The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number variations (CNVs), and variants in a large panel of CDH-associated genes, both de novo and inherited, have been described. Due to impaired reproductive fitness, especially of syndromic CDH patients, and still significant mortality rates, the contribution of de novo variants to the genetic background of CDH is assumed to be high. This assumption is supported by the relatively low recurrence rate among siblings. Advantages in high-throughput genome-wide genotyping and sequencing methods have recently facilitated the detection of de novo variants in CDH.
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Syndrome | OMIM | Gene | Chromosomal Location | Genomic Coordinates (GRCh38/hg38) | Additional Malformations | References | |
---|---|---|---|---|---|---|---|
PDAC syndrome | #615524 | RARB | 3p24.3 | chr3: 25,428,263–25,597,932 | Micro-/Anophtalmia, pulmonary hypoplasia, cardiac abnormalities | [45] | |
Cornelia de Lange syndrome | #122470 | NIPBL | 5p13.2 | chr5: 36,876,769–37,066,413 | Hypertelorism, synophrys, low anterior hairline, upper limb malformations | [40,46,47] | [40][46][47] |
Coffin-Siris syndrome | #135900, #614609 | ARID1B, SMARCA4 | 6q25.3 | chr6: 156,776,020–157,210,779 chr19: 10,961,001–11,062,256 |
Growth retardation, long eyelashes, frequent respiratory tract infections, hypotonia, developmental delay | [14,48] | [14][48] |
Congenital heart defects and skeletal malformations syndrome (CHDSKM) | #617602 | ABL1 | 9q34.12 | chr9: 130,713,016–130,885,683 | Dysmorphic facial features, congenital heart disease, skeletal abnormalities, joint laxity, failure to thrive, gastrointestinal problems, male genital anomalies | [14,49] | [14][49] |
Gene | Chromosomal Location | Genomic Coordinates (GRCh38/hg38) | Number of Cases with | de novo | Variants | References | Design/Method of Studies |
---|---|---|---|---|---|---|---|
PRKACB | 1p31.1 | chr1: 84,078,062–84,238,498 | 1 | [14] | trio WES | ||
targeted sanger sequencing | |||||||
DLST |
Gene | Chromosomal Location | Genomic Coordinates (GRCh38/hg38) | Number of Cases with | de novo | Variants | References | Design/Method of Studies | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
HSPG2 | 1p36.12 | chr1: 21,822,244–21,937,310 | 2 | [13,14] | [13][14] | trio WES | |||||||
SLC5A9 | 1p33 | chr1: 48,222,716–48,248,638 | 1 | [14] | trio WES | ||||||||
ATAD3A | 1p36.33 | chr1: 1,512,175–1,534,685 | 1 | [12] | trio WES/WGS | ZNF362 | 1p35.1 | chr1: 33,256,492–33,300,719 | 1 | [17] | trio WES/WGS | ||
POGZ | 1q21.3 | chr1: 151,402,724–151,459,494 | 1 | [12] | trio WES/WGS | HSPG2 | 1p36.12 | chr1: 21,822,244–21,937,310 | 1 ° | [17] | trio WES | ||
KDM5B | 1q32.1 | chr1: 202,724,495–202,808,421 | 1 | [12] | trio WES/WGS | Apert syndrome | #101200 | FGFR2 | 10q26.13 | ||||
UBAP2L | 1q21.3 | chr1: 154,220,955–154,270,847 | 1 | chr10: 121,479,857–121,598,403 | [17Acrocephaly, micrognathia, limb malformations | ] | trio WGS[50] | ||||||
trio WES/WGS | Denys-Drash syndrome, Meacham syndrome | #194080, #608978 | WT1 | 11p13 | chr11: 32,389,058–32,435,360 | Male pseudohermaphroditism, cardiac abnormalities | [51,52] | [51][52] | |||||
POGZ | 1q21.3 | chr1: 151,402,724–151,459,494 | 1 | [12] | |||||||||
MYT1L | 2p25.3 | chr2: 1,789,124–2,331,348 | clinical WES | 1 | [12] | trio WES/WGS | Kabuki syndrome | #147920 | KMT2D | 12q13.12 | chr12: 49,018,978–49,060,794 | Mental retardation, short stature, eversion of eyelids, finger pads | [ |
DISP1 | 1q41 | 14 | chr1: 222,815,039–223,005,995 | , | 43 | ,44, | [43][44 | 53] | 1[ | [27]14]] | |||
FOXP1 | 3p13 | targeted sanger sequencing | chr3: 70,954,708–71,583,978 | [ | 53 | 1] | |||||||
[ | 12 | ] | trio WES/WGS | Marfan syndrome Type 1 | #154700 | FBN1 | 15q21.1 | chr15: 48,408,313–48,645,709 | Congenital contractures, arachnodactyly, aortic dilatation, cardiac valve insufficiency | [14 | |||
INHBB | |||||||||||||
SRGAP3 | 2q14.2 | chr2: 120,346,136–120,351,803 | 1 | [14] | trio WES | ,54] | [14][54] | ||||||
3p25.3 | chr3: 8,980,594–9,249,213 | 1 | [ | 12] | trio WES/WGS | Geleophysic dysplasia 2 | #614185 | FBN1 | 15q21.1 | chr15: 48,408,313–48,645,709 | Short stature, cardiac valvular thickening, skin thickening, joint problems | ||
TTC21B | 2q24.3 | [ | 17 | ] | |||||||||
chr2: 165,873,362–165,953,776 | 1 | [ | 17 | ] | trio WGS | Rubinstein-Taybi syndrome 2 | |||||||
KPNA1 | 3q21.1 | chr3: 122,421,902–122,514,939 | 1 | [17] | trio WGS | #613684 | EP300 | 22q13.2 | chr22: 41,092,592–41,180,077 | Failure to thrive, cardiovascular abnormalities, motor and speech delays, dysmorphic facial features | [ | ||
ROBO1 | 3p12.3 | chr3: 78,598,688–79,019,015 | 14 | 1 | [17] | ,55] | [14][55] | ||||||
targeted panel sequencing | |||||||||||||
NAA15 | 4q31.1 | chr4: 139,301,505–139,391,384 | 1 | [12] | trio WES/WGS | Focal dermal hypoplasia | #305600 | PORCN | Xp11.23 | chrX: 48,508,992–48,520,808 | Sparse hair, anophtalmia, limb malformations, Pentalogy of Cantrell | ||
FOXP1 | 3p13 | chr3: 70,954,708–71,583,978 | 1 | [15] | [ | 42] | |||||||
clinical WES | |||||||||||||
SMO | 7q32.1 | chr7: 129,188,633–129,213,545 | Craniofrontonasal syndrome | #304110 | EFNB1 | Xq13.1 | chrX: 68,829,021–68,842,160 | Coronal craniosynostosis, duplex thumb, partial agenesis of corpus callosum | |||||
1 | [ | 12 | ] | RAF1 | 3p25.2 | [41] |
trio WES/WGS | ||||||||||||
chr3: 12,583,601–12,664,117 | ||||||||||||
1 | ||||||||||||
[ | ||||||||||||
12 | ||||||||||||
] | ||||||||||||
trio WES/WGS | ||||||||||||
14q24.3 | ||||||||||||
chr14: 74,881,916–74,903,743 | ||||||||||||
1 | ||||||||||||
[ | ||||||||||||
14 | ||||||||||||
] | ||||||||||||
GATA4 | 8p23.1 | chr8: 11,704,202–11,760,002 | 1 | [57] | targeted panel sequencing | FAT4 | 4q28.1 | chr4: 125,314,955–125,492,932 | 1 | [ | ||
ZFPM2 | 17 | ] | 8q23.1 | chr8: 105,318,438–105,804,539 | 3 | [12,23,68] | [12trio WGS | |||||
] | [ | 23 | ] | [68] | WES, trio WES/WGS, targeted sanger sequencing | CDO1 | 5q22.3 | chr5: 115,804,733–115,816,659 | 1 | [14] | trio WES | |
FOXP4 | 6p21.1 | chr6: 41,546,426–41,602,384 | ||||||||||
EMX2 | 10q26.11 | chr10: 117,542,746–117,549,546 | 1 | [121 | [12] | trio WES/WGS | ||||||
PTPN12 | 7q11.23 | chr7: 77,537,295–77,640,069 | 1 | [14] | trio WES | |||||||
] | trio WES/WGS | |||||||||||
WT1 | 11p13 | chr11: 32,389,058–32,435,360 | 3 | [12,16] | [12][16] | trio WES/WGS | ||||||
PTPN11 | 12q24.13 | chr12: 112,419,112–112,504,764 | 3 | [12,16,17] | [12][16][17] | trio WES/WGS | BRAF | 7q34 | chr7: 140,719,327–140,924,810 | 1 | [12] | trio WES/WGS |
trio WES | ||||||||||||
MEIS2 | 15q14 | chr15: 36,889,204–37,100,549 | 1 | [12] | trio WES/WGS | GATA4 | 8p23.1 | chr8: 11,704,202–11,760,002 | 3 | [17,22,56] | [17][22][56] | targeted sanger sequencing, trio WGS |
TBX6 | 16p11.2 | chr16: 30,085,793–30,091,924 | 1 | [11] | WES | EYA1 | 8q13.3 | chr8: 71,197,511–71,548,061 | 1 | [11,57] | [11][57] | WES, targeted panel sequencing |
CTCF | 16q22.1 | chr16: 67,562,467–67,639,176 | 1 | [17] | trio WGS | TLN1 | 9p13.3 | chr9: 35,696,948–35,732,195 | 1 ° | [17] | trio WES | |
AP1G1 | 16q22.2 | chr16: 71,729,000–71,808,834 | 1 | PLPP6 | 9p24.1 | chr9: 4,662,294–4,665,258 | 1 | [14] | trio WES | |||
[ | 12 | ] | trio WES/WGS | |||||||||
MYH10 | 17p13.1 | chr17: 8,474,207–8,630,761 | 1 | [17] | NOTCH1 | 9q34.3 | chr9: 136,494,433–136,546,048 | 1 | [17] | trio WGS | ||
targeted panel sequencxing | ||||||||||||
SRSF1 | 17q22 | chr17: 58,000,919–58,007,246 | 1 | [17] | trio WGS | CTR9 | 11p15.3 | chr11: 10,751,246–10,779,746 | 1 * | [16] | trio WES | |
MYRF | 11q12.2 | chr11: 61,752,636–61,788,518 | 11 | [12,17,61,62, | [17][61 | 63] | [12]][62][63] | trio WES/WGS, clinical WES, trio WGS | ||||
PTPN11 | 12q24.13 | chr12: 112,419,112–112,504,764 | 1 | [12] | trio WES/WGS | |||||||
HNRNPC | 14q11.2 | chr14: 21,210,613–21,269,421 | 1 | [17] | trio WGS | |||||||
BMP4 | 14q22.2 | TCF12 | 15q21.3 | chr15: 56,918,644–57,289,853 | 1 | [15] | clinical WES | |||||
SIN3A | 15q24.2 | chr15: 75,370,933–75,455,783 | 1 | [14] | trio WES | |||||||
NR2F2 | 15q26.2 | chr15: 96,330,700–96,340,258 | 4 | [16,17,21,57, | ||||||||
LONP1 | 19p13.3 | chr19: 5,691,835–5,720,572 | 2 | [17] | trio WGS | 65 | ||||||
CIC | 19q13.2 | chr19: 42,268,537–42,295,796 | 1 | [12] | trio WES/WGS | |||||||
LAMA5 | 20q13.33 | chr20: 62,309,065–62,367,312 | 1 | [12] | trio WES/WGS | |||||||
DIDO1 | 20q13.33 | chr20: 62,877,738–62,937,952 | 1 | [12] | trio WES/WGS | chr14: 53,949,736–53,956,825 | 1 | |||||
HSD17B10 | Xp11.22 | [ | chrX: 53,431,261–53,434,370 | 64] | 1 | [12] | trio WES/WGS | |||||
FLNA | Xq28 | chrX: 154,348,529–154,371,283 | 1 | [17] | ] | [16][17][21][57][65] | clinical WES, targeted panel sequencing, trio WES, trio WGS | |||||
TRAF7 | 16p13.3 | chr16: 2,155,782–2,178,129 | 1 | [15] | clinical WES | |||||||
trio WGS | ANKRD11 | 16q24.3 | chr16: 89,285,175–89,490,318 | 1 | [17] | trio WGS | ||||||
MYH10 | 17p13.1 | chr17: 8,474,207–8,630,761 | 1 | [66] | clinical WES | |||||||
TP53 | 17p13.1 | chr17: 7,668,421–7,687,490 | 1 * | [16] | trio WES | |||||||
NLK | 17q11.2 | chr17: 28,042,677–28,196,381 | 1 | [17] | trio WGS | |||||||
FZD2 | 17q21.31 | chr17: 44,557,484–44,561,262 | 1 | [32] | aCGH | |||||||
ATXN7L3 | 17q21.31 | chr17: 44,191,805–44,198,070 | 1 | [17] | trio WGS | |||||||
ALYREF | 17q25.3 | chr17: 81,887,835–81,891,586 | 1 | [12] | trio WES/WGS | |||||||
GATA6 | 18q11.2 | chr18: 22,169,589–22,202,528 | 1 | [67] | trio WES | |||||||
NACC1 | 19p13.13 | chr19: 13,118,264–13,141,147 | 1 | [12] | trio WES/WGS | |||||||
LONP1 | 19p13.3 | chr19: 5,691,835–5,720,572 | 1 | [14] | trio WES | |||||||
LTBP4 | 19q13.2 | chr19: 40,601,369–40,629,818 | 1 | [38] | targeted sanger sequencing | |||||||
ZC3H4 | 19q13.32 | chr19: 47,064,187–47,113,776 | 1 | [12] | trio WES/WGS | |||||||
PCNA | 20p12.3 | chr20: 5,114,953–5,126,626 | 1 | [12] | trio WES/WGS | |||||||
chr20: 36,092,712–36,230,343 | 1 | [ | 12 | ] | trio WES/WGS | |||||||
ARFGEF2 | ||||||||||||
ZBTB18 | 1q44 | 20q13.13 | chr20: 48,921,711–49,036,693 | 1 | [14] | trio WES | ||||||
chr1: 244,051,283–244,057,476 | 1 | [ | 12 | ] | EPB41L1 | 20q11.23 | ADNP | 20q13.13 | chr20: 50,888,918–50,931,437 | 1 | [17] | trio WGS |
SCAF4 | 21q22.11 | chr21: 31,671,000–31,732,118 | 1 | [17] | trio WGS | |||||||
DDX3X | Xp11.4 | chrX: 41,333,348–41,350,287 | 1 | [15] | clinical WES | |||||||
USP9X | Xp11.4 | chrX: 41,085,445–41,236,579 | 1 ° | [17] | trio WES/WGS | |||||||
CLCN4 | Xp22.2 | chrX: 10,156,975–10,237,660 | 1 | [14] | trio WES | |||||||
HCCS | Xp22.2 | chrX: 11,111,301–11,123,078 | 1 | [15] | clinical WES | |||||||
STAG2 | Xq25 | chrX: 123,961,314–124,102,656 | 1 | [14] | trio WES |