Establishing a reference group for distal 18q-: clinical description and molecular basis

Abstract

Although constitutional chromosome abnormalities have been recognized since the 1960s, clinical characterization and development of treatment options have been hampered by their obvious genetic complexity and relative rarity. Additionally, deletions of 18q are particularly heterogeneous, with no two people having the same breakpoints. We identified sixteen individuals with deletions that, despite unique breakpoints, encompass the same set of genes within a 17.6 Mb region. This group represents the most genotypically similar group yet identified with distal 18q deletions. As the deletion is of average size when compared with other 18q deletions, this group can serve as a reference point for the clinical and molecular description of this condition. We performed a thorough medical record review as well as a series of clinical evaluations on 14 of the 16 individuals. Common functional findings included developmental delays, hypotonia, growth hormone deficiency, and hearing loss. Structural anomalies included foot anomalies, ear canal atresia/stenosis, and hypospadias. The majority of individuals performed within the low normal range of cognitive ability but had more serious deficits in adaptive abilities. Of interest, the hemizygous region contains 38 known genes, 26 of which are sufficiently understood to tentatively determine dosage sensitivity. Published data suggest that 20 are unlikely to cause an abnormal phenotype in the hemizygous state and five are likely to be dosage sensitive: TNX3, NETO1, ZNF407, TSHZ1, and NFATC. A sixth gene, ATP9B, may be conditionally dosage sensitive. Not all distal 18q- phenotypes can be attributed to these six genes; however, this is an important advance in the molecular characterization of 18q deletions.

Expansion of the clinical phenotype of the distal 10q26.3 deletion syndrome to include ataxia and hyperemia of the hands and feet

“…For example, with del(15)(q11.2), although the breakpoints are clustered, the phenotypic presentation ranges from apparently normal to moderate intellectual disability with a constellation of associated malformations (Vanlerberghe et al, ). More similar to the current study are the heterogeneous distal deletions of the long arm of chromosome 18q (18q‐ syndrome), some phenotypic features are nearly 100% penetrant, while others are observed in only a minor fraction of the patients (Cody et al, ). One possibility is that the variability in the presentation of patients with this deletion may be due to the presence of a modifier gene(s) either within or outside of the 10q26.3 region that affects the expressivity of specific features.…”

Consequences of chromsome18q deletions

“…Although each individual has a unique region of hemizygosity, there is a group of individuals whose breakpoints are between two genes that are 1.76 Mb apart. Because this is as as close to a recurrent genotype as we have detected and because these individual's deletions are about average in size compared to our entire cohort with terminal deletions we have referred to this as the Distal 18q‐ Reference Group [Cody et al, ]. Their region of hemizygosity is shown in Figure .…”

“…The individuals with interstitial hemizygosity have FISH confirmed interstitial deletions. The position of the TCF4 gene; which has a significant phenotypic, effect is indicated as is the hemizygous region for the18q‐ Reference Group described previously [Cody et al, ].…”

“…Thus it is problematic to develop clinical anticipatory guidance using a “syndrome” approach, such as has been done for Down or Turner syndromes. In the past we have tried to impose this approach for the sake of conformity with other genetic references; however, this is only truly useful for the small number of individuals who have terminal deletions with breakpoints between the same two genes [Cody et al, ].…”

Complex Rearrangement Involving Three Chromosomes, Four Breakpoints and a 2.7-Mb Deletion in the 18q Segment Observed in a Girl with Mild Learning Difficulties

“…A group of over 290 individuals with a terminal or interstitial deletion of 18q was analyzed using aCGH, and no overlaps of the deleted regions were found [Heard et al, 2009]. More than half of 16 individuals of the previous group with terminal deletion of 18q, with a breakpoint upstream CDH7 , have delayed myelination of the brain, foot anomalies, atretic and stenotic ear canals, hypospadias in males, tapered fingers, flat midface, proximally placed thumbs, and congenital heart anomalies [Cody et al, 2014]. Using the UCSC genome browser (http://genome.ucsc.edu) and the OMIM database (http://www.omim.org/), we observed that the deleted region of 18q22.1 between 65,612,478 and 68,326,910, as in our patient, includes the CDH7 , CDH19 , DSEL protein-coding genes.…”