Whole exome sequencing in a patient with uniparental disomy of chromosome 2 and a complex phenotype

Abstract

Whole exome sequencing and chromosomal microarrays are two powerful technologies that have transformed the ability of researchers to search for potentially causal variants in human disease. This study combines these tools to search for causal variants in a patient found to have maternal uniparental isodisomy of chromosome 2. This subject has a complex phenotype including skeletal and renal dysplasia, immune deficiencies, growth failure, retinal degeneration and ovarian insufficiency. Eighteen non-synonymous, rare homozygous variants were identified on chromosome 2. Additionally, five genes with compound heterozygous mutations were detected on other chromosomes that could lead to a disease phenotype independent of the uniparental disomy found in this case. Several candidate genes with potential connection to the phenotype are described but none are definitively proven to be causal. This study highlights the potential for detection of a large number of candidate genes using whole exome sequencing complicating interpretation in both the research and clinical settings. Forums must be created for publication and sharing of detailed phenotypic and genotypic reports to facilitate further biological discoveries and clinical counseling.

Keywords: Bardet-Biedl syndrome; DNA copy number variations; comparative genomic hybridization; high-throughput nucleotide sequencing; uniparental disomy; whole exome sequencing.

Figure 1. Cervical abnormalities

(a) Photo of the patient at age 21. (b) Radiographic image of the cervical spine showing fusion of C2 and C3, shortening of the vertebral bodies of C4 and C5, and partial fusion of C6 and C7.

Figure 2. Upper and lower digits

Upper panel shows images of the dorsal and palmar surfaces as well as a radiographic image of the left hand. Left hand is notable for brachydactyly and clinodactyly, as well as some soft tissue syndactyly of the 2^nd to 4^th digits. Lower panel shows left dorsal foot and radiographic images of both feet. The patient has pes planus, widely spaced 1^st and 2^nd toes, and mild syndactyly of the 2^nd and 3^rd toes.

Figure 3. Microarray results for chromosomes 1 and 2

Array results for chromosome 1 are shown for comparison. There are no abnormalities on chromosome 1. For each chromosome, the upper panel displays the CNV scatter plot showing that no CNV was detected on either chromosome (black dots indicate Cy5/Cy3 ratio between 0.25 and −0.25; blue dots indicate Cy5/Cy3 ratio > 0.25 and red dots indicate Cy5/Cy3 ratio <−0.25). The bottom panel displays the zygosity plot. In the zygosity plot, the top and bottom tracks indicate homozygous status while the middle track indicates heterozygous status. In chromosome 1, there are many dots distributed across the heterozygous as well as homozygous tracks. However, on chromosome 2, the paucity of heterozygous SNPs (i.e. lack of dots in the middle track) across the whole chromosome in this sample indicates the whole chromosome loss of heterozygosity. The absence of loss of heterozygosity in the rest of the genome and the copy neutral status of the chromosome 2 indicates the UPD status of chromosome 2 in this subject.