Novel dominant-negative NR2F1 frameshift mutation and a phenotypic expansion of the Bosch-Boonstra-Schaaf optic atrophy syndrome
Introduction
Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy, developmental delay and intellectual disability (OMIM 615722) (Bosch et al., 2014). This disorder is caused by mutations in NR2F1, which encodes a highly conserved nuclear receptor protein consisting of two functional domains, the DNA-binding domain and die ligand-binding domain. However, the ligand of NR2F1 remains still unknown. There are currently 31 cases with BBSOAS described in the literature. Most variants in NR2F1, which have been described so far, are missense mutations. Interestingly, individuals with whole-gene deletions are considered to show a milder phenotype compared to those who carry a deleterious missense mutation (Chen et al., 2016). Here we report on a 9 year-old boy with a novel frameshift mutation in the ligand-binding domain in the last exon of NR2F1, who presented with a severe phenotype of BBSOAS.
Section snippets
Clinical report
Prenatal ultrasound examinations of the male patient revealed a polyhydramnios Due to an impending uterine rupture a caesarian section was performed in the 33 + 2 gestational week. The birth measurements were in the normal range, but the occipitofrontal circumference (OFC) of 34 cm (1.37 SD) was relatively large. A developmental delay was apparent at the age of 8 months, the patient was not able to turn or reach for things. He was able to walk at the age of 2 years and started to speak first
Discussion
A total of 31 patients with BBSOAS have been described in the literature so far. Out of these 31 patients, there are eight patients with whole-gene deletions of NR2F1 ranging from 582 kb to 5 Mb in size as well as five patients with smaller indels (Chen et al., 2016; Kaiwar et al., 2017; Martin-Hernandez et al., 2018). Missense variants in NR2F1 are the most common mechanism with 18 patients having a de novo variant. The DNA-binding domain (DBD) is considered as a mutational hotspot, since 11
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
We declare no conflicts of interest.
Acknowledgement
We would like to thank the patient and his parents for participating in this work.
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The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations
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