Integrated Genomic Approach: A Five Exon Intragenic Deletion in UNC80 Combines With a Novel Splice Variant to Cause...

Rare diseases impact ~6%-8% of the population, thus constituting an issue for public health worldwide. The increasing application of genomic technologies in the routine diagnosis of these conditions is documenting the need to integrate multiple techniques in the most complex cases. We describe a 14-year-old boy and his 4-year-old sister, both presenting with neonatal hypotonia, severe global developmental delay, major feeding difficulties with the need for assisted nutrition, inability to speak and walk autonomously, epilepsy, central sleep apnea, and facial dysmorphism, in whom exome sequencing revealed the novel c.798 + 1G>T variant in the UNC80 gene at the heterozygous state. While reverse phenotyping was compatible with a clinical diagnosis of infantile hypotonia, psychomotor retardation, and characteristic facies type 2 syndrome, chromosomal microarray disclosed a microdeletion involving 5 exons (40-44) in the other allele. Our findings expand the mutational repertoire of UNC80 and demonstrate that infantile hypotonia, psychomotor retardation, and characteristic facies type 2 syndrome may also be caused by intragenic copy number variations. The combination of multiple techniques, also comprising exon-level resolution array, is a resource in real-world diagnostics of rare diseases.