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

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.

Fig. 1. Variants in NR2F2.

a Distribution of non-synonymous variants on the NR2F2 protein (NM_021005.4, NP_066285.1). The variants identified in this study are shown in black font, and the previously published variants (except one which is marked with #) are in colored font as per the reported phenotype/clinical features. The location of the functional domains in NR2F2 protein were adapted from Wang et al. 2019 [18]. b Schematic representation of the coding exons, the splice variants, and the 5’ UTR variant reported in the NR2F2 gene (NM_021005.4). ^#We also reviewed whole exome sequencing data from the Pediatric Cardiac Genomics Consortium (PCGC) cohort [37, 38], which consists of individuals with cardiac defects and identified one additional case with a rare de novo NR2F2 variant (p.(Gly98Ser), Supplementary Table 4). The cardiac phenotypes, in this case, were secundum atrial septal defect, left aortic arch with normal branching pattern. This case is not included in the current cohort but has been shown in Fig. 1. CHD congenital heart defect; CDH congenital diaphragmatic hernia; DSD disorders of sexual development including 46,XX DSD and 46,XY DSD; “Others” phenotype described in Arsov et al. 2021 [14] includes asplenia. Note that though many of the previously reported affected individuals were ascertained using a disease specific disease cohort, there might be other clinical manifestations which may or may not have been described [, –27] and [Supplementary Table 1].