A novel homozygous splicing variant in FRA10AC1: further delineation of the phenotype

Biallelic variants in FRA10AC1, encoding a component of the spliceosomal C complex that is crucial for functional mRNA processing, have been recently associated with a neurodevelopmental disorder characterized by developmental delay, variable dysmorphic facies, growth retardation, and corpus callosum abnormalities. Skeletal and congenital heart defects were observed in some patients. To date, only 10 patients from 6 unrelated families with FRA10AC1 variants have been reported in the literature. Herein, we describe a new patient harboring a loss-of-function variant in FRA10AC1. Our patient presented with global developmental delay, hypotonia, dysmorphic facies, hyperactivity, and severe intellectual disability. He had no seizures. Unusual findings noted in the patient were fused kidneys and bilateral cone dystrophy. Brain MRI showed a hypoplastic corpus callosum, delayed myelination, and a small cyst in the caudate nucleus. Exome sequencing revealed a novel homozygous variant in the donor splice site of exon 7 of the FRA10AC1 (c.465+1G>A) as the likely cause of the patient's phenotype. Thorough investigations of the exome data did not reveal any additional potential pathogenic variants to justify the patient's renal and ocular phenotypes. The identified c.465+1G>A was confirmed by studying the patient's mRNA to result in exon skipping and early protein truncation, p.(Trp127CysfsTer8). Our study increases the number of patients and variants associated with FRA10AC1-related disorder and contributes to increasing our understanding of FRA10AC1 role in neurodevelopmental disorders. In addition, it reinforces kidney and ocular anomalies as part of this multisystem disorder.