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Copy number gains in RBFOX1: rare population variants or incompletely penetrant CNVs? Case reports and review of the literature

Laboratory Genetics and Genomics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction
RBFOX1 (RNA-binding fox-1 homolog 1) [MIM: 605104] at 16p13.3 encodes an RNA-binding protein involved in the regulation of tissue-specific splicing. This gene is not currently associated with a known clinical disorder in OMIM. However, copy number variants (CNVs) in this gene have been described in a limited number of individuals with variable phenotypes, including heterotaxy, neurodevelopmental disorders and congenital heart defects. Since CNVs in this gene have also been observed in unaffected controls, the contribution of RBFOX1 to these phenotypes is unclear.

The interpretation of RBFOX1 CNVs is further complicated by the fact that this gene has numerous splice isoforms of different lengths, which share several exons at the 3' end but vary at the 5’end and the position of the transcription start site. Based on data from the GTEX database this gene is highly expressed in tissue from brain, heart, and skeletal muscle, and brain tissue might preferably express different isoform(s) compared to other tissues. Of note, databases of CNVs in unaffected controls including the Database of Genomic Variants (DGV) show that CNVs involving the 3’end of the gene are rare, whereas more variation is observed at the 5’ end (exclusively affecting the longer isoforms of the gene). In addition, while intragenic deletions are observed in the population, intragenic duplications are relatively rare.

Case Presentation
We report three unrelated cases where postnatal chromosomal microarray analysis (CMA) identified copy number gains involving RBFOX1. We also provide a systematic review of the literature and compile the published functional evidence regarding this gene.

The indications for referral in these three cases were congenital anomalies including congenital heart defects (e.g Tetralogy of Fallot, and ventricular septal defect), duodenal atresia, bilateral renal agenesis, absent bladder, and pulmonary atresia. All three patients were tested in the newborn period, so there was limited information regarding developmental progress.

Diagnostic Workup
Two cases showed similar gains involving exon 4 of 16 of the MANE Select transcript (NM_018723.4) which may represent intragenic duplications.  The third case showed a copy number gain involving exon 2 of 16 (which falls in the 5’ untranslated region) of the MANE Select transcript (NM_018723.4), also corresponding to the translation start site of other transcripts (e.g. NM_001415889.1, exon 1 of 16). All three copy number gains are rare in the general population (no similar gains in the Database of Genomic Variants Gold Standard Variants) although there are rare overlapping gains observed in the gnomAD Structural Variants dataset. Similar gains have also been reported in ClinVar, the majority of which are classified as variants of uncertain significance. Among ClinVar submissions that included clinical information, various phenotypes were observed including autism and developmental delay.

In all three cases, the RBFOX1 gain was reported as a variant of uncertain clinical significance and was the only clinically significant finding identified by CMA. Parental testing was recommended but only performed for one of the three cases, which found the CNV to be inherited.

Conclusion
The interpretation of RBFOX1 intragenic copy number variants is challenging given different consequences for different transcripts, potential for tissue-specific isoforms, and the observation of CNVs in unaffected individuals. The cases reported herein provide additional cases in which a possible association between CNVs in RBFOX1 and multiple congenital anomalies including cardiac anomalies could be speculated. Given the limited phenotypic information, the potential contributions of RBFOX1 to neurodevelopmental phenotypes in our cohort is uncertain, although considering observations from the literature and ClinVar the possibility of incomplete penetrance for neurodevelopmental disorders cannot be excluded. Furthermore, given the architecture and tissue-specific expression patterns of this gene, it is possible that CNVs in different parts of the gene may have different functional consequences.

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