MIM 611913 ?28,362,920-30,240,053 [26] PAC CTD-2215A12

73 1 M del(1)(q21.1) 484 kb Cooper et al.2 DDd Fam(M)143,324,038-144,680,159 [44] RP11-293J20

74 2 F dup(1)(q21.1) 1.3 Mb Cooper et al.2 DDg,v Fam(M)144,867,339-146,812,122 [64] BAC RP11-772D10del(15)(q11.2) 433 kb Cooper et al.2 ?19,047,782-20,637,722 [81] Not confirmed

75 2 M del(2)(p16.3) 181 kb Winniowiecka-Kowalnik et al.9 Fam(P)50,882,643-51,079,704 [22] BAC RP11-391D19 NRX1 DD

76 6 F dup(4)(q13.1) 2.9-3.1 Mb 1 0 DD Fam(M)62,377,421-65,477,422 [44] BAC RP11-359H08del(15)(q13.2-q13.3) 2,12-2.27 Mb MIM 612001 DD Fam(M)28,153,38630,423,221 [62] BAC RP11-463D21

77 5 M del(4)(q31.1-q31.21) 3.0 Mb 16 12 DD DN140,386,294-143,571,949 [39] BAC RP11-495M18del(15)(q11.2) 448 kb Cooper et al.2 DD ?20,203,448-20,768,926 [80]

78 3 M del(15)(q11.2) 531 kb Cooper et al.2 DD Fam(P)20,280,758-20,811,926 [81] MLPA ME028

79 6 F del(15)(q11.2) 609 kb Cooper et al.2 DD ?19,047,782-20,851,703 [83]

80 6 M del(15)(q11.2) 380.5 kb Cooper et al.2 DD ?20,280,757-20,768,925 [78]

81 11 M del(15)(q11.2) 609 kb Cooper et al.2 DD ?20,203,348-20,851,703 [83]

82 1 F del(15)(q11.2) 531 kb Cooper et al.2 DD ?20,249,915-20,851,703 [81]

83 4 F del(15)(q13.1-q13.3) 3.3 Mb MIM 612001 DDw ?27,040,639-30,297,189 [83]dup(2)(p25.3) 337 kb 2 1 ?1,615,327-1,952,152 [5]

84 9 F del(15)(q13.2-q13.3) 2.1 Mb MIM 612001 DDf DN28,207,146-30,297,189 [61] BAC RP11-463D21

85 2 F del(15)(q13.2-q13.3) 2.4 Mb MIM 612001 DD ?

28,177,335-30,686,820 [63]86 8 M del(16)(p13.11) 1.0 Mb Cooper et al.2 DDx Fam(M)

14,817,778-16,035,348 [14] BAC RP11-139D0787 3 F (16)(p12.3-p13.11) 3.4 Mb Mefford et al.10 DDy DN

15,187,528-18,808,840 [42] BAC RP-816P0388 1 M (16)(p12.3) 1.24 Mb Mefford et al.10 DD DN

16,768,981-18,214,331 [19] BAC RP-816P03(16)(p13.11) 592 kb Mefford et al.10 DN15,187,527-15,949,069 [8] BAC RP11-139D07

89 1 M (16)(p12.1-p12.22) 940 kb Girirajan et al.11 DD ?21,375,203-22,315,403 [16] BAC RP11-101E07

90 4 M del(16)(p11.2) 517 kb MIM 611913 DD ?29,581,485-30,098,040 [8]

91 5 M del(16)(p11.2) 598 kb MIM 611913 DDr,z,aa,bb DN29,385,582-30,240,052 [9] PAC CTD-2215A12

92 1 F del(16)(p11.2) 597 kb MIM 611913 DD Fam(P)29,385,582-30,240,053 [9] PAC CTD-2215A12dup(X)(p22.31) 1.59 Mb 7 5 Fam(M)6,423,935-8,144,243 [95] Vysis STS

93 12 F del(16)(p11.2) 598 kb MIM 611913 DD ?29,385,582-30,240,053 [9]dup(2)(p21) 25 kb 2 2 ?44,371,841-44,401,513 [13]

94 3 M del(16)(p11.2) 659 kb MIM 611913 DD ?29,500,313-30,279,475 [9]

95 5 M dup(16)(p11.2) 341 kb Shinawi et al12 DD Fam(M)29,756,699-30,098,040 [7] PAC CTD-2215A12del(15)(q15.3) 96.7 kb Zang et al.13 ?41,638,870-41,735,609 [20] BAC RP11-263I19 (See incidental findings)

96 6 F dup(16)(p11.2) 812 kb Shinawi et al.12 DDf ?29,238,828-30,240,053 [11]

97 7 M dup(17)(q12) 1.4 Mb Cooper et al.2 DDcc ?31,635,490-33,708,909 [45]

98 5 F dup(22)(q11.22-q11.23) 1.9 Mb Shimojima et al.14 DDdd ?21,235,038-23,395,546 [62] BAC RP11-594L10

99 - 183 CNVs of unknown clinical significance (84 cases) – See Supplementary Table 6184 - 217 Incidental findings of pathogenic CNVs (32 cases) – See Supplementary Table 7* Number of consecutive oligonucleotides displaced.† Primary gene candidate stated where known, otherwise total number of genes within the lesion(s) is stated, or the syndrome, or the reference. HGNC refers to genes recognized by the Hugo Gene Nomenclature Committee and OMIM refers to genes recognized by Online Mendelian Inheritance in Man. Relevant references are given.‡ DD, developmental delay: with comorbidities acongenital myopathy, bcongenital adrenal hypoplasia, ccerebellar hypoplasia, dhypertelorism, eNF1, fdysmorphic, gclub feet, hcoloboma, ibifid uvula, jsubmucous cleft, kduodenal atresia, lcleft palate, magenesis of corpus callosum, nlong limbs, omicrocephaly, pcaudal appendage, qpolydactyly, rmacrocephaly, smicrognathia, tplagiocephaly, uunusual thumbs, vtracheomalacia, wnephrotic syndrome, xhemihypertrophy, ywaddling gait, zsensorineural hearing loss, aapalmar crease, bbepicanthic folds, ccheterotopic nodules in left lateral ventricle,ddgut malrotation.§Fam, familial; Fam(M), known maternal origin; Fam(P), known paternal origin; FamX, familial on the X chromosome; del, deletion;dup, duplication; DN, de novo; M origin, mutation of maternal origin; IT, insertional translocation; ?, one or both parents not available for testing or has not responded to request for parental testing; S, a CNV that segregates with the disorder in the family; T, association with a translocation; ST-MLPA, subtelomere multiplex ligation-dependent probe amplification.║Aneuploidy, translocation, ring chromosome, large deletion or mosaicism confirmed by light microscopy of metaphase cells.

References1. Furrow A, Theisen A, Velsher L et al. Duplication of the STS region in males is a benign copy-number variant. Am J Med Genet

Part A 2011; 155A: 1972-5.2. Cooper GM, Coe BP, Girirajan S et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011; 9: 838-

46.3. Magri C, Piovani G, Pilotta A, Michele T, Buzi F, Barlati S. De novo deletion of chromosome 2q24.2 region in a mentally

retarded boy with muscular hypotonia. Eur J Med Genet 2011; 54: 361-4.4. Ravnan JB, Tepperberg JH, Papenhausen P et al. Subtelomere FISH analysis of 11688 cases: an evaluation of the frequency and

pattern of subtelomere arrangements in individuals with developmental disabilities. J Med Genet 2006; 43: 478-89.

5. Bamshad M, Le T, Watkins WS et al. The spectrum of mutations in TBX3: Genotype/Phenotype relationship in Ulnar-Mammary syndrome. Am J Hum Genet 1999; 64: 1550-62.

6. Bruno DL, Anderlid BM, Lindstrand A et al. Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes. J Med Genet 2010; 47: 299-311.

7. Nagamani SC, Erez A, Shen J et al. Clinical spectrum associated with recurrent genomic rearrangements in chromosome 17q12. Eur J Hum Genet 2010; 18: 278-84.

8. Ou Z, Berg JS, Yonath H et al. Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes. Genet Med 2008; 10: 267-77.

9. Wisniowiecka-Kowalnik B, Nesteruk M, Peters SU et al. Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay. Am J Med Genet Part B Neuropsychiatr Genet 2010; 153B: 983-93.

10. Mefford HC, Eichler EE. Duplication hotspots, rare genomic disorders, and common disease. Curr Opin Genet Dev 2009; 19: 196-204.

11. Girirajan S, Rosenfeld JA, Cooper GM et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet 2010; 42: 203-9.

12. Shinawi M, Liu P, Kang S-HL et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet 2010; 47: 332-41.

13. Zhang Y, Malekpour M, Al-Madani N et al. Sensorineural deafness and male infertility: a contiguous gene deletion syndrome. J Med Genet 2007; 44: 233-40.

14. Shimojima K, Imai K, Yamamoto T. A de novo 22q11.22q11.23 interchromosomal tandem duplication in a boy with developmental delay, hyperactivity, and epilepsy. Am J Med Genet Part A 2010; 152A: 2820-6.

Supplementary Table 2 Patients with intellectual disability as the referral reason for diagnostic cytogenetics: 100 cases with CNVs from 314 referrals____________________________________________________________________________________________________________Case Age Sex CNV(s) CNV size(s) Genes involved† Overlapping Family (years) Start End (bp) [Oligos*] FISH probe(s) HGNC OMIM phenotypes‡ study§

____________________________________________________________________________________________________________Established pathogenic microdeletion/microduplication/aneuploidy syndromes (16 cases)218 17 F del(X)(p22.33-q28) 45,X║ Turner ID DN219 10 M dup(X)(p22.33-q28) 47,XXY║ Klinefelter ID DN220 9 M dup(1)(q21.1) 1.3 Mb MIM 612475 IDa Fam(P)

144,867,339-146,812,122 [64] RP11-772D10221 15 M del(2)(p15-p16.1) 2.7 Mb MIM 612513 ID ?

60,687,773-63,450,283 [55] BAC RP11-470L12222 14 M del(4)(p16.3) 332 kb Mild Wolf-Hirschhorn ID DN

792,790-1,323,162 [6] BAC RP11-728M01del(4)(p16.3) 57 kb Mild Wolf-Hirschhorn DN1,786,989-1,851,704 [22] BAC RP11-1170P16

223 34 F dup(7)(q11.23) 1.54 Mb Williams-Beuren IDb Fam(M)72,287,913-73,831,310 [72] Vysis Williams probe duplication syndrome

224 2 M del(9)(q34.3) 803 kb 9q subtelomeric ID DN139,390,032-140,193,696 [71] ST-MLPA P036B/P069 deletion syndromedup(10)(q23.1) 679 kb 1 0 Fam(M)86,113,467-86,792,728 [11] BAC RP11-121P20

225 7 M del(9)(q34.3) 1.92 Mb 9q subtelomeric IDc DN138,272,005-140,193,696 [91] PAC 112N13 deletion syndrome

226 47 F del(10)(q26.2-q26.3) 7.6 Mb MIM 609625 ID T127,647,144-qter [147] PAC-137E24dup(1)(p36.33) 473 kb 23 8pter-1,351,721 [49] PAC-203K6

227 34 F del(15)(q24.1-q24.2) 3.1 Mb 15q24 microdeletion ID ?

70,671,628-73,856,817 [57] BAC RP11-592B13228 9 F del(17)(q11.2) 1.2 Mb NF1 microdeletion ID ?

26,058,031-27,450,863 [93]229 3 M del(17)(q11.2-q12) 6.1 Mb NF1 microdeletion ID ?

26,482,775-32,707,706 [149]230 34 F del(18)(p11.21-p11.32) 13.9 Mb 18p- deletion ID DN, T

138,993-14,071,858 [277] Cytogenetic studiesdup(X)(p22.33) 1.46 Mb 9 1717,270-1,474,194 [285] Cosmid c34F5

231 17 F del(22)(q11.21) 2.7 Mb 54 36 IDd,e,f ?17,145,109-19,835,388 [150] MLPA PO69

232 17 F del(22)(q11.21) 2.64 Mb Di George ID ?17,198,399-19,835,388 [149] Vysis TUPLEI/22q11.2

233 1 M dup(22)(q11.21) 2.6 Mb MIM 608363 ID Fam(M)17,198,399-19,870,318 [148] MLPA PO69dup(4)(q35.2) 823 kb 2 1 DN190,306,506-qter [45] PAC 963K6

Predicted pathogenic CNVs (25 cases)234 64 F dup(X)(p22.31) 2.5 Mb Li et al.1 ID ?

6,153,255-8.680,729 [169] Vysis STS probe235 35 F (X)(p22.13-p22.2) 8.33 Mb 56 42 ID ?

10,659,172-18,986,452 [397]236 10 F del(1)(p21.3) 612 kb 1 1 IDg,h DN

97,554,604-98,157,173 [11] BAC RP11-626C12del(1)(p21.2-p21.3) 2.97 Mb 19 15 DN98,708,906-101,677,503 [43] BAC RP11-473D14del(1)(q23.3) 736 kb 27 22 DN159,367,077-160,102,945 [12] BAC RP11-696E14

237 28 M del(3)(q13.32-q21.1) 3.8 Mb 44 36 IDc ?120,282,940-124,315,433 [69] BAC RP11-29A22

238 19 M dup(2)(q32.1-32.3) 6.4 Mb 30 19 IDi ?

185,802,823-192,310,183 [92] BAC RP11-622E16239 10 F del(5)(q14.3) 2.5 Mb MEF2C ID DN

86,296,771-88,888,521 [36] BAC RP11-393D20 LeMeur et al.2

dup(X)(p22.31) 266 kb 2 2 Fam(P)8,601,794-8,966,118 [15] BAC RP11-738L17

240 22 M del(5)(q34-q35.1) 6.9 Mb 28 18 IDj ?164,957,446-171,871,302 [123] RP11-297G08

241 18 M del(6)(q27) 233 kb 4 4 IDc,k Fam(M)170,529,510-170,762,985 [37] ST-MLPA P069

242 3 M dup(7)(q21.3-q22.1) 1.97 Mb 45 25 ID DN97,601,033-99,573,398 [51] Cytogenetic rearrangementdel(7)(q21.3-q22.1) 6.3 Mb 61 29 DN148,315,304-154,670,440 [94] Cytogenetic rearrangement

243 22 F del(8)(p23.1) 2.6 Mb 69 19 ID DN8,117,300-10,865,791 [56] BAC RP11-143J23dup(8)(p23.1) 1.2 Mb DN11,163,609-12,511,884 [67] BAC RP11-794G08

244 28 F dup(11)(q21-q23.3) 23.7 Mb 151 85 ID DN92,908,210-116,849,024 [338] Cytogenetic studiesdup(10)(p12.33) 871 kb 2 1 Fam(P)18,856,722-19,850,745 [13] BAC RP11-2N07

245 10 F del(12)(p13.32-p13.33) 1.35 Mb 9 5 ID Fam(M)2,105,645-3,553,705 [124] BAC RP11-391L19

246 31 M del(12)(p12.1) 1.97 Mb 4 3 ID DN22,220,444-24,380,623 [30] BAC RP11-650N09del(16)(q23.1) 187 kb 4 3 Fam(P)73,901,722-74,231,239 [3] RP11-435P13

247 13 M dup(12)(q13.12-q13.13) 1.05 Mb 26 13 ID ?47,999,974-49,040,962 [17] BAC RP11-52C09del(X)(p11.3) 5.0 kb ZNF41 ID ?47,215,186-47,220,142 [4] Repeat array Shoichet et al.3

248 45 F del(13q32.2-13q33.1) 5.2 Mb 27 18 IDl,m DN97,571,990-102,777,477 [106] BAC RP11-782G13 Kirchhoff et al.4

249 1 M dup(15)(q11.2-q13.3) 11.3 Mb 135 24 IDn DNSupernumery marker chromosome 18,946,233-30,297,189 [742] Light microscopy5

250 15 F del(2)(p25.3) 193 kb 1 1 IDo ?7,049-200,422 [43]del(15q21.3-q22.1) 2.6 Mb 15 9 ?54,399,517-57,029,582 [48] Tempesta et al.5

dup(X)(q28) 83 kb 2 2 ?154,802,648-154,886,079 [41]

251 25 M dup(16)(p13.3) 979 kb CREBBP IDi ?3,656,067-4,634,924 [53] Thienpont et al.6

dup(X)(p22.33) 88 kb 1 1 ?228,331-315,993 [71]

252 6 M del(16)(p11.2) 517 kb 26 15 ID ?29,581,485-30,098,040 [8] CTD-2215A12dup(2)(q33.1) 226 kb 1 1 ?199,882,880-200,108,540 [33]

253 14 M del(16)(q24.1-q24.2) 1.24 Mb 6 4 ID DN85,115,107-86,529,470 [20] BAC RP11-27E06

254 16 M dup(17)(q12) 1.39 Mb LHX1, HNF1B ID ?31,930,198-33,323,002 [45] BAC RP11-383B12

255 17 F del(18)(q21.2-q21.31) 4.5 Mb 13 8 ID DN48,746,496-53,222,309 [136] BACS RP11-344A21 and RP11-476H06

256 19 F del(19)(p13.3) 658 kb 21 13 IDc,p DN1,500,162-2,157,803 PAC CTD-2268M01

257 22 F dup(19)(q12-q13.12) mosaic 8.6 Mb - 15 IDq DNSupernumery marker chromosome 32,545,077-40,754,416 FISH probe PGA16

258 55 M dup(22)(q13.1-q13.2) 1.5 Mb 35 22 ID ?39,288,826-40,843,500 [29]del(15)(q11.2) 447 kb 13 5 ?

20,203,447-20,768,925 [81] Cooper et al.7

Established pathogenic disease susceptibility CNVs (8 cases)259 41 M del(1)(q21.1) 1.3 Mb Cooper et al.7 IDr ?

144,974,172-146,290,802 [64] BAC RP11-772D10260 16 M dup(1)(q21.1) 2.0 Mb Cooper et al.7 ID ?

142,491,723-144,510,930 [46] 261 40 M del(15)(q11.2) 356 kb Cooper et al.7 ID Fam(M)

20,280,758-20,636,508 [77] MLPA ME028262 10 M del(15)(q11.2) 609 kb Cooper et al.7 ID ?

19,047,782-20,851,703 [83]263 21 F del(15)(q11.2) 648 kb Cooper et al.7 ID ?

19,047,782-21,208,406 [84]264 36 M del(16)(p13.11) 1.22 Mb Cooper et al.7 IDs ?

14,669,769-16,102,049 [16] BAC RP11-139D07dup(16)(p11.2) 598 kb MIM 611913 ?29,385,582-30,240,053 [9] PAC CTD-2215A12dup(X)(q28) 734 kb 8 4 ?148,459,573-149,346,254 [12] BAC RP11-386D07

265 4 M del(16)(p12.1) 570 kb Girirajan et al.8 IDt ?21,745,023-22,315,403 [10] BAC RP11-101E07dup(X)(p11.23) 61.3 kb FTSJ1 Fam(M)48,202,320-48,263,671 [86] CTD-2215A12

266 7 M dup(16)(p11.2) 659 kb MIM 611913 ID Fam(M)29,581,485-30,240,053 [9] PAC CTD-2215A12dup(6)(q26) 122 kb See Supplementary Table 7 ?162,668,308-162,790,389 [3]del(15)(q15.3) 97 kb See Supplementary Table 7 ?41,638,870-41,735,609 [20]

267 - 183 CNVs of unknown clinical significance (84 cases) – See Supplementary Table 6184 - 217 Incidental findings of pathogenic CNVs (32 cases) – See Supplementary Table 7

* Number of consecutive oligonucleotides displaced.† Primary gene candidate stated where known, otherwise total number of genes within the lesion(s) is stated, or the syndrome, or the reference. HGNC refers to genes recognized by the Hugo Gene Nomenclature Committee and OMIM refers to genes recognized by Online Mendelian Inheritance in Man. Relevant references are given.‡ ID, intellectual disability: with comorbidities aleft convergent squint, bpsychosis, cdysmorphic,dcleft palate, emicrotia, fgrooved nasal tip, gglobal dystonia, hceliac disease, imarfanoid build, jcerebral palsy, kcerebellar hypoplasia, lataxia, mnystagmus, nhypotonia, oobesity, pventricular septal defect, qabnormal thumbs, rskeletal abnormalities, sIgA nephritis, tpatchy lack of myelination§ Fam, familial: Fam(M), known maternal origin; Fam(P), known paternal origin; FamX, familial on the X chromosome; del, deletion, dup, duplication; DN, de novo; M origin, mutation of maternal origin; IT, insertional translocation; ?, one or both parents not available for testing or has not responded to request for parental testing; S, a CNV that segregates with the disorder in the family; T, association with a translocation; ST-MLPA, subtelomere multiplex ligation-dependent probe amplification.║Aneuploidy, translocation, ring chromosome, large deletion or mosaicism confirmed by light microscopy of metaphase cells.

References1. Li F, Shen Y, Kohler U, Sharkey FH et al. Interstitial microduplication of Xp22.31: Causative of intellectual disability or benign

copy number variant? Eur J Med Genet 2010; 53: 93-9.2. Le Meur N, Holder-Espinasse M, Jaillard S et al. MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region

or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J Med Genet 2010; 47: 22-9.

3. Shoichet SA, Hoffmann K, Menzel C et al. Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X-linked mental retardation. Am J Hum Genet 2003; 73: 1341-54.

4. Kirchhoff M, Bisgaard AM, Stoevea R et al. Phenotype and 244k array-CGH characterization of chromosome 13q deletions: an update of the phenotypic map of 13q21.1-qter. Am J Med Genet Part A 2009; 149A: 894-905.

5. Tempesta S, Sollima D, Ghezzo S et al. Mild mental retardation in a child with a de novo interstitial deletion of 15q21.2q22.1: a comparison with previously described cases. Eur J Med Genet 2008; 51: 639-45.

6. Thienpont B, Bena F, Breckpot J et al. Duplications of the Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome. J Med Genet 2010; 47: 155-61.

7. Cooper GM, Coe BP, Girirajan S et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011; 9: 838-46.

8. Girirajan S, Rosenfeld JA, Cooper GM et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet 2010; 42: 203-9.

Supplementary Table 3 Patients with autism spectrum disorder as the referral reason for diagnostic cytogenetics: 28 cases with CNVs from 222 referrals____________________________________________________________________________________________________________Case Age Sex CNV(s) CNV size(s) Genes involved† Overlapping Family (years) Start End (bp) [Oligos*] FISH probe(s) HGNC OMIM phenotypes‡ study§

____________________________________________________________________________________________________________Established pathogenic microdeletion/microduplication syndromes (1 case)318 13 M dup(15)(q11.2-q13.1) 7.41 Mb MIM 608636 ASDa DN

18,946,233-26,3543,594 [655] MLPA P064B and Vysis Prader-Willi/Angelman SNRPN probe Predicted pathogenic CNVs (1 case)319 12 F del(1)(q25.3) 1.7 Mb 10 6 ASD DN

178,877,791-180,763,292 [30] BAC RP11-762A17Established pathogenic disease susceptibility CNVs (8 cases)320 7 M del(1)(q21.1) 2.85 Mb MIM 612474 ASDb ?

144,440,711-147,421,643 [74] 321 2 M del(15)(q11.2) 447 kb Cooper et al.1 ASD ?

20,203,447-20,768,925 [81]322 14 M del(16)(p11.2) 517 kb Weiss et al.2 ASD ?

29,581,485-30,098,040 [8] PAC CTD-2215A12 Shinawi et al.3

323 – 340 CNVs of unknown clinical significance (17 cases) – See Supplementary Table 6341- 345 Incidental findings of pathogenic CNVs (5 cases) – See Supplementary Table 7*Number of consecutive oligonucleotides displaced.†Primary gene candidate stated where known, otherwise total number of genes within the lesion(s) is stated, or the syndrome, or the reference. HGNC refers to genes recognized by the Hugo Gene Nomenclature Committee and OMIM refers to genes recognized by Online Mendelian Inheritance in Man, Relevant references are given.‡ ASD, autism spectrum disorder: with comorbidities aanti-psychotic monitoring, bcongenital hypothyroidism.§ DN, de novo.

References

1. Cooper GM, Coe BP, Girirajan S et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011; 9: 838-46.

2. Weiss LA, Shen Y, Korn JM et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med2008; 358: 667-75.

3. Shinawi M, Liu P, Kang S-HL et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet 2010; 47: 332-41.

Supplementary Table 4 Patients with autism spectrum disorder and developmental delay as the referral reason for diagnostic cytogenetics: 23 cases with CNVs from 110 case referrals____________________________________________________________________________________________________________Case Age Sex CNV(s) CNV size(s) Genes involved† Overlapping Family (years) Start End (bp) [Oligos*] FISH probe(s) HGNC OMIM phenotypes‡ study§___________________________________________________________________________________________________________Established pathogenic microdeletion/microduplication syndromes (3 cases)346 19 M del(X)(p22.31) 1.6 Mb STS ASD & DDa,b ?

6,423,935-8,057,482 [96] Not confirmed347 5 M dup(7)(q11.23) 1.4 Mb Williams-Beuren ASD & DDc Fam(M)

72,287,913-73,832,310 [71] MLPA P064B duplication syndrome348 2 F del(22)(q13.33) 793 kb 22q13 microdeletion ASD & DD T

48,732,185-49,525,101 [70] Subtelomeric probe syndromedup(8)(q24.3) 585 kb 18 9145,665,207-146,250,795 [39] Subtelomeric probe

Predicted pathogenic CNVs (2 cases)349 2 M del(2)(p16.3) 137 kb NRXN1 ASD & DD Fam(P)

50,882,643-51,020,200 [17] PAC CTD-2026D10350 10 M del(6)(q25.2-q26) 6.45 Mb 41 25 ASD & DDd,e,f ?

155,336,831-161,974,393 [105] Not confirmed Nagamani et al.1

dup(15)(q11.1) 534 kb 2 046,150,814-50,159,640 [29] Not confirmed

Established pathogenic disease susceptibility CNVs (4 cases)351 7 M del(15)(q11.2) 488 kb Cooper et al.2 ASD & DD I

20,249,915-20,811,925 [82] Not confirmed352 4 M del(15)(q11.2) 562 kb Cooper et al.2 ASD & DD

20,203,447-20,851,703 [82] Not confirmeddel(6)(p12.3-p21.1) 358 kb 2 1 Fam(P)44,897,932-45,404,501 [6] BAC RP11-818O21

353 8 M del(16)(p12.1) 522 kb Girirajan et al.3 ASD & DD ?

21,745,023-22,315,403 [10] BAC RP11-101E07dup(1)(q31.1) 522 kb 0 0 ?187,075,347-187,597,905 [10] BAC RP11-618P09

354 6 M del(16)(p12.1) 570 kb Girirajan et al.3 ASD & DD ?21,635,897-22,530,130 [10] Not confirmed

355 - 364 CNVs of unknown clinical significance (10 cases) – See Supplementary Table 6365- 368 Incidental findings of pathogenic CNVs (4 cases) – See Supplementary Table 7* Number of consecutive oligonucleotides displaced.† Primary gene candidate stated where known, otherwise total number of genes within the lesion(s) is stated, or the syndrome, or the reference. HGNC refers to genes recognized by the Hugo Gene Nomenclature Committee and OMIM refers to genes recognized by Online Mendelian Inheritance in Man. Relevant references are given.‡ ASD, autism spectrum disorder; DD, developmental delay: with comorbidities amicrocephaly, bX-linked ichthyosis,cmacrocephaly,dcoloboma, edeafness, fundescended testes.§ Fam, familial: Fam(M), known maternal origin; Fam(P), known paternal origin; del, deletion; dup, duplication; ?, one or both parents not available for testing or has not responded to request for parental testing; T, association with a translocation.

References1. Nagamani SC, Erez A, Eng C et al. Interstitial deletion of 6q25.2-q25.3: a novel microdeletion syndrome associated with

microcephaly, developmental delay, dysmorphic features and hearing loss. Eur J Med Genet 2009; 17: 573-81.2. Cooper GM, Coe BP, Girirajan S et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011; 9: 838-

46.3. Girirajan S, Rosenfeld JA, Cooper GM et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe

developmental delay. Nat Genet 2010; 42: 203-9.

Supplementary Table 5 Patients with autism spectrum disorder and intellectual disability as the referral reason for diagnostic cytogenetics: 21 cases with CNVs from 55 case referrals____________________________________________________________________________________________________________Case Age Sex CNV(s) CNV size(s) Genes involved† Overlapping Family (years) Start End (bp) [Oligos*] FISH probe(s) HGNC OMIM phenotypes‡ study§___________________________________________________________________________________________________________Established pathogenic microdeletion/microduplication/aneuploidy syndromes (3 cases)369 10 M dup(X)(p22.33-q28) 47,XXY║ Klinefelter ASD & IDa DN370 12 M del(7)(q11.23) 1.54 Mb Williams ASD & ID ?

72,287,913-73,831,310 [72] Vysis Williams probe371 2 M dup(17)(p11.2-p13.1) 9.56 Mb║ CMT1A ASD & ID DN

9,956,982-19,513,384 [193] Potocki-Lupski Predicted pathogenic CNVs (2 cases)372 6 M dup(X)(p21.1) 580 kb 1 1 ASD & ID Fam(M)

33,128,600-33,708,771[25] BACs RP11-415K03 and RP11-711F24373 9 F del(5)(q21.1-q22.3) 13.8 Mb 35 25 ASD & ID Fam(M), S

101,024,486-115,061,111 [221] BAC RP11-626D16Established pathogenic disease susceptibility CNVs (2 cases)374 13 F dup(1)(q21.1) 381 kb Cooper et al.1 ASD & ID Fam(M)

144,126,573-144,610,725 [42] BAC RP11-293J20375 11 M del(2)(q11.2) 1.4 Mb Cooper et al.1 ASD & ID Fam(M)

96,017,637-97,630,840 [16] BACs RP11-67L23 and RP11-61O17376 – 385 CNVs of unknown clinical significance (10 cases) – See Supplementary Table 6386 - 389 Incidental findings of pathogenic CNVs (4 cases) – See Supplementary Table 7* Number of consecutive oligonucleotides displaced.† Primary gene candidate stated where known, otherwise total number of genes within the lesion(s) is stated, or the syndrome, or the reference. HGNC refers to genes recognized by the Hugo Gene Nomenclature Committee and OMIM refers to genes recognized by Online Mendelian Inheritance in Man. Relevant references are given.‡ ASD, autism spectrum disorder; ID, intellectual disability: with comorbidities aobesity.

§ Fam, familial: Fam(M), known maternal origin; del, deletion; dup, duplication; DN, de novo; ?, one or both parents not available for testing or has not responded to request for parental testing; S, a CNV that segregates with the disorder in the family.║ Large duplication confirmed by light microscopy of metaphase cells.

References1. Cooper GM, Coe BP, Girirajan S et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011; 9: 838-

46.

Supplementary Table 6 CNVs of unknown clinical significance____________________________________________________________________________________________________________Case Age Sex CNV(s) Oligos CNV Size(s) Genes involved* Overlapping phenotypes (years) displaced HGNC OMIM ____________________________________________________________________________________________________________Developmental delay (with associated co-morbidities) (85 cases)99 1 M dup(X)(p22.33) 152 363 kb 3 5100 14 M dup(X)(p22.31) 20 97 kb 1 1101 6 M del(X)(p21.2) 4 24 kb 1 1 Arnold-Chiari malformation102 5 M del(X)(p11.3) 4 5 kb 1 1103 2 M del(X)(p11.2) 3 6 kb 1 1 Cerebral palsy104 1 M del(X)(q13.1) 13 63.6 kb 1 1105 28 F dup(X)(q13.3) 17 187 kb 3 2 Madelung and digit deformity106 3 M dup(X)(q21.1) 3 22 kb 1 1107 12 F del(X)(q21.31) 33 301 kb 1 1108 3 M dup(X)(q23) 3 144 kb 0 0 Ataxia, hypothermia at night109 2 F del(X)(q27.2) 9 372 kb 4 2110 2 M dup(X)(q28) 30 328 kb 2 2111 5 F dup(X)(q28) 12 734 kb 8 4112 15 F dup(1)(q22) 5 252 kb 5 3113 1 F dup(1)(q43) 9 577 kb 2 2 Fibrosis of extra ocular muscles114 8 M dup(1)(q44) 35 2.3 Mb 30 5115 2 F dup(2)(p25.3) 8 459 kb 2 2116 3 F dup(2)(p24.3) 11 637 kb 0 0117 9 M del(2)(p23.2) 3 119 kb 2 1118 1 M dup(2)(p21) 13 27 kb 1 1119 5 M del(2)(p16.3) 3 18 kb 1 1120 9 F del(2)(q14.3) 9 (de novo) 511 kb 0 0 2-3 syndactyly121 1 M dup(2)(q14.3) 13 739 kb 0 0122 6 F dup(2)(37.3) 36 237 kb 4 3 Polymicrogyria123 4 M del(3)(p26.3) 3 11.8 kb 1 1

124 10 F del(3)(p26.3) 20 135 kb 1 1125 3 M dup(3)(p26.3) 13 921 kb 2 2 Agenesis of corpus callosum126 8 M dup(3)(p26.3) 10 534 kb 1 0127 44 F del(3)(p26.2) 3 159 kb 2 2 de novo inv(3)(p26q27)128 1 F del(3)(p22.1) 8 370 kb 1 0129 65 M del(3)(p14.2) 21 1.3 Mb 1 1130 3 F del(4)(p15.1) 7 308 kb 0 0

dup(8)(p23.2-p23.3) 4 307 kb 1 1131 4 M dup(4)(q13.2-q13.3) 11 758 kb 6 5132 6 F del(4)(q31.21) 10 758 kb 1 1133 6 M del(4)(q34.3) 6 224 kb 0 0134 18 F del(5)(p15.2) 13 877 kb 0 0135 17 M del(5)(p14.2-p14.3) 18 1.28 Mb 2 2 Hearing loss, hypertelorism136 6 F del(5)(q14.3) 11 846 kb 0 0137 4 M del(5)(q14.3) 6 356 kb 0 0138 13 F del(5)(q21.2-q21.3) 44 3.0 Mb 1 1 Hypermobility139 9 F dup(5)(q21.3-q22.1) 13 963 kb 2 1 Renal tubular dysgenesis140 7 F dup(5)(q23.3) 6 305 kb 1 1141 7 M del(6)(p12.3) 18 1.3 Mb 2 0142 7 F dup(6)(q14.3-q15) 19 1.03 Mb 1 1143 2 M del(6)(q16.3) 5 28 kb 1 1144 7 M dup(6)(q22.1) 8 509 kb 2 1145 7 M dup(6)(q24.1) 16 1.1 Mb 0 0146 1 F dup(7)(p21.3) 9 599 kb 1 1 Microcephaly147 3 F dup(7)(p21.3) 19 1.46 Mb 3 1 Macrocephaly148 4 M dup(7)(p14.1) 15 141 kb 1 1

del(15)(q15.3) 23 99 kb 5 4 Incidental finding (see Supp Table 2)149 1 M del(7)(p11.2) 49 939 kb 14 8150 2 M dup(7)(q21.13) 22 1.6 Mb 3 1 Aortic stenosis151 12 M dup(7)(q22.1) 7 393 kb 3 1152 1 F dup(8)(p22) 9 608 kb 1 1

153 8 M del(8)(p22) 19 1.3 Mb 4 3 Dysmorphic154 6 F del(8)(q11.21-q11.22)51 3.46 Mb 7 5 Dysmorphic155 9 M dup(8)(q11.23) 7 503 kb 2 2156 5 M dup(8)(q24.3) 15 1.0 Mb 3 2157 10 F del(10)(q21.1) 3 241 kb 1 1158 8 F dup(10)(q26.3) 39 236 kb 9 5159 2 M del(11)(p14.1) 5 254 kb 3 1160 3 M del(11)(p12) 8 596 kb 0 0 Dysmorphic

del(15)(q15.3) 20 97 kb 2 2 Incidental finding (see Supp Table 2)161 5 M del(11)(q21) 6 357 kb 0 0

dup(18)(p11.23-p11.31) 19 1.4 Mb 4 2162 2 F dup(12)(p11.1) 44 1.2 Mb 2 0163 4 F dup(12)(q24.13) 33 575 kb 8 3 Vitiligo, deafness164 7 M del(13)(q21.33) 3 141 kb 1 1 Sparse hair, thick skin palms/soles165 4 M dup(2)(q33.1) 4 15 kb 0 0 Pulmonary stenosis

dup(14)(q24.2) 9 517 kb 7 4166 4 M del(14)(q31.3) 6 331 kb 0 0 Deaf, optic atrophy, ataxia167 3 M dup(14)(q32.13) 10 622 kb 5 4168 10 F dup(15)(q13.2-q13.3) 53 de novo 1.56 Mb 8 4 2-3 syndactyly169 1 M dup(15)(q21.2) 20 860 kb 6 5 Dysmorphic170 5 M dup(15)(q26.1) 29 325 kb 1 1171 18 M del(16)(p13.2) 21 158 kb 0 0 Dysmorphic172 2 M del(16)(p13.2) 9 572 kb 0 0173 1 F dup(16)(q23.1) 10 533 kb 2 1174 17 M del(17)(p13.3) 3 5.1 kb 1 1175 3 M del(17)(p13.3) 7 13.8 kb 1 1176 5 M del(17)(q11.2) 21 127 kb 3 2177 7 F dup(17)(q25.1) 13 880 kb 15 11178 4 M del(18)(q12.2-q12.3) 30 2.02 Mb 0 0179 5 F del(18)(q22.1) 7 492 kb 1 1180 5 F del(14)(q31.3) 6 331 kb 0 0

del(19p12) 8 508 kb 5 0181 7 M dup(19)(p12) 56 566 kb 5 1182 1 F dup(21)(q22.3) 9 548 kb 5 4

dup(X)(p22.32) 27 477 kb 1 1183 5 M del(22)(q13.31) 7 227 kb 1 1Intellectual disability (with associated co-morbidities) (36 cases)267 16 F dup(X)(p11.4) 17 59 kb 1 1 Obesity268 10 F dup(X)(q21.1) 3 22 kb 2 2269 14 M dup(X)(q21.33) 11 851 kb 2 1 Insertional translocation270 9 F dup(X)(q22.3) 12 489 kb 2 2 Bulbous nose, abnormal teeth,

bilateral congenital cataracts271 12 M dup(X)(q28) 25 313 kb 2 1272 15 M dup(1)(q23.1) 8 515 kb 6 2273 6 F dup(1)(q43) - 507 kb 1 0 Large mouth, hypertelorism274 7 M del(2)(p25.3) 47 612 kb 4 2 Obesity275 3 M del(2)(p16.3) 3 18 kb 1 1276 10 M del(2)(q13) 21 1.6 Mb 8 4277 12 M del(2)(q22.1) 6 399 kb 1 0278 22 M del(3)(p22.1) 9 420 kb 1 0 Hypospadias, coloboma of retina,

dysmorphic features279 32 F dup(3)(q21.3) 5 290 kb 5 3

dup(12)(q21.31) 8 524 kb 1 0280 6 F dup(4)(q35.1-q35.2) 37 2.65 kb 15 9281 7 F dup(6)(q22.31) 6 403 kb 3 1 Cutaneous haemangiomas282 15 M dup(6)(q24.1) 8 532 kb 0 0 Macrocephaly283 14 M dup(7)(p21.3) 19 1.46 Mb 3 1284 9 M dup(7)(q21.12-q21.13) 17 1.2 Mb 2 0285 22 F dup(8)(p23.2-p23.3) 22 720 kb 6 4

dup(1)(p31.1) 9 601 kb 1 1286 29 F dup(8)(q11.23) 8 610 kb 2 2287 13 M dup(8)(q12.3-q13.1) 6 433 kb 0 0

288 9 M dup(9)(p24.3) 39 375 kb 3 2289 27 M dup(9)(q31.1-q31.2) 28 1.6 Mb 16 8290 10 M del(9)(q33.1) 4 159 kb 2 1291 5 M dup(10)(p13) 9 586-778 kb 1 0292 9 F del(11)(q22.1) 10 589 kb 0 0293 20 F dup(11)(q24.2) 5 252 kb 1 0294 49 F dup(12)(p11.1) 44 1.2 Mb 3 2295 13 F dup(13)(q12.12) 9 494 kb 4 4 Cerebellar vermis hypoplasia,

microcephaly296 4 M del(14)(q31.1) 4 244 kb 1 0297 31 F dup(14)(q32.13) 12 749 kb 6 5298 6 F dup(16)(p13.11) 20 1.7 Mb 16 7299 25 F dup(16)(p13.11) 10 643 kb 7 3

del(15)(q15.3) 20 97 kb 5 4300 15 M dup(17)(q22-q23.2) 17 1.3 Mb 15 10301 19 F dup(19)(q13.2-q13.31) 6 397 kb 9 6302 15 M dup(22)(q12.3) 5 170 kb 1 1Autism spectrum disorder (with associated co-morbidities) (18 cases)323 3 M del(X)(p21.2) 12 98 kb 1 1 Antimongoloid slant324 7 M del(1)(p31.1) 10 516 kb 1 0325 6 M dup(1)(p31.1) 14 752 kb 4 2 Obesity326 3 M dup(2)(p22.1-p22.2) 17 1.1 Mb 9 7327 11 M del(2)(p16.3) 9 66 kb 1 1328 6 F dup(3)(p14.2) 5 261 kb 1 1329 3 F del(3)(q25.1) 9 576 kb 3 2330 3 M dup(7)(q21.13) 21 1.6 Mb 2 0

del(11)(q14.1) 4 247 kb 1 1331 5 M dup(8)(q22.3) 3 139 kb 2 2332 7 F dup(X)(q26.3) 6 380 kb 4 2

dup(8)(q12.1) 12 789 kb 3 2333 6 M dup(9)(p24.3) 14 478 kb 3 3

334 7 M del(10)(q22.3) 8 333 kb 4 2335 6 F del(11)(q14.3-q21) 26 1.7 Mb 6 2336 3 M dup(12)(p13.33) 40 1.5 Mb 11 8337 6 M del(X)(p21.2) 12 98 kb 1 1

del(15)(q13.1-q13.2) 38 2.5 Mb 12 4338 7 M del(20)(p12.1) 9 611 kb 2 1339 10 M del(X)(p21.2) 12 98 kb 1 1

dup(22)(q111.22-q11.23) 36 642 kb 43 6340 2 M dup(22)(q11.23-q11.23) 26 1.2 Mb 27 16Autism spectrum disorder and developmental delay (with associated co-morbidities) (10 cases)355 2 M dup(X)(p22.2) 12 818 kb 3 2 Fragile X diagnosed concurrently

dup(X)(q21) 19 91 kb 1 1356 2 M dup(X)(q21.1) 87 745 kb - 3357 8 M del(2)(p11.2-p12) 9 531 kb 0 0358 17 M dup(6)(q22.31) 12 803 kb 2 2359 10 M dup(6)(q24.3-q25.1) 43 3.1 Mb 26 19 Lethargy, hoarse voice360 5 M del(8)(p23.1-p23.2) 45 2.71 Mb 0 0361 3 F dup(8)(q24.23) 6 354 kb 1 0362 13 M dup(10)(q11.21) 24 70 kb 1 1363 2 M del(13)(q21.1) 13 944 kb 1 0364 3 M del(13)(q31.1) 21 1.35 Mb 1 0Autism spectrum disorder and intellectual disability (with associated co-morbidities) (10 cases)376 5 M dup(X)(p11.4) 17 58 kb 1 1 Microcephaly377 13 F del(2)(p25.2) 9 538 kb 0 0378 9 M dup(4)(q21.3) 46 3.2 Mb 15 10

dup(5)(p14.2-p14.3) 18 1.4 Mb 2 2del(13)(q21.33-q22.1)7 433 kb 2 1

379 11 M dup(15)(q26.1) 29 383 kb 2 1380 11 M dup(16)(p13.3) 9 495 kb 10 9

381 15 M del(16)(p13.2-p13.3) 48 424 kb 0 0 382 22 M del(16)(q23.1) 16 817 kb 1 1 Dysmorphic, cleft palate,

hypospadias, metopic suture stenosis383 8 M dup(16)(p13.3) 6 329 kb 10 5384 42 M dup(18)(q22.1) 12 805 kb 2 0385 20 F dup(19)(p12) 11 598 kb 6 1__________________________________________________________________________________________________________* HGNC refers to genes recognized by the Hugo Gene Nomenclature Committee and OMIM refers to genes recognized by Online Mendelian Inheritance in Man.

Supplementary Table 7 CNVs of incidental clinical significance ____________________________________________________________________________________________________________Case Age Sex CNV(s) Oligos CNV Size(s) Genes involved* Incidental clinical findings (years) displaced HGNC OMIM ____________________________________________________________________________________________________________Developmental delay (with associated co-morbidities) (34 cases)184 31 F del(X)(p22.31) 70 1.4 Mb 1 1 X-linked ichthyosis carrier and

del(X)(p21.1) 14 118 kb 1 1 Duchenne muscular dystrophy carrierdel(3)(p26.3) 6 26 kb 1 1dup(21)(2q22.11) 8 170 kb 4 3

185 1 F del(X)(p21.1) 13 102 kb 1 1 Duchenne muscular dystrophy carrier186 9 M del(X)(p21.1) 14 128 kb 1 1 Duchenne muscular dystrophy carrier187 7 F dup(X)(p21.1) 19 143 kb 1 1 Duchenne muscular dystrophy carrier

del(4)(q34.3) 8 471 kb 0 0188 7 F del(1)(q43) 3 106 kb 1 0 Retinal-renal ciliopathy carrier189 2 M dup(1)(q43) 5 211 kb 3 2 Methylcobalamin carrier190 1 M del(2)(p21) 4 39 kb 2 2 Hypotonia-cystinuria syndrome carrier191 5 M dup(2)(p21) 12 24.1 kb 1 1 Hypotonia-cystinuria syndrome carrier190 2 F dup(2)(p21) 12 24.1 kb 1 1 Hypotonia-cystinuria syndrome carrier191 9 F dup(2)(p21) 12 24.1 kb 1 1 Hypotonia-cystinuria syndrome carrier192 3 F dup(2)(p21) 13 25.7 kb 2 2 Hypotonia-cystinuria syndrome carrier193 1 M dup(2)(p21) 13 26.7 kb 1 1 Hypotonia-cystinuria syndrome carrier194 8 F del(2)(q13) 35 102 kb 2 2 Juvenile nephronophthisis carrier and

Joubert syndrome 4 carrier197 16 M dup(5)(q12.1) 5 281 kb 3 2 Cockayne syndrome carrier

Mitochondrial disorder carrier198 5 F del(5)(q13.2) 13 989 kb 2 3 Spinal muscular atrophy carrier

dup(6)(q27) 36 155 kb 3 3199 6 M dup(5)(q31.2) 5 295 kb 6 5 Marinesco-Sjogren syndrome carrier200 1 F del(6)(q26) 5 324 kb 1 1 Early onset Parkinson disease carrier201 6 M dup(6)(q26) 8 492.7 kb 2 2 ?Early onset Parkinson disease carrier

202 8 M del(7)(q35) 19 151 kb 1 1 Cortical dysplasia focal epilepsy carrier203 4 M dup(13)(q12.12) 6 249 kb 2 1 Limb-girdle muscular dystrophy carrier

del(15)(q15.3) 18 24.9 kb 2 2 Deafness and male infertility carrier204 10 M dup(14)(q32.12) 3 110 kb 2 1 ?Cutis laxa Type 1 carrier

?Macular degeneration carrier205 4 F del(15)(q15.3) 21 98 kb 5 4 Deafness and male infertility carrier206 5 M del(15)(q15.3) 20 27 kb 2 2 Deafness and male infertility carrier207 1 F del(15)(q15.3) 20 32.5 kb 2 2 Deafness and male infertility carrier208 6 M del(15)(q15.3) 22 98 kb 5 4 Deafness and male infertility carrier209 2 M del(15)(q15.3) 21 98 kb 5 4 Deafness and male infertility carrier210 6 M del(15)(q15.3) 21 98 kb 5 4 Deafness and male infertility carrier211 3 M del(15)(q15.3) 22 98 kb 5 4 Deafness and male infertility carrier212 14 M del(15)(q15.3) 20 97 kb 5 4 Deafness and male infertility carrier213 9 M del(15)(q15.3) 21 99 kb 5 4 Deafness and male infertility carrier214 5 M del(15)(q15.3) 21 98 kb 5 4 Deafness and male infertility carrier215 8 M del(17)(p12) 51 1.33 Mb 8 3 Neuropathy with liability to pressure palsies216 5 M dup(17)(p12) 50 1.25 Mb 6 2 Charcot-Marie-Tooth disease type 1A217 5 M dup(19)(q13.33) 3 135 kb 7 4 ?Infantile bilateral striatal necrosis carrierIntellectual disability (with associated co-morbidities) (15 cases)303 10 F del(X)(p22.13) 3 6.4 kb 1 1 ?Nance Horan syndrome carrier304 14 F del(X)(p21.1) 13 20.5 kb 1 1 ?Duchenne muscular dystrophy carrier

dup(6)(p21.32) 8 61 kb 4 4 Congenital adrenal hyperplasia carrier305 13 M del(X)(p21.1) 5 27 kb 1 1 ?Becker muscular dystrophy risk306 5 M dup(1)(q42.3) 22 162 kb 2 2 ?Congenital hypoparathyroidism-

retardation-dysmorphism syndrome carrier307 32 F del(2)(q13) 35 102 kb 2 2 Juvenile nephronophthisis carrier

Joubert syndrome 4 carrier308 9 M del(5)(q12.1) 5 284 kb 4 2 Cockayne syndrome carrier

Mitochondrial complex I deficiency carrier309 8 M del(5)(q13.3-q14.1) 43 3.1 Mb 19 15 Hermansky-Pudlak syndrome 2 carrier

Mucopolysaccharidosis type VI carrier

dup(7)(q31.31) 24 1.7 Mb 3 3310 8 M del(6)(q23.3) 3 8 kb 1 1 Joubert syndrome 3 carrier311 15 M dup(15)(q12) 16 196 kb 1 1 Albinism oculocutaneous type II carrier312 44 F del(15)(q15.3) 20 31 kb 5 4 Deafness and male infertility carrier313 17 M del(15)(q15.3) 20 32 kb 5 4 Deafness and male infertility carrier314 48 M del(15)(q15.3) 20 97 kb 5 4 Deafness and male infertility carrier315 28 M del(15)(q15.3) 24 197 kb 8 6 Deafness and male infertility carrier316 38 F del(15)(q15.3) 22 99 kb 5 4 Deafness and male infertility carrier317 21 F del(17)(p13.3) 3 159 kb 4 3 Canavan dis/Nephropathic cystinosis carrier

del(11)(p11.2) 3 1.4 kb 1 1Autism spectrum disorder (with associated co-morbidities) (5 cases)341 5 M dup(X)(p22.31) 94 1.6 Mb 7 4 STS duplication342 5 M dup(2)(p21) 15 33.3 kb 2 2 Hypotonia-cystinuria syndrome carrier343 8 F del(14)(q12) 3 107 kb 1 0 Complex 1 deficiency carrier344 10 M del(6)(q13) 8 430 kb 2 1 Methylmalonic aciduria carrier345 4 M del(17)(p13.3) 17 60.6 kb 3 3 Nephropathic cystinosis carrierAutism spectrum disorder and developmental delay (with associated co-morbidities) (4 cases)365 2 M del(1)(q31.3) 3 94 kb 4 3 Haemolytic uraemic syndrome carrier

dup(11)(q22.3) 6 367 kb 4 2366 4 F del(15)(q15.3) 20 96.7 kb 5 4 Deafness and male infertility carrier367 6 F del(15)(q15.3) 20 32.5 kb 2 2 Deafness and male infertility carrier368 2 M del(17)(p13.3) 3 160 kb 4 3 Canavan dis/Nephropathic cystinosis carrierAutism spectrum disorder and intellectual disability (with associated co-morbidities) (4 cases)386 39 M dup(X)(p21.1) 12 92 kb 1 1 ?Becker muscular dystrophy387 8 M del(2)(p25.3) 52 738 kb 5 2

dup(2)(p21) 4 256 kb 3 2 Risk of nonpolyposis colorectal cancer388 3 M dup(2)(p21) 11 22 kb 1 1 Hypotonia-cystinuria syndrome carrier389 13 M dup(2)(p21) 11 22 kb 1 1 Hypotonia-cystinuria syndrome carrier____________________________________________________________________________________________________________

* HGNC refers to genes recognized by the Hugo Gene Nomenclature Committee and OMIM refers to genes recognized by Online Mendelian Inheritance in Man.