Srebniak Et Al. Prenatal SNP Array Testing in 1000 Fetuses with Ultrasound Anomalies: Causative

Srebniak et al. Prenatal SNP array testing in 1000 fetuses with ultrasound anomalies: causative, unexpected and susceptibility CNVs

Supplemental material - The cases presented in this supplemental material are submitted to ClinVar database ( numbers SCV000224042 - SCV000224117).

Table S1. Causative genetic abnormalities found in fetuses with ultrasound anomalies after excluding common aneuploidies by RAD.

Indication for invasive testing as mentioned on the request form / Additional prenatal and postnatal features diagnosed after invasive sampling / Outcome / Array finding [hg18](full description according to ICSN) / M/S / Description
1 / holoprosencephaly / dysmorphic features / TOP / arr[hg18] 2p21(44,796,945x2, 44,867,229-45,029,698x1,45,033,654x2) dn / S / de novo 0.2Mb partial deletion of SIX3 (2p21) associated with holoprosencephaly
2 / IUGR, NTD, small omphalocele, CHD, multicystic kidney, SUA / N.D. / TOP / arr[hg18] 2q32.2q37.3(189,901,112x2,190,058,398-242,678,246x3,242,951,149x2) dn, 9p24.3p24.1(1x2, 36,587-7,575,382x1,7,577,716x2) dn / M / de novo unbalanced translocation: der(9),t(2;9)(q32.2;p24.1) dn (52Mb gain in 2q and 7Mb deletion in 9p)
3* / hygroma colli / N.D. / TOP / arr[hg18] 3p26.3p26.1(1x2, 41,894-6,164,342x1, 6,164,636x2) mat, 19q13.12q13.43(41,133,957x2, 41,169,695-63,798,054x3, 63,798,055x2) mat / M / maternally inherited derivative chromosome: der(3)t(3;19)(p26.1;q13.12) mat (6.1Mb deletion on 3p and 22.6Mb gain on 19q)
4 / hydrothorax, NT > 3.5 mm / N.D. / TOP / arr[hg18] 3q25.2q29(154,913,338x2, 154,919,951-199,329,630x3,199,501,827x2) pat, 4q35.1q35.2(184,604,987x2, 184,610,805-191,162,351x1,191,273,063x2) pat / M / paternally inherited derivative chromosome der(4)t(3;4)(q25.2;q35.1) pat (44.6Mb gain in 3q and 6.6Mb deletion in 4q)
5* / CL / IUGR, bilateral CL/P, complex CHD, dysmorphic features, epilepsy, feeding problems, hearing loss, brain abnormalities / LB with anomalies / arr[hg18] 4p16.3p16.1(38,283x2, 38,283-8,321,040x1,8,321,040x2) dn / S / de novo 8.3Mb deletion on 4p causing Wolf-Hirschhorn syndrome
6 / complex CHD / N.D. / TOP / arr[hg18] 4p16.3p11(1x2, 38,283-49,248,567x3, 49,248,567x2) dn / M / de novo unbalanced translocation: der(22)t(4;22)(p11;p11) dn (49Mb gain in the short arm of chromosome 4 resulting in trisomy 4p due to derivative chromosome)
7 / CL, cerebellar anomaly, talipes / CL/P, no auditory canal visible in right ear, dysmorphic features / TOP / arr[hg18] 4p16.3p15.32(1x2, 38,283-18,362,284x1, 18,385,195x2) mat, 7q35q36.3(144,752,492x2, 144,767,578-158,800,251x3, 158,812,247x2) mat / S / maternally inherited derivative chromosome: der(4)t(4;7)(p15.32;q35) mat (18.4Mb deletion in 4p and 14.1Mb gain in 7q) resulting in 4p- associated with Wolf- Hirschhorn syndrome
8 / cerebral cyst / N.D. / TOP / arr[hg18] 4q31.3q32.2(153,354,409x2, 153,386,621-164,227,442x1, 164,303,066x2) dn / M / de novo 10.9Mb 4q32 deletion associated with 4q32 deletion syndromewith ID, obesity, facial dysmorphic features and brachydactyly(Tzschach et al. 2010).
9 / hygroma colli / hydrops foetalis / TOP / arr[hg18] 4q32.1q35.2(157,381,964x2, 157,386,196-191,162,351x1, 191,273,063x2) dn, 15q11.2q13.3(18,421,386x2, 18,421,386-30,302,973x1, 30,383,373x2) dn / M / de novo unbalanced translocation: der(4)t(4;15)(q32.1;q13.3) dn (33.8Mb deletion in 4q and 11.9Mb deletion in 15q)
10 / borderline ventriculomegaly, CCA, hypoplastic cerebellum, short femur, polyhydramnios, retrognathy, suspected low-set ears and flat nose / N.D. / TOP / arr[hg18] 5p15.33p14.3(1x2, 91,139-23,278,442x1, 23,287,592x2) dn, 19q13.41q13.43(57,993,489x2, 58,049,723-63,798,054x3, 63,811,651x2) dn / M / de novo unbalanced translocation: der(5)t(5;19)(p14.3;q13.41) dn (23.3Mb deletion in 5p and 5.8Mb gain in 19q)
11 / complex CHD, IUGR / none / TOP / arr[hg18] 5q35.3(179,278,602x2, 179,286,688-180,638,145x1, 180,857,866x2) mat, 16q24.2q24.3(86,358,459x2, 86,364,482-88,685,456x3, 88,827,254x2) mat / S / maternally inherited derivative chromosome der(5)t(5;16)(q35.3;q24.2) mat (1.5Mb deletion at 5q and 2.5Mb gain at 16q)
12 / mild bilateral ventriculomegaly, small cerebellum, suspected simplified gyral pattern / none / TOP / arr[hg18] 6q26q27(161,632,025x2, 161,640,013-170,740,474x1, 170,899,992x2) dn / S / de novo 9.2Mb deletion in 6q26q27 causing 6q deletion syndrome associated with intellectual disabilities, hypotonia, seizures, brain anomalies, and specific dysmorphic features including short neck, broad nose with bulbous tip, large and low-set ears and downturned corners of the mouth (Bertini et al. 2006).
13 / abnormal position of the feet, NT > 3,5 mm, hypoplastic cerebellum and vena cava sinistra / cerebellar abnormalities , left isomerism of the lungs, eartags, dysmorphic features / TOP / arr[hg18] 6q27(164,672,305x2, 164,703,703-170,740,474x1, 170,899,992x2) mat, 9p24.3p21.3 (1x2, 36,587-22,924,328x3, 22,933,509x2) mat / M / maternally inherited derivative chromosome der(6)t(6;9)(q27;p21.3) mat (6.2Mb deletion in 6q and 22.9Mb gain in 9p)
14 / IUGR, SUA, CCA?, CHD, aberrant position lower leg / complex CHD, dysmorphic features, left isomerism of lungs, absent gall bladder, renal tubular microcysts, persistent omphalomesenteric duct, CCA, mild ventriculomegaly, brain abnormalities / TOP / arr[hg18] 6q27(167,704,044x2, 167,716,064-170,740,474x1, 170,899,992x2) mat, 16p13.3p13.13 (1x2, 45,320-10,739,945x3, 10,753,492x2) mat / S / maternally inherited derivative chromosome der(6)t(6;16)(q27;p13.13) mat (3.2Mb deletion on 6q and 10.7Mb gain on 16p)
15* / ventriculomegaly, cerebellar hypoplasia / postaxial polydactyly, brain abnormalities / TOP / arr[hg18] 6q27(170,394,538x2, 170,399,929-170,740,474x1, 170,899,992x2) dn, 13q31.1q34(79,325,724x2, 79,348,454-114,125,098x3, 114,142,980x2) dn / M / de novo unbalanced translocation: der(6)t(6;13)(q27;q31.1) dn (34.8 Mb gain in 13q and 0.5Mb deletion in 6q)
16 / hydrocephalus / broad thumbs, preaxial polydactyly, syndactyly / TOP / arr[hg18] 7p14.1(42,068,497x2, 42,072,941-42,202,805x1, 42,210,900x2) mat / S / maternally inherited 0.13Mb partial deletion of GLI3 (7p14.1) associated with Greig cephalopolysyndactyly syndrome (mother is also affected)
17 / CCA / dysmorphic features / TOP / arr[hg18] 8p23.3p23.1(1x2, 166,818-6,961,460x1, 6,961,460x2) dn, 8p23.1p11.1(11,935,618x2, 12,595,527-43,765,570x3, 43,765,570x2) dn / M / de novo complex abnormality of the short arm of chromosome 8: 46,XX,dic(8)(:p10->p23.1:p23.1->qter) dn (6.9Mb deletion in band 8p23.3p23.1 and 31.5Mb gain in band 8p23.1p11.1)
18* / ventriculomegaly / CCA, dysplasia of hippocampus, dysmorphic features / IUFD / arr[hg18] 8p23.3q24.3(1x2, 166,818-146,263,890x2~3, 146,274,826x2) dn / S / de novo mosaic trisomy 8 (~10%)
19 / NT > 3.5 mm / N.D. / IUFD / arr[hg18] 9p24.3q33.1(1x2, 36,587-116,836,807x3, 116,843,541x2) mat, 13q11q12.11(18,161,735x2, 18,161,735-19,424,761x1, 19,431,905x2) mat / M / maternally inherited unbalanced translocation der(9)t(9;13)(q33.1;q12.11) mat (116Mb duplication in chromosome 9 and 1.2Mb deletion at 13q11q12.11)
20 / Femur < P5,echogenic bowel / microcephaly, dysmorphic features cytomegaly of adrenals / TOP / arr[hg18] 9p24.3q34.3(1x2, 36,587-140,164,310x2~3, 140,273,252x2) dn / M / de novo mosaic trisomy 9 in ca. 50-60% of the cells
21 / club feet and pyelectasis / NTD, bilateral microphthalmia with eye abnormalities, unilateral hydronephrosis, unilateral renal agenesis, abnormal lobulation of both lungs, ascites, dysmorphic features, SUA / TOP / arr[hg18] 9p24.3q34.3(1x2, 36,587-140,164,310x2~3, 140,273,252x2) dn / M / de novo mosaic trisomy 9in ca. 50% of the cells
22* / club feet, bilateral pyelectasis / N.D. / TOP / arr[hg18] 9q34.3(138,079,483x2, 138,086,988-140,164,310x1, 140,273,252x2) dn / S / de novo del(9) causingKleefstra syndrome (9q34 deletion syndrome) (2.2Mb terminal deletion in 9q)
23* / IUGR, CHD?, echogenic bowel, cerebral cyst, NT > 3.5 mm / polyhydramnios, small kidneys, possibly abnormal gall bladder, cavum vergae; child died on the day of birth / LB with anomalies / arr[hg18] 10p15.3p12.31 (1x2, 125,708-22,467,406x1, 22,536,110x2) dn, 18p11.32 (1x2, 2,842-1,227,426x3, 1,245,184x2) dn / M / de novo unbalanced translocation: der(10)t(10;18)(p12.31;p11.32) dn (22.5Mb deletion on 10p and 1.2Mb gain on 18p)
24 / complex CHD, TOF, horse shoe kidney, hydronephrosis, aberrant v. umbilicalis, polyhydramnios / N.D. / TOP / arr[hg18] 10q26.11q26.3(120,616,552x2, 120,625,378-135,280,033x1, 135,374,737x2) mat, 20p13p12.2(1x2, 11,244-10,950,532x3, 10,953,238x2) mat / S / maternally inherited derivative chromosome der(10)t(10;20)(q26.11;p12.2) mat (14.7Mb deletion in 10q and 10.9Mb gain in 20p)
25 / bilateral, enlarged, echogenic kidneys / macroglossia, hemihypertrophy / LB with anomalies / arr[hg18] 11p15.5p15.2(1x2, 193,788-15,566,164x2, 15,576,109x2) hmz pat / S / de novo homozygosity at 11p15 - mosaic partial paternal UPD 11p15 associated with Beckwith -Wiedemann syndrome
26* / IUGR, thumb malformation, suspected cardiomyopathy (thickened myocard) / dysmorphic features, increased number of mitochondria with abnormal morphology / TOP / arr[hg18] 12p13.33(1x2, 61,880-2,975,268x1, 2,980,134x2) dn, 19p13.3p13.2(1x2, 218,039-7,499,589x3, 7,499,589x2) dn / S / de novo unbalanced translocation: der(12)t(12;19)(p13.3;p13.3) dn (2.9Mb deletion at 12p13.33 and 7.3Mb gain at 19p13.3)
27 / holoprosencephaly, CHD, club hands / N.D. / IUFD / arr[hg18] 13q31.1q34(86,113,411x2, 86,117,597-114,125,098x1~2, 114,142,980x2) dn / M / de novo mosaic 28Mb terminal deletion in 13q31.1qter causing 13q deletion syndrome
28* / holoprosencephaly, club foot, dilated right atrium / Arnold Chiari type II, ambiguous genitalia, anus imperforatus, bilateral unilobar lungs, dysmorphic features / TOP / arr[hg18] 13q31.1q34(86,318,347x2, 86,318,347-114,125,098x1, 114,125,098x2) dn / M / de novo 28Mb terminal deletion on 13q causing 13q deletion syndrome
29* / IUGR, polyhydramnios / hypotonia, gastro-oesophageal reflux, PEG feeding tube, congenital hip dysplasia , constipation, apnea, amblyopia, myopia, hypothyroidism, ichthyosis, mental retardation, idiopathic thrombocytopenic purpura, dysmorphic features / LB with anomalies / arr[hg18] 14q32.13q32.31(94,789,199x2, 94,797,233-100,809,433x1, 100,814,651x2) dn / S / de novo terminal deletion 6.0Mb deletion on chr14q32
30* / NT > 3.5 mm / isomerism of the right lung, dysmorphic features / TOP / arr[hg18] 16q22.3q24.1(69,869,552x2, 69,877,147-84,633,027x1, 84,635,138x2) dn / M / de novo 14.7Mb 16q22-q24 deletion associated with failure to thrive in infancy, poor growth, delayed psychomotor development, hypotonia, and dysmorphic features, including large anterior fontanel, high forehead, diastasis of the cranial sutures, broad nasal bridge, hypertelorism, low-set abnormal ears, and short neck (OMIM 614541)
31 / ventriculomegaly / CHD / TOP / arr[hg18] 17q21.31(41,056,230x2, 41,063,083-41,560,151x1, 41,560,151x2) dn / S / de novo 0.49Mb deletion in band 17q21.31 overlapping with critical region of 17q21.31 microdeletion syndrome (Koolen-de Vries syndrome) (deletion of CRHR1, MAPT and partial deletion KANSL1). Ventriculomegaly was also observed in a fetus with this microdeletion syndrome (Tan et al. 2009).
32* / twin pregnancy:
fetus 1: no structural abnormalities
fetus 2: bowed femora / skeletal dysplasia, unilateral hydronephrosis, polyhydramnion / selective reduction / arr[hg18] 17q24.3(65,401,023x2, 65,401,023-68,139,025x1, 68,139,025x2) dn / S / de novo 2.7Mb deletion of 17q24.3 associated with campomelic dysplasia
33 / pyelectasis, CHD, Blakes Pouch cyst / N.D. / TOP / arr[hg18] 22p13q13.33(1x2, 14,550,436-49,515,911x2~3, 49,691,432x2) dn / M / de novo mosaic trisomy 22 (~50%) associated with cardiac abnormalities, microcephaly, dysmorphic features and growth retardation (Wang et al. 2007).
34* / twin pregnancy:
fetus 1: SUA, severe IUGR, echogenic bowel, pericardiac effusion
fetus 2: no structural abnormalities / cardiomegaly / IUFD / arr[hg18] 22q11.21(17,026,514x2, 17,036,495-19,792,353x1, 20,125,656x2) dn / S / de novo 2.7 Mb deletion in 22q11 overlapping with DiGeorge region
35 / jugular sacs, diaphragmatic hernia, intracranial abnormalities / anal atresia, dysmorphic features / TOP / arr[hg18] 22q11.1q11.21(14,449,498x2, 14,550,436-17,013,978x4, 17,020,300x2) dn / S / de novo tetrasomy of 22q11 associated with Cat Eye syndrome, possibly causative for the brain anomalies, but not causative for diaphragmatic hernia
36* / plexus choroideus cysts, complex CHD / N.D. / TOP / arr[hg18] 22q11.21(17,026,514x2, 17,036,495-19,792,353x1, 20,125,656x2) dn / S / de novo 2.7 Mb deletion in 22q11 overlapping with DiGeorge region
37 / NTD, SUA, clubfeet / none / LB with anomalies / arr[hg18] 22q11.21(17,026,514x2, 17,036,495-19,792,353x1, 20,125,656x2) dn / S / de novo 2.7 Mb deletion in 22q11 overlapping with DiGeorge region, possibly causative for NTD
38 / unilateral multicystic kidney dysplasia, agenesis of the left kidney, anhydramnios small thorax / small lungs, underdevelopment of the right testicle, dysmorphic features / TOP / arr[hg18] 22q11.21(17,026,514x2, 17,036,495-19,792,353x1, 20,125,656x2) mat / S / maternally inherited 2.7 Mb deletion in 22q11 overlapping with DiGeorge region
39 / complex CHD / none / LB / arr[hg18] 22q11.21(17,026,514x2, 17,036,495-19,792,353x1, 20,125,656x2) dn / S / de novo 2.7 Mb deletion in 22q11 overlapping with DiGeorge region
40 / complex CHD / none / TOP / arr[hg18] 22q11.21(17,026,514x2, 17,036,495-19,792,353x1, 20,125,656x2) dn / S / de novo 2.7 Mb deletion in 22q11 overlapping with DiGeorge region
41 / NT > 3.5 mm, SUA, IUFD / N.D. / IUFD 13 1/7 w / arr[hg18] 22q11.21(17,026,514x2, 17,036,495-19,792,353x1, 20,125,656x2) dn / S / de novo 2.7 Mb deletion in 22q11 overlapping with DiGeorge region
42* / complex CHD / none / LB with anomalies / arr[hg18] 22q11.21(18,686,993x2, 19,063,667-19,792,353x1, 20,125,656x2) pat / S / paternally inherited 1Mb deletion in 22q11 overlapped with DiGeorge region
43* / IUGR, plexus choroïdeus cysts, microcephaly, nuchal fold, echogenic focus heart, club foot / brain abnormalities / TOP / arr[hg18] 22q11.21(19,354,880x2, 19,380,552-19,792,353x1, 20,125,656x2) mat / S / maternally inherited 0.6Mb microdeletion at 22q11 (overlapping with the distal DiGeorge region)
44 / complex CHD / dysmorphic features / TOP / arr[hg18] Xq24(118,209,451x2, 118,384,922-118,654,685x0, 118,664,575x2) mat / S / maternally inherited 0.36Mb deletion in Xq24 associated with UBE2A deficiency syndrome in male patients (de Leeuw et al. 2010) and OMIM#300860) associated with ID, absent speech, seizures, urogenital anomalies, frequently including a small penis, and skin abnormalities, which include generalized hirsutism, low posterior hairline, myxedematous appearance, widely spaced nipples, hairwhorls and facial dysmorphisms. Patients with the deletion showed heart abnormalities (VSD).

Table S2. Unexpected pathogenic abnormalities found in foetuses with ultrasound anomalies after excluding common aneuploidies by RAD. They were all classified as untreatable as the abnormal phenotype cannot be prevented (in contrary to cancer risk factor or treatable metabolic disease).

Indication for invasive testing as mentioned on the request form / Additional prenatal and postnatal features diagnosed after invasive sampling / Out-come / Array finding [hg18](full description according to ICSN) / M/S / Description
1 / complex CHD / broad uvula, skeletal abnormalities / TOP / arr[hg18] 2q33.1q33.2(201,594,603x2, 201,612,711-204,341,401x1, 204,348,009x2) dn / S / early-onset untreatable disorder: de novo 2.7Mb deletion in 2q33 overlapping with 2q33.1 microdeletion syndrome associated with facial dysmorphic features, feeding problems, developmental delay, speech delay or absence, behavioral problems ('happy' personality), growth restriction and cleft or high palate (Balasubramanian et al. 2011). The deletion does not overlap with SATB2. So far no patients with this deletion were reported to have a heart defect.
2 / complex CHD / right isomerism of lungs, some renal micro cysts, abnormal cilia / TOP / arr[hg18] 15q11.2q13.1(21,234,742x2, 21,235,224-26,210,229x1, 26,217,954x2) dn / S / early-onset untreatable disorder: de novo 5.0 Mb deletion in 15q11.2q13.1 overlapping with PW/AS region, SNP analysis demonstrated loss of the maternal allele resulting in Angelman syndrome.
3 / polyhydramnios, short femur at 35 gestation weeks / birth weight 2775g, no congenital abnormalities, several airway infections, normal development / LB / arr[hg18] 22q11.21(17,026,514x2, 17,036,495-19,792,353x1, 20,125,656x2) dn / S / early-onset untreatable disorder:de novo 2.7 Mb deletion in 22q11 overlapping with the DiGeorge region.
4 / megacystis and hydronephrosis / lower urinary tract obstruction, anal atresia, underdevelopment of legs / TOP / arr[hg18] Xq26.3-q28(137,685,484x2, 137,700,451-148,610,577x0, 148,638,707x2) dn / M / early-onset untreatable disorder: de novo 10.9Mb interstitial deletion in band Xq26.3-q28 in a male fetus overlapping with (F9-Hemophilia B, FMR1, FMR2 and IDS-Hunter).
5 / CCA, mild ventriculomegaly / N.D. / TOP / arr[hg18] Yp11.32(305,562x2, 308,839-558,728x1, 563,862x2) pat / S / early-onset untreatable disorder: paternally inherited 0.25Mb deletion in Yp11.32 causing deletion of the entire SHOX gene (OMIM 312865) associated with variable phenotype (short stature, but also Leri-Weill dyschondrosteosis).

Table S3. Susceptibility loci for neurodevelopmental disorders found in foetuses with ultrasound anomalies (all submicroscopic).

Indication for invasive testing as mentioned on the request form / Additional prenatal and postnatal features diagnosed after invasive sampling / Outcome / Array finding [hg18](full description according to ICSN) / Description
1 / NT > 3.5 mm / none / LB / arr[hg18] 1q21.1q21.2(142,655,719x2, 142,655,719-147,999,901x3, 148,015,559x2) pat / paternally inherited 5Mb gain in 1q21 overlapping with both proximal 1q21 microdeletion (TAR region) and distal microduplication region; the proximal duplication is associated with DD/ID, dysmorphic features and behavioral problems and the distal duplication is associated with ID, autism spectrum disorders, schizophrenia, micro/macrocephaly, congenital heart defect and renal and urinary tract anomalies (Rosenfeld et al. 2012).
2 / NTD / none / TOP / arr[hg18] 2p16.3(50,658,979x2, 50,663,502-50,847,759x1, 50,856,110x2) dn / de novo 0.2Mb deletion in band 2p16.3 (NRXN1) associated with broad spectrum of neurodevelopmental disorders such as autism and schizophrenia (Rujescu et al. 2009; Ching et al. 2010; Schaaf et al. 2012).
3 / microcephaly, encephalocèle, polycystic kidneys, postaxial polydactyly, short long bones, abnormal position of the feet / dysmorphic features, hypoplastic lungs, CHD, ductal plate malformation in liver / TOP / arr[hg18] 15q11.2(20,305,686x2, 20,305,686-20,667,673x1, 20,667,673x2) / ca. 362kb recurrent deletion in 15q11.2 (TUBGCP5, CYFIP1, NIPA2, NIPA1) - a susceptibility locus for developmental delay, behavioral problems and epilepsy (inheritance unknown)
4* / NT > 3.5 mm / complex CHD, SUA, ear tags, dysmorphic features / TOP / arr[hg18] 15q11.2(20,305,686x2, 20,305,686-20,667,673x1, 20,667,673x2) / ca. 362kb recurrent deletion in 15q11.2 (TUBGCP5, CYFIP1, NIPA2, NIPA1) - a susceptibility locus for developmental delay, behavioral problems and epilepsy (inheritance unknown)
5 / IUFD, SUA / none / IUFD / arr[hg18] 15q11.2(20,305,686x2, 20,305,686-20,667,673x1, 20,667,673x2) / ca. 362kb recurrent deletion in 15q11.2 (TUBGCP5, CYFIP1, NIPA2, NIPA1) - a susceptibility locus for developmental delay, behavioral problems and epilepsy (inheritance unknown - parents do not wish to know whether one of them is a carrier)
6 / NT > 3.5mm / dysmorphic features / IUFD / arr[hg18] 15q11.2(20,305,686x2, 20,305,686-20,667,673x1, 20,667,673x2) mat / maternally inherited ca. 362kb recurrent deletion in 15q11.2 (TUBGCP5, CYFIP1, NIPA2, NIPA1) - a susceptibility locus for developmental delay, behavioral problems and epilepsy
7 / CHD / none / TOP / arr[hg18] 15q11.2(20,305,686x2, 20,305,686-20,667,673x1, 20,667,673x2) / approx. 362kb recurrent deletion in 15q11.2 (TUBGCP5, CYFIP1, NIPA2, NIPA1) - a susceptibility locus for developmental delay, behavioral problems and epilepsy (inheritance unknown)
8 / NT > 3.5 mm / none / LB / arr[hg18] 15q11.2(20,305,686x2, 20,305,686-20,667,673x1, 20,667,673x2) pat / paternally inherited approx. 362kb recurrent deletion in 15q11.2 (TUBGCP5, CYFIP1, NIPA2, NIPA1) - a susceptibility locus for developmental delay, behavioral problems and epilepsy
9 / NTD / unilateral agenesis musculus sternocleidomastoïdeus / TOP / arr[hg18] 15q11.2(20,305,686x2, 20,305,686-20,667,673x1, 20,667,673x2) dn / de novo approx. 362kb recurrent deletion in 15q11.2 (TUBGCP5, CYFIP1, NIPA2, NIPA1) - a susceptibility locus for developmental delay, behavioral problems and epilepsy
10* / mild ventriculomegaly, echogenic focus in left ventricle, pericardial effusion / N.D. / N.D. / arr[hg18] 15q11.2(20,305,686x2, 20,305,686-20,667,673x1, 20,667,673x2) mat / maternally inherited approx. 362kb recurrent deletion in 15q11.2 (TUBGCP5, CYFIP1, NIPA2, NIPA1) - a susceptibility locus for developmental delay, behavioral problems and epilepsy
11 / CCA, polyhydramnios / none / TOP / arr[hg18] 15q13.2q13.3(28,443,879x2, 28,714,809-30,383,373x3, 30,710,239x2) mat / maternally inherited 1.9 Mb gain at 15q13.3 (including CHRNA7), susceptibility locus for mental disability, developmental delay, hypotonia and neuropsychiatric disorders
12* / ventriculomegaly, short long bones / severe pulmonary stenosis with dilated cardiomyopathy, abnormal cerebral ventricles, hepatomegaly, contractures of the fingers, dysmorphic features, child died on the 8th day post-partum, no further examination / LB with anomalies / arr[hg18] 16p11.2(28,249,997x2, 28,392,057-29,265,749x1, 29,328,401x2) dn / de novo 1Mb deletion at 16p11.2 associated with developmental delay and obesity, but also with autism spectrum disorders, ID, speech delay and schizophrenia
13 / tumour in the face / median CL / LB with anomalies / arr[hg18] 16p11.2(28,560,820x2,28,733,106-28,949,515x3, 28,991,004x2) dn / de novo216kb gain at 16p11.2 associated with being underweight, developmental delay, ID and psychiatric disease (Jacquemont et al. 2011).
14 / twin pregnancy (fetus 1 case 14, fetus 2 case 15):
fetus 1: IUFD / CP, SUA, possibly a coarctation aortae, asymmetrical growth restriction (brainsparing) / IUFD (TTTS) / arr[hg18] 16p11.2(28,560,820x2,28,733,106-28,949,515x3, 28,991,004x2) pat / paternally inherited 216kb gain at 16p11.2 associated with being underweight, developmental delay, ID and psychiatric disease (Jacquemont et al. 2011).
15 / fetus 2 : IUFD / none / IUFD (TTTS) / arr[hg18] 16p11.2(28,560,820x2,28,733,106-28,949,515x3, 28,991,004x2) pat / paternally inherited 216kb gain at 16p11.2 associated with being underweight, developmental delay, ID and psychiatric disease (Jacquemont et al. 2011).
16 / twin pregnancy (fetus 1 case 16, fetus 2 case 17):
fetus 1: oesophageal atresia, polyhydramnios / none / LB without anomalies / arr[hg18] 16p11.2(29,241,059x2, 29,265,749-30,107,306x1, 30,235,818x2) / 1Mb deletion at 16p11.2 associated with developmental delay and obesity, but also with autism spectrum disorders, ID, speech delay and schizophrenia. (inheritance unknown - the mother is not a carrier, father not available for testing)
17 / fetus 2: IUGR, TTTS / none / LB without anomalies / arr[hg18] 16p11.2(29,241,059x2, 29,265,749-30,107,306x1, 30,235,818x2) / 1Mb deletion at 16p11.2 associated with developmental delay and obesity, but also with autism spectrum disorders ID, speech delay an schizophrenia. (inheritance unknown - the mother is not a carrier, father not available for testing)
18 / ventriculomegaly / minimal hypospadia / LB with anomalies / arr[hg18] 16p11.2(29,522,477x2, 29,535,521-30,107,306 x1, 30,235,818x2) dn / de novo 0.64Mb deletion in band 16p11.2 autism susceptibility locus for autism spectrum disorders and other neurodevelopmental and psychiatric conditions such as mental disability, schizophrenia and speech delay
19 / IUGR / none / LB / arr[hg18] 16p12.1(21,647,732x2, 21,858,916-22,338,671x1, 22,536,524x2) / 0.68Mb deletion in 16p12.1 associated with DD, learning problems and neuropsychiatric phenotypes (Girirajan et al. 2010) (inheritance unknown) not reported to parents
20 / twin pregnancy:
fetus 1: no ultrasound anomalies
fetus 2: IUGR and oligohydramnios / none / TOP / arr[hg18] 16p12.1(21,647,732x2, 21,858,916-22,338,671x1, 22,536,524x2) pat / twin pregnancy where the abnormal twin has a paternally inherited 0.68Mb deletion in 16p12.1 associated with DD, learning problems and neuropsychiatric phenotypes (Girirajan et al. 2010)
21* / occipital encephalocele, hydrothorax, hernia diafragma, Dandy Walker malformation
SUA / eventration of the diaphragm, Meckel Gruber syndrome / TOP / arr[hg18] 16p13.11(14,679,290x2, 14,960,247-16,215,852x3, 16,540,862x2) / 1.2Mb gain at 16p13.11: recurrent microduplication associated with schizophrenia, autism spectrum disorders and ADHD (Ullmann et al. 2007; Ingason et al. 2011; Girirajan et al. 2012). Recently an association with sporadic aorta dissection was published (Kuang et al. 2011) (inheritance unknown)
22 / CL, asymmetrical IUGR / CL/P / LB with anomalies / arr[hg18] 16p13.11(15,147,132x2, 15,155,584-16,215,852x1, 16,540,862x2) dn / de novo 1Mb recurrent microdeletion in 16p13.11 (MR/MCA susceptibility locus) associated with increased risk for MR/MCA and epilepsy. Possibly causative for cleft lip/palate.
23 / IUFD at term / none / IUFD / arr[hg18] 16p13.11(15,147,132x2, 15,155,584-16,215,852x3, 16,540,862x2) mat / maternally inherited 1Mb gain in band 16p13.11 associated with schizophrenia, autism spectrum disorders and ADHD (Ullmann et al. 2007; Ingason et al. 2011; Girirajan et al. 2012). Recently an association with sporadic aorta dissection was published (Kuang et al. 2011) (inheritance unknown)
24 / early IUGR / none / LB without anomalies / arr[hg18] 22q11.21(17,279,124x2, 17,281,004-19,337,485x3, 19,339,596x2) mat / maternally inherited 2 Mb gain in band 22q11.21 overlapping with the DiGeorge region, possibly causative for IUGR
25 / IUGR, complex CHD / N.D. / TOP / arr[hg18] 22q11.21q11.22(19,790,220x2, 19,792,353-21,290,419x3, 21,349,958x2) pat / paternally inherited 1.5Mb gain in band 22q11.21q11.22 overlapping with the distal DiGeorge region, possibly causative for IUGR
26 / echogenic bowel / none / LB without anomalies / arr[hg18] 22q11.23(21,996,474x2, 22,003,184-23,322,266x3, 23,409,925x2) mat / maternally inherited 1.4Mb gain in band 22q11.23 distal to the distal DiGeorge region possibly associated with mental disability, developmental delay and dysmophic features (Coppinger et al. 2009; Ribeiro-Bicudo et al. 2013).
27 / plexus choroideus cyst, congenital cystic adenomatoid malformation of the lung / low birth weight, lungsequester, earpits, abnormal helix, hearing loss / LB with anomalies / arr[hg18] 22q11.21q11.22(20,354,150x2, 20,358,124-21,355,613x3, 21,392,612x2) mat / maternally inherited 1Mb gain overlapped with distal DiGeorge region

Table S4. Incidental findings in parental samples found during quality control of the array profiles.

Number of cases / Pathogenic finding / Phenotype of the parent
3 / mosaic Turner syndrome (X/XX) / apparently normal without fertility problems
1 / mosaic interstitial deletion in 2q37.1 / a mother with a history of recurrent abortions
1 / mosaic 1q10qter gain / apparently healthy father, no signs of hematologic malignancy
1 / constitutional mosaic trisomy 8 (FISH on cheek swab cells confirmed the trisomy 8 in 43% of the analyzed interphases) / apparently healthy father, no dysmorphic features or structural anomalies;
no signs of hematologic malignancy

Abbreviations used in tables

* - cases published before in (Srebniak et al. 2011) or (Srebniak et al. 2012). The chromosomal breakpoints may slightly differ from published before as the CNVs were reanalyzed to provide minimal and maximal breakpoints according to the requirement of EJHG.

CCA – corpus callosum agenesis

CL, CL/P – cleft lip, cleft lip/palate

CHD– congenital heart disease

DD – developmental delay