Abstract
Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TF2) encodes a transcription factor which is expressed at high levels during mammalian development. Rare heterozygous Mendelian variants in NR2F2 were initially identified in individuals with congenital heart disease (CHD), then subsequently in cohorts of congenital diaphragmatic hernia (CDH) and 46,XX ovotesticular disorders/differences of sexual development (DSD); however, the phenotypic spectrum associated with pathogenic variants in NR2F2 remains poorly characterized. Currently, less than 40 individuals with heterozygous pathogenic variants in NR2F2 have been reported. Here, we review the clinical and molecular details of 17 previously unreported individuals with rare heterozygous NR2F2 variants, the majority of which were de novo. Clinical features were variable, including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations, thus expanding the phenotypic spectrum associated with NR2F2 variants. The variants seen were predicted loss of function, including a nonsense variant inherited from a mildly affected mosaic mother, missense and a large deletion including the NR2F2 gene. Our study presents evidence for rare, heterozygous NR2F2 variants causing a highly variable syndrome of congenital anomalies, commonly associated with heart defects, developmental delays/intellectual disability, dysmorphic features, feeding difficulties, hypotonia, and genital anomalies. Based on the new and previous cases, we provide clinical recommendations for evaluating individuals diagnosed with an NR2F2-associated disorder.
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Data availability
The data in this study is available in the manuscript, Supplementary information, tables, and figures. The NR2F2 variants reported in this study are submitted in ClinVar. The following variants have been previously submitted by the clinical testing labs/research groups in ClinVar NM_021005.4: c.1019del:p.(Lys340SerfsTer39), c.746G>A:p.(Trp249Ter), c.558dup:p.(Arg187AlafsTer122), c.269A>G:p.(His90Arg), c.1022C>A:p.(Ser341Tyr), c.1097G>C:p.(Arg366Pro) (Variation IDs: 2429770, 598763, 1805610, 1064859, 128232, 521133). The details of the two variants - c.287G>T:p.(Cys96Phe), c.257C>G:p.(Ser86Trp) which were ascertained as part of the DDD study are available in the DECIPHER website (https://www.deciphergenomics.org/patient/259383/genotype/191257/browser; https://www.deciphergenomics.org/patient/282004/genotype/197133/browser). The Clinvar IDs for the remaining variants are listed below (Variation IDs: 2570648, 2570646, 2570643, 2570644, 2570645, 2570642, 2570647).
References
Al Turki S, Manickaraj AK, Mercer CL, Gerety SS, Hitz MP, Lindsay S, et al. Rare variants in NR2F2 cause congenital heart defects in humans. Am J Hum Genet. 2014;94:574–85.
Polvani S, Pepe S, Milani S, Galli A. COUP-TFII in health and disease. Cells. 2019;9:101.
Lin FJ, Qin J, Tang K, Tsai SY, Tsai MJ. Coup d'Etat: an orphan takes control. Endocr Rev. 2011;32:404–21.
Pereira FA, Qiu Y, Zhou G, Tsai MJ, Tsai SY. The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development. Genes Dev. 1999;13:1037–49.
Zhao F, Franco HL, Rodriguez KF, Brown PR, Tsai MJ, Tsai SY, et al. Elimination of the male reproductive tract in the female embryo is promoted by COUP-TFII in mice. Science. 2017;357:717–20.
Kurihara I, Lee DK, Petit FG, Jeong J, Lee K, Lydon JP, et al. COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity. PLoS Genet. 2007;3:e102.
Petit FG, Jamin SP, Kurihara I, Behringer RR, DeMayo FJ, Tsai MJ, et al. Deletion of the orphan nuclear receptor COUP-TFII in uterus leads to placental deficiency. Proc Natl Acad Sci USA. 2007;104:6293–8.
Takamoto N, Kurihara I, Lee K, Demayo FJ, Tsai MJ, Tsai SY. Haploinsufficiency of chicken ovalbumin upstream promoter transcription factor II in female reproduction. Mol Endocrinol. 2005;19:2299–308.
Takamoto N, You LR, Moses K, Chiang C, Zimmer WE, Schwartz RJ, et al. COUP-TFII is essential for radial and anteroposterior patterning of the stomach. Development. 2005;132:2179–89.
You LR, Takamoto N, Yu CT, Tanaka T, Kodama T, Demayo FJ, et al. Mouse lacking COUP-TFII as an animal model of Bochdalek-type congenital diaphragmatic hernia. Proc Natl Acad Sci USA. 2005;102:16351–6.
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.
Arsov T, Kelecic J, Frkovic SH, Sestan M, Kifer N, Andrews D, et al. Expanding the clinical spectrum of pathogenic variation in NR2F2: asplenia. Eur J Med Genet. 2021;64:104347.
Qiao XH, Wang Q, Wang J, Liu XY, Xu YJ, Huang RT, et al. A novel NR2F2 loss-of-function mutation predisposes to congenital heart defect. Eur J Med Genet. 2018;61:197–203.
Reuter MS, Chaturvedi RR, Liston E, Manshaei R, Aul RB, Bowdin S, et al. The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease. Genet Med. 2020;22:1015–24.
Richter F, Morton SU, Kim SW, Kitaygorodsky A, Wasson LK, Chen KM, et al. Genomic analyses implicate noncoding de novo variants in congenital heart disease. Nat Genet. 2020;52:769–77.
Wang J, Abhinav P, Xu YJ, Li RG, Zhang M, Qiu XB, et al. NR2F2 loss‑of‑function mutation is responsible for congenital bicuspid aortic valve. Int J Mol Med. 2019;43:1839–46.
Upadia J, Gonzales PR, Robin NH. Novel de novo pathogenic variant in the NR2F2 gene in a boy with congenital heart defect and dysmorphic features. Am J Med Genet A. 2018;176:1423–26.
Kammoun M, Souche E, Brady P, Ding J, Cosemans N, Gratacos E, et al. Genetic profile of isolated congenital diaphragmatic hernia revealed by targeted next-generation sequencing. Prenat Diagn. 2018;38:654–63.
Bashamboo A, Eozenou C, Jorgensen A, Bignon-Topalovic J, Siffroi JP, Hyon C, et al. Loss of function of the nuclear receptor NR2F2, encoding COUP-TF2, causes testis development and cardiac defects in 46,xx children. Am J Hum Genet. 2018;102:487–93.
Qiao L, Wynn J, Yu L, Hernan R, Zhou X, Duron V, et al. Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes. Genet Med. 2020;22:2020–28.
Li AH, Hanchard NA, Furthner D, Fernbach S, Azamian M, Nicosia A, et al. Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns. Genome Med. 2017;9:95.
High FA, Bhayani P, Wilson JM, Bult CJ, Donahoe PK, Longoni M. De novo frameshift mutation in COUP-TFII (NR2F2) in human congenital diaphragmatic hernia. Am J Med Genet A. 2016;170:2457–61.
Matsunami N, Shanmugam H, Baird L, Stevens J, Byrne JL, Barnhart DC, et al. Germline but not somatic de novo mutations are common in human congenital diaphragmatic hernia. Birth Defects Res. 2018;110:610–17.
Schwab ME, Dong S, Lianoglou BR, Aguilar Lucero AF, Schwartz GB, Norton ME, et al. Exome sequencing of fetuses with congenital diaphragmatic hernia supports a causal role for NR2F2, PTPN11, and WT1 variants. Am J Surg. 2022;223:182–86.
Zidoune H, Ladjouze A, Chellat-Rezgoune D, Boukri A, Dib SA, Nouri N, et al. Novel genomic variants, atypical phenotypes and evidence of a digenic/oligogenic contribution to disorders/differences of sex development in a large North African cohort. Front Genet. 2022;13:900574.
Carvalheira G, Malinverni AM, Moyses-Oliveira M, Ueta R, Cardili L, Monteagudo P, et al. The natural history of a man with ovotesticular 46,XX DSD caused by a novel 3-Mb 15q26.2 deletion containing NR2F2 gene. J Endocr Soc. 2019;3:2107–13.
Brady PD, DeKoninck P, Fryns JP, Devriendt K, Deprest JA, Vermeesch JR. Identification of dosage-sensitive genes in fetuses referred with severe isolated congenital diaphragmatic hernia. Prenat Diagn. 2013;33:1283–92.
Poot M, Verrijn Stuart AA, van Daalen E, van Iperen A, van Binsbergen E, Hochstenbach R. Variable behavioural phenotypes of patients with monosomies of 15q26 and a review of 16 cases. Eur J Med Genet. 2013;56:346–50.
Mosca AL, Pinson L, Andrieux J, Copin H, Bigi N, Puechberty J, et al. Refining the critical region for congenital diaphragmatic hernia on chromosome 15q26 from the study of four fetuses. Prenat Diagn. 2011;31:912–4.
Dateki S, Fukami M, Tanaka Y, Sasaki G, Moriuchi H, Ogata T. Identification of chromosome 15q26 terminal deletion with telomere sequences and its bearing on genotype-phenotype analysis. Endocr J. 2011;58:155–9.
Rump P, Dijkhuizen T, Sikkema-Raddatz B, Lemmink HH, Vos YJ, Verheij JB, et al. Drayer’s syndrome of mental retardation, microcephaly, short stature and absent phalanges is caused by a recurrent deletion of chromosome 15(q26.2—>qter). Clin Genet. 2008;74:455–62.
Davidsson J, Collin A, Bjorkhem G, Soller M. Array based characterization of a terminal deletion involving chromosome subband 15q26.2: an emerging syndrome associated with growth retardation, cardiac defects and developmental delay. BMC Med Genet. 2008;9:2.
Poot M, Eleveld MJ, van 't Slot R, van Genderen MM, Verrijn Stuart AA, Hochstenbach R, et al. Proportional growth failure and oculocutaneous albinism in a girl with a 6.87 Mb deletion of region 15q26.2—>qter. Eur J Med Genet. 2007;50:432–40.
Rujirabanjerd S, Suwannarat W, Sripo T, Dissaneevate P, Permsirivanich W, Limprasert P. De novo subtelomeric deletion of 15q associated with satellite translocation in a child with developmental delay and severe growth retardation. Am J Med Genet A. 2007;143A:271–6.
Hoang TT, Goldmuntz E, Roberts AE, Chung WK, Kline JK, Deanfield JE, et al. The congenital heart disease genetic network study: cohort description. PLoS One. 2018;13:e0191319.
Pediatric Cardiac Genomics C, Gelb B, Brueckner M, Chung W, Goldmuntz E, Kaltman J, et al. The congenital heart disease genetic network study: rationale, design, and early results. Circ Res. 2013;112:698–706.
Rastetter RH, Bernard P, Palmer JS, Chassot AA, Chen H, Western PS, et al. Marker genes identify three somatic cell types in the fetal mouse ovary. Dev Biol. 2014;394:242–52.
Acknowledgements
We would like to thank all the families who participated in this study. The National Institutes of Health (NIH) Common Fund, through the Office of Strategic Coordination and the Office of the NIH Director, the Vanderbilt University Medical Center clinical site (U01HG007674).
Funding
The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Sanger Institute [grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study was approved by the UK Research Ethics Committee (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. Wendy Chung acknowledges funding support from grants P01HD068250 and U01 HL131003. Sara Sanz Benito acknowledges funding from the Fondo de Investigación Sanitaria (PI15/01647 [SB-S]). Maria Francesca Bedeschi, Nuria C Bramswig and Ariane Schmetz are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]. Nuria C Bramswig and Ariane Schmetz acknowledge that this work was partly done within the Zentrum für Seltene Erkrankungen of the University Hospital Düsseldorf (ZSED).
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MG collected, analyzed and interpreted the data, drafted the introduction, results, discussion, figures, and tables. MG, LSM, MM, DL, EB, SBS, SMW, KL, PA, AS, LB, ATW, JMS, KS, FD, BC, BI, MFB, AP, JA, EZ, JPS, ADI, JM, VS, SL, SB, IT, JDC, CTG, WKC, SB, EB, NCB, AS provided the clinical data, wrote the clinical case descriptions, methods, critically reviewed and edited the manuscript. EB conceived the study, interpreted the data, and critically reviewed the manuscript.
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The Institutional Review Board of the Children’s Hospital of Philadelphia approved this study. Informed consent was obtained from all individual participants included in the study. Families of individuals 2 &12 consented for publication of images.
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Ganapathi, M., Matsuoka, L.S., March, M. et al. Heterozygous rare variants in NR2F2 cause a recognizable multiple congenital anomaly syndrome with developmental delays. Eur J Hum Genet 31, 1117–1124 (2023). https://doi.org/10.1038/s41431-023-01434-5
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DOI: https://doi.org/10.1038/s41431-023-01434-5
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