Facial and brain anomalies in holoprosencephaly related chromosome aberrations characterized

Researchers at Signature Genomic Laboratories, which performs diagnostic genetic testing of chromosome abnormalities in individuals with unexplained physical and developmental disabilities, recently characterized a broad spectrum of facial and brain anomalies in individuals with chromosome aberrations associated with holoprosencephaly.

“These results are exciting because they demonstrate how microarray testing allows us to broaden the clinical spectrum associated with various chromosome aberrations”

Holoprosencephaly is a disorder in which the forward-most portion of the brain fails to fully divide into hemispheres (the right and left “sides” of the brain) during embryonic development. Holoprosencephaly can vary in severity: in its most severe form, in which the hemispheres completely fail to divide, holoprosencephaly can adversely affect brain function or result in death, whereas milder forms do not affect brain function but can result in facial deformities.

Most studies of the genetic bases of holoprosencephaly have examined groups of patients with clinical diagnoses of full holoprosencephaly. Several candidate genetic regions have been identified in such these studies, but such studies do not account for potential variability in the severity of clinical features. Researchers at Signature Genomic Laboratories took a novel “genotype-first” approach, identifying all individuals with chromosome aberrations associated with holoprosencephaly in their database of over 40,000 cases tested at their laboratory and working with the referring physicians of each case to determine the extent of holoprosencephaly, if present. The researchers also searched their patient database for any cases referred for testing because of holoprosencephaly.

The results of the study, which were published in the journal Human Genetics, showed that most cases with holoprosencephaly had deletions of one of four major holoprosencephaly genes, which is consistent with previous studies. Interestingly, several individuals with deletions of genes that had previously only been hypothesized to be associated with holoprosencephaly had mild forms of the disorder, which supports these genes’ association with holoprosencephaly. Conversely, deletions of several candidate genes were present in individuals with no form of holoprosencephaly, which suggests deletion of these genes alone is not sufficient to cause the disorder. Researchers also identified a previously unreported abnormality associated with holoprosencephaly, an extra piece of DNA on one copy of chromosome 13, which was identified in two individuals with holoprosencephaly, one with a full form of the disorder and one with a mild form.

“These results are exciting because they demonstrate how microarray testing allows us to broaden the clinical spectrum associated with various chromosome aberrations,” said Lisa G. Shaffer, Ph.D., President and CEO of Signature Genomic Laboratories and senior author of the study. “In the past, individuals were selected for study because they displayed the clinical features that were thought to be typical of a specific genetic disorder. Microarray analysis has allowed researchers to expand the boundaries of 'typical' for some of these disorders.”

SOURCE Signature Genomic Laboratories