SIX3 deletions and incomplete penetrance in families affected by holoprosencephaly.
Bethany Stokes, Seth I Berger, Beth A Hall, Karin Weiss, Ariel F Martinez, Donald W Hadley, David R Murdock, Subhadra Ramanathan, Robin D Clark, Erich Roessler, Paul Kruszka, Maximilian Muenke
Author Information
Bethany Stokes: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Seth I Berger: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Beth A Hall: Minnesota Perinatal Physicians, Allina Health, Minneapolis, Minnesota, USA.
Karin Weiss: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Ariel F Martinez: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Donald W Hadley: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
David R Murdock: Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Subhadra Ramanathan: Division of Medical Genetics, Department of Pediatrics, Loma Linda University Children's Hospital, Loma Linda, California, USA.
Robin D Clark: Division of Medical Genetics, Department of Pediatrics, Loma Linda University Children's Hospital, Loma Linda, California, USA.
Erich Roessler: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Paul Kruszka: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. ORCID
Maximilian Muenke: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Holoprosencephaly (HPE) is failure of the forebrain to divide completely during embryogenesis. Incomplete penetrance has not been reported previously in SIX3 whole gene deletions, which are known to cause HPE. Both chromosomal microarray and whole exome sequencing (WES) were used to evaluate families with inherited HPE. Two families showed inherited deletions that contain SIX3 and were incompletely penetrant for HPE. Using WES, we ruled out parental mosaicism, a SIX3 hypomorph, and clinically significant variants in genes that are known to interact with SIX3 as causes of incomplete penetrance. We demonstrate the importance of molecular cascade testing in families with HPE and we answer important questions about incomplete penetrance.
