Table 2.
Twenty-Seven ASD Cases with De Novo Rearrangements
| FamID | Sex | Typea | Chromosomeb | Size (bp)c | CNV | Genesd | Phenotype Comments | |
|---|---|---|---|---|---|---|---|---|
| 1 | SK0181-004 | M | CHR (SPX) | 3p14.1-p13 (a) | 5,346,900 | loss | 13 genes | IQ/LOFe 78, language mod delay,f speech 2+,g RB2+,h dysmorph 3+,i congenital unilateral sensorineural hearing loss |
| t(6;14)(q13;q21) (k) | N/A | none | 11 genes | |||||
| 2 | SK0152-003 | M | CHR (MPX) | 3p25.1-p24.3 (a) | 1,409,600 | loss | 12 genes | LOF 31, RL/ELj mod/sev delay, speech 3+, RB2+, dysmorph 0, hypotonia affecting FM & GM development |
| 5p15.31-p15.2 (a) | 3,429,389 | loss | 8 genes | |||||
| 12q12 (a) | 422,842 | loss | 4 genes | |||||
| t(5;7)(p15p13) (k) | N/A | none | CDH18 | |||||
| 3 | SK0215-006 | M | CHR (SPX) | 1p21.3 (a) | 1,092,500 | loss | DPYD whole | LOF 31, language sev delay, RB3+, dysmorph N/A |
| 4 | SK0205-004 | F | CHR (SPX) | 5p15.33-p15.2 (k) | 13,800,984 | loss | 46 genes | IQ/LOF & language mild delay, RB1+, dysmorph 3+, Cri du Chat syndrome |
| 5 | SK0083-003 | M | CHR (SPX) | 7q31.1-q31.31 (k) | 11,023,507 | loss | 25 genes | IQ/LOF 56, language sev, speech 3+, RB1+, dysmorph 3+, febrile seizures |
| 6 | SK0131-003 | F | CHR (SPX) | 7q31.1-q32.2 (k) | 15,486,722 | loss | >50 genes | IQ/LOF 74, RL/EL mod/sev delay, speech 2+, RB2+, dysmorph 3+, microcephaly |
| 7 | SK0243-003 | M | CHR (SPX) | 15q23-q24.2 (k) | 4,289,500 | loss | >50 genes | LOF severely impaired, language sev delay, RB2+, dysmorph 3+, severe scoliosis, hiatal hernia |
| 8 | SK0073-003 | F | CHR (SPX) | 15q11.2-q13.3 (k) | 11,922,600 | gain | >50 genes | IQ/LOF 49, RL/EL mod delay, RB3+, dysmorph N/A, premature (34 wks), hypotonia |
| 9 | SK0245-005 | M | CHR (SPX) | 15q11.2-q13.3 (k) | 11,871,747 | gain | >50 genes | IQ/LOF 47, RL/EL sev delay, RB3+, dysmorph N/A |
| 10 | SK0218-003 | F | CHR (MPX) | 18q21.32-q23 (k) | 20,358,999 | loss | >50 genes | LOF severely impaired, RL/EL nonverbal, RB3+, dysmorph 3+, seizures, microcephaly, strabismus, hypotonia, cleft palate, club feet |
| 11 | NA0039-000 | F | CHR (SPX) | 22q13.31-q13.33 (k) | 3,231,700 | loss | 41 genes | LOF < 40, language sev delay, RB0, dysmorph 2+, hypotonia, mega cisterna magna, submucous cleft palate, single umbilical artery; father has balanced reciprocal translocation (14;22), proband inherited der(22), sister with ADHD also has unbalanced karyotype with der(14) |
| 12 | NA0097-000 | F | CHR (SPX) | Xp22.33- p22.31 (a) | 5,825,311 | loss | 21 genes+NLGN4 | IQ/LOF 117, language average, speech 2+, RB1+, dysmorph 0, carries maternal balanced reciprocal 11;12 translocation |
| 13 | SK0283-003 | F | CHR (SPX) | 47,XX, ring chr1 (k) | N/A | gain | >50 genes | IQ/LOF 30, RL/EL sev delay, RB2+, dysmorph 3+, microcephaly, blood dyscrasia, failure to thrive |
| 14 | SK0195-003 | M | CHR (SPX) | t(5;8;17)(q31.1;q24.1;q21.3) (k) | N/A | none | 5 genes | IQ/LOF unknown, language nonverbal, RB2+, dysmorph 3+, bifid uvula |
| 15 | SK0306-004 | F | SPX | 2q32.1 (a) | 97,130 | loss | None | IQ/LOF 68, RL/EL mild delay, speech 2+,i RB2+, dysmorph 3+, severe hypotonia |
| 16 | NA0002-000 | M | SPX | 7q36.2 (a) | 66,462 | loss | DPP6 exonic | IQ/LOF unknown, RL/EL sev delay, RB3+, dysmorph 0 |
| 17 | SK0262-003 | M | SPX | 8p23.3 (a) | 791,089 | gain | DLGAP2 exonic | IQ/LOF 68, RL/EL mod delay, RB4+, dysmorph N/A |
| 18 | MM0278-003 | M | SPX | 12q24.21-q24.33 (a) | 18,218,000 | gain | >50 genes | IQ/LOF 24, language sev delay, speech 1+, RB3+, dysmorph 1+, seizures; scoliosis, lower limb anomaly |
| 19 | NA0067-000 | M | SPX | 16q24.3 (a) | 265,667 | loss | ANKRD11 exonic | IQ/LOF unknown, language mod delay, RB3+, dysmorph 2+, motor delay, alloimmune ITP |
| 20 | MM0088-003 | F | MPX | 16p11.2 (a) | 675,829 | loss | 28 genes | IQ/LOF 82, RL/EL mod delay, RB3+, dysmorph 0 |
| 21 | SK0102-004 | M | SPX | 16p11.2 (a) | 432,600 | gain | 24 genes | IQ/LOF 39, RL/EL sev delay, speech 2+, RB3+, dysmorph 2+, epilepsy, scoliosis, diaphragmatic hernia |
| 22 | SK0019-004 | M | SPX | 16p11.2 (a) | 675,829 | loss | 28 genes | IQ/LOF 93, RL/EL average, speech 2+, RB3+, dysmorph 1, hyperphagia and severe obesity |
| 23 | SK0244-003 | M | SPX | 21q22.3 (a) | 353,936 | gain | 4 genes | IQ/LOF 80, RL/EL mild delay, RB1+, dysmorph N/A |
| 24 | MM0109-003 | F | SPX | 20q13.33 (a) | 1,427,661 | gain | 44 genes | IQ/LOF 27, language nonverbal, RB3+, dysmorph 1+ |
| 22q13.33 (a) | 276,702 | loss | 13 genes+SHANK3 | |||||
| 25 | SK0119-003k | M | MPX | 22q11.21 (a) | 2,771,300 | loss | >50 genes | IQ/LOF 77, RL/EL mod/sev delay, dysmorph 3+, velocardiofacial syndrome |
| 26 | SK0297-003 | M | SPX-MZ | 22q11.21 (a) | 4,281,262 | gain | >50 genes | IQ/LOF 75, RL/EL average, speech 1+, RB3+, dysmorph 2+, seizures, MZ twin (discordant for ASD) |
| 27 | SK0306-004 | F | SPX | Xp11.23-p11.22 (a) | 4,643,367 | gain | >50 genes | IQ/LOF 68, RL/EL mild delay, speech 2+, RB2+, dysmorph 3+, severe hypotonia |
Probands with abnormal karyotypes (CHR) (1–14) are separated from probands belonging to simplex (SPX) and multiplex (MPX) families with normal karyotypes (15–27). Families are grouped and sorted based on simplex (SPX), multiplex (MPX), and chromosomal abnormalities (CHR). Simplex families with affected monozygotic twins are denoted as SPX-MZ. Some cases here are also recurrent and appear in Table 3 and some of the family pedigrees are shown in Figure 2 and Figure S2. For multiplex families, the de novo events were not detected in affected siblings.
De novo event detected by either karyotype (k) or microarray (a).
All de novo CNV detected by the array were validated with qPCR, whereas translocations and larger deletions/duplications detected by karyotyping were confirmed by FISH. In all cases where an unbalanced change occurs, CNV size is based on array results. The breakpoints have not been accurately defined, and CNVs may be smaller or larger than posted.
If the CNV intersects only a single gene (suggesting that it may disrupt the gene), the term “exonic” is used, and if the CNV encompasses the entire gene, the term “whole” is used. The term “intronic” is used for CNV that overlaps noncoding parts of a single gene.
IQ/LOF, level of functioning denotes average of Vineland Social, Communication, and daily living scores and nonverbal IQ, when available.
Language was rated as average, nonverbal, mild, mod (moderately delayed), or sev (severely delayed).
Speech refers to the severity of impaired speech intelligibility, most likely resulting from oral motor apraxia (1+, mild; 2+, moderate; 3+, severe unintelligibility; or 0, intelligible speech).
RB: repetitive behavior score was derived from ADI and ADOS ratings (1+, mild; 2+, moderate; 3+, severe repetitive behaviors; or 0, no repetitive behaviors).
Dysmorphology scores were based on anthropometric measurement abnormalities and qualitative features documented either by a clinical geneticist or a developmental pediatrician. Anomalies were reviewed by a single clinical geneticist and assigned score: 0, not dysmorphic; 1+, mild; 2+, moderate; 3+, severe degree of dysmorphism. Children with known genetic syndromes received a score of 3+. N/A, not assessed for dysmorphic features.
RL, receptive language; EL, expressive.
SK0119-003 originally entered the study with an ASD diagnosis but upon re-examination after CNV detection was assessed to be below cutoffs for ASD.