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 nonsynonymous, rare homozygous variants were identified on chromosome 2. Additionally, 5 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.

A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders

“…Recently, a female child, also with UPDmaternal of chromosome 2 and complex phenotype, distinct from our patient, had been exome sequenced and many (18) candidate variants were identified on the UPD chromosome, none definitively pathogenic (Carmichael et al 2012). None of that girl's phenotypes are coincident with our patient, suggesting that an imprinting disease is not the likely cause of the diseases in these children.…”

Whole Exome Sequencing to Identify Genetic Causes of Short Stature

“…DNA samples from patients and unaffected family members were analyzed using Agilent SurePrint G3 custom 4×180K comparative genomic hybridization (CGH) and SNP microarray (Agilent Technologies) as previously described [13]. Candidate CNVs were filtered using standard clinical practices in the DNA diagnostic laboratory at Boston Children’s Hospital.…”

Characterization of prevalence and health consequences of uniparental disomy in four million individuals from the general population

“…UPD can cause clinical consequences by disrupting genomic imprinting, or by unmasking harmful recessive alleles in large blocks of homozygosity on the affected chromosome. Detecting UPD is a useful diagnostic tool for specific imprinting disorders and for rare Mendelian diseases caused by homozygosity 12,[16][17][18][19] .…”