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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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).
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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).
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).
The authors declare no competing interests.
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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