Research: Heterozygous rare variants in NR2F2 cause a recognizable multiple congenital anomaly syndrome with developmental delays

Eur J Hum Genet

. 2023 Jul 27.

 doi: 10.1038/s41431-023-01434-5. Online ahead of print.

Heterozygous rare variants in NR2F2 cause a recognizable multiple congenital anomaly syndrome with developmental delays

Mythily Ganapathi 1Leticia S Matsuoka 2Michael March 2Dong Li 2Elly Brokamp 3Sara Benito-Sanz 4Susan M White 5 6Katherine Lachlan 7 8Priyanka Ahimaz 9Anshuman Sewda 9Lisa Bastarache 10Amanda Thomas-Wilson 1Joan M Stoler 11Nuria C Bramswig 12Julia Baptista 13 14Karen Stals 13Florence Demurger 15Benjamin Cogne 16 17Bertrand Isidor 16 17Maria Francesca Bedeschi 18Angela Peron 19 20Jeanne Amiel 21 22Elaine Zackai 2John P Schacht 9Alejandro D Iglesias 9Jenny Morton 23Ariane Schmetz 12Undiagnosed Diseases NetworkVerónica Seidel 24Stephanie Lucia 11Stephanie M Baskin 25 26Isabelle Thiffault 27Joy D Cogan 28Christopher T Gordon 21Wendy K Chung 9Sarah Bowdin 29Elizabeth Bhoj 30

Collaborators, Affiliations expand


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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