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Genet Med. 2018 Jan;20(1):14-23. doi: 10.1038/gim.2017.68. Epub 2017 Jun 22.

In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics.

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Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Speech and Language Pathology Section, Department of Rehabilitation Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, Bethesda, Maryland, USA.
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
Stanford University School of Medicine and Lucile Packard Children's Hospital, Stanford, California, USA.
Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland, USA.
Department of Neurology, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.
Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.


PurposeWith improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the underlying molecular causes.MethodsParticipants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.ResultsSemilobar HPE was the most common subtype of HPE, seen in 50% of the participants. Neurodevelopmental disabilities were found to correlate with HPE subtype. Factors associated with long-term survival included HPE subtype not alobar, female gender, and nontypical facial features. Four participants had de novo pathogenic variants in ZIC2. WES analysis of 11 participants did not reveal plausible candidate genes, suggesting complex inheritance in these cases. Indeed, in two probands there was a history of uncontrolled maternal type 1 diabetes.ConclusionIndividuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Based on the facial characteristics and molecular evaluations, we suggest that classic genetic causes of HPE may play a smaller role in this cohort.

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