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Novel Genetic Mechanisms of Congenital Diaphragmatic Hernia

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Novel Genetic Mechanisms of Congenital Diaphragmatic Hernia 3/8/2019 Congenital diaphragmatic hernia • 1 in 3000 births Novel genetic mechanisms of congenital • 8% of all birth defects diaphragmatic hernia • Annual US cost is $158 million • 20%-40% mortality • 40% -50% Non-isolated Wendy Chung, MD PhD Kennedy Family Professor of Pediatrics and Medicine - Up to 25% with CHD Columbia University - Developmental delay/ID common DHREAMS protocol • Birth cohort L CDH • Neonates affected with diaphragm defects • Samples from affected case and both biological parents (Trio collection) • Developmental assessments at 2 and 5 years • Retrospective cohort • Children and adults with a personal history of a diaphragm defect • Samples from affected case and both biological parents (Trio collection) • Genetic analysis Chongqing Three Gorges • Natural history studies Central Hospital 1 3/8/2019 Study protocol Genetic Evidence for CDH • Eligible subjects • Children and fetuses • Familial aggregation • Protocol • Higher rate of concordance in monozygotic v.s. dizygotic twins • Collection of blood from proband and biological parents • Mouse studies elucidated the role of several genes in • Over 100 data points on prenatal history, NICU stay, surgical report, and family history diaphragm development • Prospective cohort • Coup-TFII, Slit3, Gata4, Fog2, Wt1 • Collection of skin and diaphragm at time of surgery • Pulmonary Hypertension assessment at 1 and 3 months • Chromosome anomalies (10-30%) • 2 year developmental assessment • T21, T18, T13, tetrasomy12p, 15q26, 8p23.1, 1q41-q42 • Vineland Adaptive Behavior Scale II • • Bayley Scales of Infant Development III Single gene disorder (15-??%) • 5 year developmental assessment • Donnai-Barrow syndrome (LRP2 2q31), Mathew-Wood syndrome • Vineland Adaptive Behavior Scale II (STRA6 15q24), Denys-Drash (WT1, 11q13) • Child Behavior Check List, Parent and Teacher • GATA6, GATA4, ZFPM2 and others • Wechsler Preschool and Primary Scale of Intelligence IV Published Current Study Duplication Deletion Deletions of 8p23.1 associated with CDH p15 Translocation/ inversion a 4 3 8p23.1 8p21.2 p12=-3.3 P22.3 9 p23.1 p23.1 5 4 pter-p22 3M 6M 9M12M 15M 18M 21M p21 2 8,043,620 11,883,409 p13 01-0162 192,262 15,227,167 07-0010 7 3 q25-q31.2 q22 4 4 3 3 7,256,229 12,077,383 q31 q22-q23 Wat et al., 2009 [51] 6,504,084 12,752,448 4 2 q41-q42 2 7 4 Slavotinek et al., 2005 [53] q37 q35.2 trisomy q25.3-qter q23.3-q25 q23.3-qter 6,365,021 Chr1 Chr2 Chr3 Chr4 Chr5 Chr6 Chr7 Chr8 Chr9 Chr10 Chr11 12,611,673 Shimokawa et al., 2005 [16] 17,870,612 Faivre et al., 1998 [54] pks p11-13 ERI1 PRSS55 PINX1 CLDN23 TNKS SLC35G5 p13.11-p12.3 RP1L1 FDFT1 SGK223 MFHAS1 XKR6 BLK DEFB135 p12.3 PPP1R3B C8orf74 q12 MTMR9 CTSB MSRA FAM167A GATA4 DEFB136 q11.1-11.21 NEIL2 pter-q11 SOX7 26 q33.3-q34 3 q26 q32-qter trisomy Chr12 Chr13 Chr14 Chr15 Chr16 Chr17 Chr18 Chr19 Chr20 Chr21 trisomy Chr22 2 3/8/2019 GATA4 information p.R252W p.R283H p.N248S p.M247T c.754C>T c.848G>A p.Y244S p.N239S p.N285K p.A411V p.D425N Whole exome sequencing in familial CDH p.S70T p.P87S p.N239D p.R252P p.Q316E p.G234S p.C292R p.S429T p.G69D p.S90R p.R320W p.P407Q p.R229S p.T280M p.A294V p.G64E p.G93A c.755G>C p.G296R p.S52F p.M223T p.K329N p.H436Y p.D95A p.G221R p.I255T p.N273S p.G296S p.H28Y p.G296C p.E359K p.H28D p.S160T p.E216D p.L261P p.T277I p.L403M p.A442V p.G21V p.P163R p.F214S p.C271R p.H302R p.T354A p.G16C p.P163S p.F211L p.V267M p.V380M p.R260Q p.M310V p.A346V p.A6V p.F208L p.R266X Exon Exon1 Exon2 Exon3 Exon4 Exon6 Exon7 1 Exon5 1 615 616 783 784 909 910 997 998 1146 1147 1329 c.69_374dupTGCCGC c.341_342insA c.677delC c.1074delC c.1075delG c.366_368dupCGC c.139_141delTCC NZnF CZnF GATA GATA 1 206 211 261 265 315 442 p.R252W p.R283H 240 295 Human ACGLYHKMNGI NRPLI KPQRRLSASRRVGLSCANCQTTTTTL WRRNAEGEPVCNAC Chimpanzee ACGLYHKMNGI NRPL I KPQRRL SASRRVGL SCANCQTTTTTL WRRNAEGEPVCNAC Rhesus ACGLYHKMNGI NRPLI KPQRRLSASRRVGLSCANCQTTTTTL WRRNAEGEPVCNAC Mouse ACGLYHKMNGI NRPLI KPQRRLSASRRVGLSCANCQTTTTTL WRRNAEGEPVCNAC Rat ACGLYHKMNGI NRPLI KPQRRLSASRRVGLSCANCQTTTTTL WRRNAEGEPVCNAC Rabbit ACGLYHKMNGI NRPLI KPQRRLSASRRVGLSCANCQTTTTTL WRRNAEGEPVCNAC Dolphin ACGLYHKMNGI NRPLI KPQRRLSASRRVGLSCANCQTTTTTL WRRNAEGEPVCNAC Elephant ACGLYHKMNGI NRPLI KPQRRLSASRRVGLSCANCQTTTTTL WRRNAEGEPVCNAC Opossum ACGLYHKMNGI NRPLI KPQRRLSASRRVGLSCANCQTTTTTL WRRNAEGEPVCNAC Chicken ACGLYHKMNGI NRPLFKPQRRLSASRRVGLSCANCHTTTTTL WRRNAEGEPVCNAC X.tropicalis ACGLYHKMNGI NRPL I KPQRRL SASRRVGL SCANCHTTTTTL WRRNAEGEPVCNAC Zebrafish ACGLYHKMNGI NRPLVKPQRRLSASRRVGLSCTNCQTTTTTL WRRNAEGEPVCNAC 3 3/8/2019 A GATA4 I 1 2 +/+ • A zinc finger transcription factor that controls gene expression and differentiation in a variety of cell types. • Located at 8p23.1-p22 where there is a recurrent II microdeletion associated with both congenital heart disease and CDH (Wat et al. 2009). 1 +/+ 2 +/+ 3 +/- 4 +/+ • GATA4 is an important component of the retinoic signaling pathway. • ~14% of mice with heterozygous Gata4+/Δex2 had diaphragm III defects and ~36% had cardiac defect. (Jay et al. 2007). 1 2 +/+ 3 4 +/- 5 +/+ • The N-terminal zinc finger of GATA4 interacts with FOG2 during cardiac morphogenesis (Crispino et al. 2001). FOG2 is an important gene in diaphragm development (Ackerman et al. IV 2005). GATA4 c.754 C>T p.R252W genotype 1 +/- 2 +/+ III.4 Father A B III.4 Father Not all Genetic Conditions Run in Families De novo mutations are common in autism, schizophrenia, intellectual disabilities, seizures, birth defects, syndromes C D II.3 Grandfather II.3 Grandfather 4 3/8/2019 Number Percent Gender Male 212 58.6% Female 150 41.4% Characteristics CDH classification Types of Genetic Variants of CDH Isolated 208 57.5% Complex 149 41.2% Original DNA code patients Unknown 5 1.4% DHREAMS cohort (n=283): Time of recruitment DNA Bases -> C A G C A G C A G C A G C A G C A G C A G Neonatal 229 80.9% (n=362) Fetal 9 3.2% Amino acids -> Gln Gln Child 45 15.9% Gln Gln Gln Gln Gln Discharge vital status (n=283) Survived 241 85.2% Deceased 42 14.8% Development assessment¶ (n=283) Deleterious missense (D-mis) Likely Gene Disrupting (LGD) At 2 years follow-up 152 53.7% At 5 years follow-up 70 24.7% No assessment at either 2 or 5 years 128 45.2% Additional anomalies in complex cases (n=149) C A G C A G C G G C A G C A G C A G C A G C A G C A G U A G Cardiovascular 66 44.3% § Neurodevelopmental 37 24.8% Gln Gln Arg Gln Gln Gln Gln Gln Gln STOP Skeletal 26 17.4% Genitourinary 14 9.4% Gastrointestinal 13 8.7% Burden of coding LGD and damaging de novo Higher enrichment of damaging variants in complex variants in CDH patients cases and female cases Number of Baseline Fold Case group Variant class Number of variants Baseline expectation Fold enrichment P-value Gene Sets Variant class P-value variants expectation enrichment Complex Silent 44 44.9 0.98 0.57 Synonymous 110 109.1 1.01 0.48 (n=149) Missense 124 103.1 1.2 0.025 Missense 295 250.6 1.18 3.42E-03 D-mis 62 38.5 1.61 3.08E-04 All Genes LGD 23 13.5 1.7 0.012 D-mis 138 93.7 1.47 1.08E-05 Isolated Silent 63 62.7 1.01 0.5 LGD 57 32.9 1.73 8.60E-05 (n=208) Missense 165 144 1.15 0.046 Synonymous 34 38.8 0.88 0.80 D-mis 74 53.8 1.38 5.22E-03 Constrained Missense 112 88.1 1.27 7.91E-03 LGD 31 18.9 1.64 6.52E-03 Genes D-mis 59 38.0 1.55 9.39E-04 Female Silent 44 45.9 0.96 0.63 LGD 30 12.0 2.50 9.05E-06 (n=150) Missense 118 105.6 1.12 0.12 Synonymous 76 70.3 1.08 0.26 D-mis 64 39.3 1.63 1.85E-04 Missense 184 162.6 1.13 0.053 Other Genes LGD 29 13.9 2.09 2.51E-04 D-mis 80 55.7 1.44 1.28E-03 Male Silent 66 63.2 1.04 0.38 LGD 27 20.9 1.29 0.11 (n=212) Missense 177 145.1 1.22 5.63E-03 D-mis 74 54.3 1.36 6.45E-03 LGD 28 19 1.47 0.032 5 3/8/2019 Genes with recurrent de novo LGD or missense MYRF is a new syndromic CDH gene associated with pulmonary hypertension and pulmonary hypoplasia Sample Genetic De novo variant Diaphragm Study Cardiovascular defect Urogenital defect Other malformations variants ID Sex# (NM_001127392.2) defect c.235dupG: 01-1008 XY L-CDH ASD,VSD,ToF Bilateral undescended testes No p.G81Wfs*45 c.1303G>A:p.G435 No internal genital organs, blind- 01-0429 XX L-CDH VSD Accessory spleen R ending vagina 04-0042 XY c.2036T>C:p.V679A L-CDH ASD,VSD Unknown Unknown (Deceased) Current c.2084G>A:p.R695 Ambiguous genitalia, undescended Intellectual disability and motor 05-0050 XY CDH HLHS study H testes delay at 2 years old 01-0033 XX R-CDH Scimitar syndrome Unknown Unknown (Deceased) c.1904-1G>A 01-0591* XX Unknown HLHS Unknown Unknown (Deceased) Pulmonary Swyer syndrome with female CHU-11 XY c.1786C>T:p.Q596* Dextrocardia Right pulmonary hypoplasia hypoplasia genitalia Pulmonary Ambiguous genitalia, hypospadias, 1-02264 XY c.1160T>C:p.F387S AAH, CoA, HLHS No hypoplasia undescended testis Right hemi- c.1209G>C:p.Q403 Scimitar syndrome, AAH, PCGC[29] 1-03160 XY diaphragm Undescended testis Lung hypoplasia H ASD, BAV, HLHS, MS, VSD eventration Pulmonary Swyer syndrome with female 1-07403 XY c.1435C>G:p.L479V BAV, CoA Short stature hypoplasia genitalia Penoscrotal hypospadias, Pulmonary Scimitar syndrome, cor Mild speech delay, pulmonary Case 1 XY c.2336+1G>A micropenis, unilateral Pinz et hypoplasia triatriatum hypoplasia, tracheal anomalies cryptorchidism al.[30] Persistent urachus, Undescended Cleft spleen, thymic involution, Case 2 XY c.2518C>T:p.R840* R-CDH Scimitar syndrome testis thyroid fibrosis Ambiguous external genitalia, right Chitayat et Fetus c.1254_1255dupGA: Pulmonary Mild pulmonary hypoplasia, XY HLHS hepato-testicular fusion and left al.
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