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.

A gene dosage map of Chromosome 18: A map with clinical utility

“…A second series of tracks was created using information on critical regions for specific phenotypes that are described in Table 2. 6 Supplemental Digital Content 1, http://links.lww.com/GIM/A84 shows these two sets of tracks for the entire chromosome using these color codes. This track has two regions depicted in red as haplolethal regions.…”

“…We have found that every individual who is hemizygous for a 1.6-Mb region of 18q23 has dysmyelination of the central nervous system. 6 The responsible gene has yet to be identified.…”

“…Taken together, this information has allowed us to create a first-generation gene dosage map as a custom track on the UCSC Genome Browser. The information presented in a map format, combined with penetrance estimates, 6 can easily be compared with individual patient's aCGH results to improve prognostic information. As more is learned about the consequences of gene dosage variances, the map will be updated.…”

“…Regions were labeled as haploinsufficient if they were identified as a critical region for a phenotype in individuals with 18q-or 18p-. 6 Genes were classified as conditional haploinsufficient if there was evidence that their dosage effects were only manifest in response to an environmental factor (e.g., a drug) or required a second genetic hit to produce the phenotype. Genes were classified as haplolethal if the homozygous null allele mice were not viable.…”

Partial Duplication of 18q Including a Distal Critical Region for Edwards Syndrome in a Patient with Normal Phenotype and Oligoasthenospermia: Case Report

“…Additionally, mental retardation appeared to be mild in patients with deletions distal to 18q21.33 and severe in patients with deletions proximal to 18q21.31. More recently, a study narrowed the critical regions for 4 phenotypic features of 18q deletion phenotypes all within 18q22.3-q23: kidney malformation, dysmyelination, growth hormone response failure and aural atresia [Cody et al, 2009].…”