Background
Methods
Study subjects
Comparative genomic hybridization or microarray analysis
Array CGH data analysis and CNV calling
Validation of CNVs by quantitative real-time PCR (qPCR)
Sequence analysis of MBD5 and ORC4
Statistical analysis
Results
Study subjects
Genome-wide copy number variation analysis
Subject | Sex | Onset of IS (month) | EEG (HYPS+/-) | Genomic location/coordinates (hg19) | Genomic event | Size | Inheritance | Candidate gene(s) |
---|---|---|---|---|---|---|---|---|
Pathogenic
| ||||||||
S100 | M | 4 | + | chr17:2,405,454-2,520,464 | Del | 115 Kb | De novo |
PAFAH1B1
|
S37 | M | 5 | + | chr1:244,961,797-247,074,490 | Del | 2.1 Mb | De novo |
HNRNPU
|
S162 | F | 6 | - | chr2:147,953,313-152,061,251 | Del | 4.1 Mb | De novo |
MBD5
|
S67 | F | 10 | + | chr1:145,764,453-147,824,207 | Dup | 2.0 Mb | De novo |
CHD1L
|
Unknown clinical significance
| ||||||||
S15 | F | 2 | + | chr10:84,222,075-85,293,140 | Dup | 1.0 Mb | Paternal |
NRG3
|
S34 | M | 5 | + | chrX:102,262,951-102,659,333 | Dup | 396 kb | Maternal |
NGFRAP1
|
S134 | F | 4 | + | chr17:14,111,754-15,442,119 | Del | 1.3 Mb | Paternal |
PMP22
|
S163 | F | 4 | + | chrX:6,451,691-8,115,193 | Dup | 1.6 Mb | Paternal |
STS,VCX3A
|
S165 | M | 5 | + | chr11:101,857,720-102,256,635 | Del | 398 kb | De novo |
YAP1
|
Probably benign
| ||||||||
S2 | M | 3 | + | chr2:216,898,976-217,160,487 | Dup | 261 kb | Not determined | |
S34 | M | 5 | + | chr2:137,826,656-138,048,583 | Dup | 221 kb | Paternal | |
S42 | M | 4 | + | chr4:48,983,002-49,063,489 | Dup | 80 kb | Paternal | |
S75 | M | 6 | + | chr6:118,989,529-120,238,639 | Dup | 1.2 Mb | Not determined | |
S133 | M | 13 | - | chr8:135,644,952-135,791,363 | Dup | 146 Kb | De novo |
Pathogenic CNVs
Clinical Features | MBD5-specific mutation20,22–24
| 2q23.1 Deletion20,22–24
| Case in this study | ||
---|---|---|---|---|---|
Number | Percentage | Number | Percentage | +, present; - absent | |
Neurological
| |||||
Development delay | 20/21 | 95% | 53/55 | 96% | + |
Language impairment | 12/21 | 57% | 38/55 | 69% | + |
Seizure | 11/21 | 52% | 32/55 | 58% | + |
Infantile spasms | 0/21 | 0 | 0/55 | 0 | + |
Infantile hypotonia | 4/21 | 19% | 23/55 | 41% | + |
Growth/Endocrine
| |||||
Short stature | 5/21 | 24% | 25/55 | 45% | - |
Local hirsutism | 0/21 | 0 | 4/55 | 7% | - |
Craniofacial abnormalities
| |||||
Coarse face | 0/21 | 0 | 3/55 | 5% | + |
Broad forehead | 3/21 | 14% | 4/55 | 7% | + |
Microcephaly | 1/21 | 5% | 26/55 | 47% | +(<2SD) |
Synophrys | 2/21 | 9% | 10/55 | 18% | +mild |
Nasal abnormalities | 7/21 | 33% | 35/55 | 64% | + |
Open mouth | 3/21 | 14% | 23/55 | 42% | + |
Downturned corners of the mouth | 3/21 | 14% | 17/55 | 31% | + |
Macroglossia or protruding tongue | 2/21 | 9% | 6/55 | 11% | - |
Dental abnormalities | 4/21 | 19% | 13/55 | 24% | |
Skeletal abnormalities
| + | ||||
Small hands and feet | 1/21 | 5% | 23/55 | 42% | + |
Clinodactyly, 5th finger | 2/21 | 9% | 22/55 | 40% | + |
Brachydactyly | 0/21 | 0 | 13/55 | 24% | + |
Short fifth digit of hands/feet | 1/21 | 5% | 14/55 | 25% | + |
Absent hallux | 0/21 | 0 | 0/55 | 0 | + |
Behaviors
| - | ||||
Autistic feature | 13/21 | 62% | 44/55 | 80% | + |
Sleep disturbance | 5/21 | 24% | 17/55 | 31% | ND |
Self-injurious behavior | 2/21 | 9% | 17/55 | 31% | + |
Other
| - | ||||
Cardiovascular abnormalities | 1/21 | 5% | 4/55 | 7% | - |
Urogenital abnormalities | 1/21 | 45% | 1/55 | 2% | - |
CNVs of unknown clinical significance
Probably benign CNVs
Discussion
CNV studies | WES (epi4K)4,18
| ||||
---|---|---|---|---|---|
No of case | This study | Mefford, et al[37] | Tiwari, et al[8] | Paciokowski, et al[7] | Epi4K Consortium & Epilepsy Phenome/Genome Project |
47 | 44 | 13 | N/A (clinical case series from diagnostic lab) | infantile spasms ( n = 149) Lennox–Gastaut syndrome (n = 115). | |
Pathogenic/Possible pathogenic CNV
|
4
|
3
|
4
|
11
| 329 de novo mutation |
De novo:
|
De novo:
|
De novo:
|
De novo:
|
Mutations in more than one proband
| |
17p13 115 kb del | Xp22 290 kb del | 15q11 4.8 Mb dup | 2p16.1 4.0 Mb del | SCN1A; STXBP1; GABRB3; | |
1q44 2.1 Mb del | 16p11. 2.5 Mb dup | 16p11.2 595 kb dela
| 3p26.3 1.6 Mb dup | CDKL5; SCN8A; SCN2A; | |
2q23.1 4.1 Mb del | 3q11 1.64 Mb dup | Xp22.11 dela,b
| 7q11.23 1.4 Mb del | ALG13; DNM1; HDAC4 | |
1q21 2.1 Mb dup | 14q12 3.3 Mb dup | ||||
Inherited:
| 14q32.3 317 kb dup |
Other candidate genes:
| |||
2q32.3 421 kb del | 15q11-q13 5.3 Mb dup | CACN1A; CHD2; FLNA; | |||
19q12 1.3 Mb del | GABRB1; GRIN1; GRIN2B; | ||||
20p13 1.9 Mb del | HNRNPU; IQSEC2; MTOR; | ||||
21q21 1.3 Mb dup | NEDD4L | ||||
21q21 1.3 Mb dup | |||||
Xp22.2 435 kb dup | |||||
Unknown
| |||||
2q24.3 21.5 Mb dup |