SIX3 deletions and incomplete penetrance in families affected by holoprosencephaly

• Published in: Congenital anomalies Vol. 58; no. 1; pp. 29 - 32
• Main Authors: Stokes, Bethany, Berger, Seth I., Hall, Beth A., Weiss, Karin, Martinez, Ariel F., Hadley, Donald W., Murdock, David R., Ramanathan, Subhadra, Clark, Robin D., Roessler, Erich, Kruszka, Paul, Muenke, Maximilian
• Format: Journal Article
• Language: English
• Published: Australia Wiley Subscription Services, Inc 01.01.2018
• Subjects: Adrenal glands; Adult; Child, Preschool; DNA microarrays; Embryogenesis; Embryonic growth stage; Erythrocytes; Exome Sequencing; Eye Proteins - genetics; Forebrain; Gene Deletion; Gene Expression; Holoprosencephaly; Holoprosencephaly - diagnosis; Holoprosencephaly - genetics; Holoprosencephaly - metabolism; Holoprosencephaly - pathology; Homeobox Protein SIX3; Homeodomain Proteins - genetics; Humans; incomplete penetrance; Infant; Infant, Newborn; Microarray Analysis; Mosaicism; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Penetrance; Prosencephalon - abnormalities; Prosencephalon - metabolism; SIX3 deletion; Six3 gene; incomplete penetrance; SIX3 deletion; holoprosencephaly
• ISSN: 0914-3505; 1741-4520
• DOI: 10.1111/cga.12234

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.