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.
Note: The entry will be online only after author check and submit it.
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] |
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] |
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] |
Apert syndrome | #101200 | FGFR2 | 10q26.13 | chr10: 121,479,857–121,598,403 | Acrocephaly, micrognathia, limb malformations | [50] |
Denys-Drash syndrome, Meacham syndrome | #194080, #608978 | WT1 | 11p13 | chr11: 32,389,058–32,435,360 | Male pseudohermaphroditism, cardiac abnormalities | [51,52] |
Kabuki syndrome | #147920 | KMT2D | 12q13.12 | chr12: 49,018,978–49,060,794 | Mental retardation, short stature, eversion of eyelids, finger pads | [14,43,44,53] |
Marfan syndrome Type 1 | #154700 | FBN1 | 15q21.1 | chr15: 48,408,313–48,645,709 | Congenital contractures, arachnodactyly, aortic dilatation, cardiac valve insufficiency | [14,54] |
Geleophysic dysplasia 2 | #614185 | FBN1 | 15q21.1 | chr15: 48,408,313–48,645,709 | Short stature, cardiac valvular thickening, skin thickening, joint problems | [17] |
Rubinstein-Taybi syndrome 2 | #613684 | EP300 | 22q13.2 | chr22: 41,092,592–41,180,077 | Failure to thrive, cardiovascular abnormalities, motor and speech delays, dysmorphic facial features | [14,55] |
Focal dermal hypoplasia | #305600 | PORCN | Xp11.23 | chrX: 48,508,992–48,520,808 | Sparse hair, anophtalmia, limb malformations, Pentalogy of Cantrell | [42] |
Craniofrontonasal syndrome | #304110 | EFNB1 | Xq13.1 | chrX: 68,829,021–68,842,160 | Coronal craniosynostosis, duplex thumb, partial agenesis of corpus callosum | [41] |
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 |
SLC5A9 | 1p33 | chr1: 48,222,716–48,248,638 | 1 | [14] | trio WES |
ZNF362 | 1p35.1 | chr1: 33,256,492–33,300,719 | 1 | [17] | trio WES/WGS |
HSPG2 | 1p36.12 | chr1: 21,822,244–21,937,310 | 1 ° | [17] | trio WES |
UBAP2L | 1q21.3 | chr1: 154,220,955–154,270,847 | 1 | [17] | trio WGS |
POGZ | 1q21.3 | chr1: 151,402,724–151,459,494 | 1 | [12] | clinical WES |
DISP1 | 1q41 | chr1: 222,815,039–223,005,995 | 1 | [27] | targeted sanger sequencing |
INHBB | 2q14.2 | chr2: 120,346,136–120,351,803 | 1 | [14] | trio WES |
TTC21B | 2q24.3 | chr2: 165,873,362–165,953,776 | 1 | [17] | trio WGS |
ROBO1 | 3p12.3 | chr3: 78,598,688–79,019,015 | 1 | [17] | targeted panel sequencing |
FOXP1 | 3p13 | chr3: 70,954,708–71,583,978 | 1 | [15] | clinical WES |
RAF1 | 3p25.2 | chr3: 12,583,601–12,664,117 | 1 | [12] | trio WES/WGS |
FAT4 | 4q28.1 | chr4: 125,314,955–125,492,932 | 1 | [17] | trio WGS |
CDO1 | 5q22.3 | chr5: 115,804,733–115,816,659 | 1 | [14] | trio WES |
FOXP4 | 6p21.1 | chr6: 41,546,426–41,602,384 | 1 | [12] | trio WES/WGS |
PTPN12 | 7q11.23 | chr7: 77,537,295–77,640,069 | 1 | [14] | trio WES |
BRAF | 7q34 | chr7: 140,719,327–140,924,810 | 1 | [12] | trio WES/WGS |
GATA4 | 8p23.1 | chr8: 11,704,202–11,760,002 | 3 | [17,22,56] | targeted sanger sequencing, trio WGS |
EYA1 | 8q13.3 | chr8: 71,197,511–71,548,061 | 1 | [11,57] | WES, targeted panel sequencing |
TLN1 | 9p13.3 | chr9: 35,696,948–35,732,195 | 1 ° | [17] | trio WES |
PLPP6 | 9p24.1 | chr9: 4,662,294–4,665,258 | 1 | [14] | trio WES |
NOTCH1 | 9q34.3 | chr9: 136,494,433–136,546,048 | 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 | [12,17,61,62,63] | 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 | chr14: 53,949,736–53,956,825 | 1 | [64] | targeted sanger sequencing |
DLST | 14q24.3 | chr14: 74,881,916–74,903,743 | 1 | [14] | trio WES |
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 | [16,17,21,57,65] | clinical WES, targeted panel sequencing, trio WES, trio WGS |
TRAF7 | 16p13.3 | chr16: 2,155,782–2,178,129 | 1 | [15] | clinical WES |
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 |
EPB41L1 | 20q11.23 | chr20: 36,092,712–36,230,343 | 1 | [12] | trio WES/WGS |
ARFGEF2 | 20q13.13 | chr20: 48,921,711–49,036,693 | 1 | [14] | trio WES |
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 |
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] | trio WES |
ATAD3A | 1p36.33 | chr1: 1,512,175–1,534,685 | 1 | [12] | trio WES/WGS |
POGZ | 1q21.3 | chr1: 151,402,724–151,459,494 | 1 | [12] | trio WES/WGS |
KDM5B | 1q32.1 | chr1: 202,724,495–202,808,421 | 1 | [12] | trio WES/WGS |
ZBTB18 | 1q44 | chr1: 244,051,283–244,057,476 | 1 | [12] | trio WES/WGS |
MYT1L | 2p25.3 | chr2: 1,789,124–2,331,348 | 1 | [12] | trio WES/WGS |
FOXP1 | 3p13 | chr3: 70,954,708–71,583,978 | 1 | [12] | trio WES/WGS |
SRGAP3 | 3p25.3 | chr3: 8,980,594–9,249,213 | 1 | [12] | trio WES/WGS |
KPNA1 | 3q21.1 | chr3: 122,421,902–122,514,939 | 1 | [17] | trio WGS |
NAA15 | 4q31.1 | chr4: 139,301,505–139,391,384 | 1 | [12] | trio WES/WGS |
SMO | 7q32.1 | chr7: 129,188,633–129,213,545 | 1 | [12] | trio WES/WGS |
GATA4 | 8p23.1 | chr8: 11,704,202–11,760,002 | 1 | [57] | targeted panel sequencing |
ZFPM2 | 8q23.1 | chr8: 105,318,438–105,804,539 | 3 | [12,23,68] | WES, trio WES/WGS, targeted sanger sequencing |
EMX2 | 10q26.11 | chr10: 117,542,746–117,549,546 | 1 | [12] | trio WES/WGS |
WT1 | 11p13 | chr11: 32,389,058–32,435,360 | 3 | [12,16] | trio WES/WGS |
PTPN11 | 12q24.13 | chr12: 112,419,112–112,504,764 | 3 | [12,16,17] | trio WES/WGS |
MEIS2 | 15q14 | chr15: 36,889,204–37,100,549 | 1 | [12] | trio WES/WGS |
TBX6 | 16p11.2 | chr16: 30,085,793–30,091,924 | 1 | [11] | WES |
CTCF | 16q22.1 | chr16: 67,562,467–67,639,176 | 1 | [17] | trio WGS |
AP1G1 | 16q22.2 | chr16: 71,729,000–71,808,834 | 1 | [12] | trio WES/WGS |
MYH10 | 17p13.1 | chr17: 8,474,207–8,630,761 | 1 | [17] | targeted panel sequencxing |
SRSF1 | 17q22 | chr17: 58,000,919–58,007,246 | 1 | [17] | trio WGS |
LONP1 | 19p13.3 | chr19: 5,691,835–5,720,572 | 2 | [17] | trio WGS |
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 |
HSD17B10 | Xp11.22 | chrX: 53,431,261–53,434,370 | 1 | [12] | trio WES/WGS |
FLNA | Xq28 | chrX: 154,348,529–154,371,283 | 1 | [17] | trio WGS |
This entry is adapted from the peer-reviewed paper 10.3390/genes12091405