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

Karin Weiss, Paul Kruszka, Maria J. Guillen Sacoto, Yonit A. Addissie, Donald W. Hadley, Casey K. Hadsall, Bethany Stokes, Ping Hu, Erich Roessler, Beth Solomon, Edythe Wiggs, Audrey Thurm, Robert B. Hufnagel, Wadih M. Zein, Jin S. Hahn, Elaine Stashinko, Eric Levey, Debbie Baldwin, Nancy J. Clegg, Mauricio R. DelgadoMaximilian Muenke

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)14-23
Number of pages10
JournalGenetics in Medicine
Issue number1
StatePublished - Jan 1 2018


  • DISP1
  • ZIC2
  • holoprosencephaly
  • natural history
  • wholeexome sequencing

ASJC Scopus subject areas

  • Genetics(clinical)


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