Narrowing critical regions and determining penetrance for selected 18q- phenotypes

Abstract

One of our primary goals is to help families who have a child with an 18q deletion anticipate medical issues in order to optimize their child's medical care. To this end we have narrowed the critical regions for four phenotypic features and determined the penetrance for each of those phenotypes when the critical region for that feature is hemizygous. We completed molecular analysis using oligo-array CGH and clinical assessments on 151 individuals with deletions of 18q and made genotype-phenotype correlations defining or narrowing critical regions. These nested regions, all within 18q22.3 to q23, were for kidney malformations, dysmyelination of the brain, growth hormone stimulation response failure, and aural atresia. The region for dysmyelination and growth hormone stimulation response failure were identical and was narrowed to 1.62 Mb, a region containing five known genes. The region for aural atresia was 2.3 Mb and includes an additional three genes. The region for kidney malformations was 3.21 Mb and includes an additional four genes. Penetrance rates were calculated by comparing the number of individuals hemizygous for a critical region with the phenotype to those without the phenotype. The kidney malformations region was 25% penetrant, the dysmyelination region was 100% penetrant, the growth hormone stimulant response failure region was 90% penetrant with variable expressivity, and the aural atresia region was 78% penetrant. Identification of these critical regions suggest possible candidate genes, while penetrance calculations begin to create a predictive phenotypic description based on genotype.

FIG. 1

Kidney malformation critical region. Panel A illustrates the chromosome content for everyone with an 18q deletion and kidney malformations using the UCSC Genome Browser Custom Tracks feature. The horizontal light blue bars depict the region of chromosome 18 that is present in two copies. The darker blue sections are the breakpoint regions. All individuals who have retained a distal segment of chromosome 18 have interstitial deletions and not translocations to other chromosomes. Panel B depicts the chromosome content data from the two individuals whose deletions define the smallest common region of hemizygosity. This region is shown along with the known genes in the region.

FIG. 2

Oligonucleotide array comparative genomic hybridization microarray (aCGH) data for the two participants whose deletions define the smallest common hemizygous region for kidney malformations. The colored bars indicate the location of features that are significantly different from 0 on the log² scale; purple for participant 18q-13C and green for participant 18q-1C. Features exactly on the 0 vertical axis have a 1:1 red green color ratio between the test and reference DNA samples. The region where the purple and green bars overlap (blue) indicates their common region of deletion (i.e., the critical region). The panel on the left shows the whole chromosome 18 view of the data. The panel on the right shows a zoomed in view of the critical region; from position 69.2 to 78.4 Mb. The locations of the genes in that region are shown between the megabase scale and the data points.

FIG. 3

Calculated T1 images from individuals with 18q deletion and from typically developing children. Fitted model curves show higher T1 values in frontal white matter for children with 18q- indicating less myelin during development.

FIG. 4

Aligned critical regions. The red box on the chromosome 18 ideogram defines the region displayed below. The aCGH data from the four individuals whose breakpoints define the boundaries of the critical regions have been converted to custom tracks on the UCSC Genome Browser. The light blue bars depict the intact chromosome for each individual with their study identification number to the left. The adjoining dark blue bars depict the breakpoint region for each individual. Below the Custom tracks is the RefSeq Gene track showing the known genes aligned within the region.