Figure 3
From: Incidental copy-number variants identified by routine genome testing in a clinical population
Examples of incidental single-gene copy-number variants (CNVs) affecting dominant, adult-onset disease genes. (a–f) Complete genomic DNA analysis for a single subject (subject 82; BAB 3166), a child referred for array comparative genomic hybridization (aCGH) because of autism and epilepsy. (a) A genome-wide aCGH log2 plot displays (i) a known, benign CNV (orange dot), (ii) a deletion CNV potentially contributory to the patient’s phenotype affecting SLC9A9 (red dot, no arrow), and (iii) a deletion disrupting SPAST, the disease gene for type 4 autosomal dominant hereditary spastic paraplegia (SPG4) (red dot, arrow). (b) Local view of the SPAST CNV (pink shading), which deletes exon 13. F and R primers were used to confirm the presence of the CNV. (c) PCR confirms a heterozygous deletion in the patient. An ~2 kb band amplified from patient DNA was sequenced to determine the exact size, location, and breakpoint characteristics of the deletion (Supplementary Materials and Methods online). Pt, patient DNA; Ctrl ♂, control male DNA; Ctrl F+R, control primers (d) DNA sequencing confirms a 1,340 base pair (bp) deletion. Genomic sequence telomeric (top) and centromeric (bottom) to the deletion breakpoint, which displays six bp of microhomology (magenta), are displayed, as is the mutant patient sequence (“Pt seq”; middle). (e) DNA sequencing trace of the breakpoint region. A flipped reverse complement sequence is displayed, as sequencing was performed in reverse genomic orientation. (f) The predicted effect of this incidentally discovered removal of a 43 bp exon is a shift of translational frame, introducing a premature termination codon (PTC) in exon 14, likely leading to nonsense-mediated decay and thus acting as a null allele. Deletions of exon 13 have been described in individuals with SPG4.23 (g–i) aCGH log2 plots displaying heterozygous CNVs disrupting genes associated with dominant, adult-onset conditions in three additional patients. Gray shading indicates the minimum span of altered copy number. (g) Subject 17. (h) Subject 78. (i) Subject 41.
