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. Delgado & 1 others Maximilian Muenke

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2018

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Holoprosencephaly
Exome
Genetic Testing
Deglutition
Type 1 Diabetes Mellitus
Mothers
Magnetic Resonance Imaging

Keywords

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

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Weiss, K., Kruszka, P., Guillen Sacoto, M. J., Addissie, Y. A., Hadley, D. W., Hadsall, C. K., ... Muenke, M. (2018). In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics. Genetics in Medicine, 20(1), 14-23. https://doi.org/10.1038/gim.2017.68

In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics. / Weiss, Karin; Kruszka, Paul; Guillen Sacoto, Maria J.; Addissie, Yonit A.; Hadley, Donald W.; Hadsall, Casey K.; Stokes, Bethany; Hu, Ping; Roessler, Erich; Solomon, Beth; Wiggs, Edythe; Thurm, Audrey; Hufnagel, Robert B.; Zein, Wadih M.; Hahn, Jin S.; Stashinko, Elaine; Levey, Eric; Baldwin, Debbie; Clegg, Nancy J.; Delgado, Mauricio R.; Muenke, Maximilian.

In: Genetics in Medicine, Vol. 20, No. 1, 01.01.2018, p. 14-23.

Research output: Contribution to journalArticle

Weiss, K, Kruszka, P, Guillen Sacoto, MJ, Addissie, YA, Hadley, DW, Hadsall, CK, Stokes, B, Hu, P, Roessler, E, Solomon, B, Wiggs, E, Thurm, A, Hufnagel, RB, Zein, WM, Hahn, JS, Stashinko, E, Levey, E, Baldwin, D, Clegg, NJ, Delgado, MR & Muenke, M 2018, 'In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics', Genetics in Medicine, vol. 20, no. 1, pp. 14-23. https://doi.org/10.1038/gim.2017.68
Weiss K, Kruszka P, Guillen Sacoto MJ, Addissie YA, Hadley DW, Hadsall CK et al. In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics. Genetics in Medicine. 2018 Jan 1;20(1):14-23. https://doi.org/10.1038/gim.2017.68
Weiss, Karin ; Kruszka, Paul ; Guillen Sacoto, Maria J. ; Addissie, Yonit A. ; Hadley, Donald W. ; Hadsall, Casey K. ; Stokes, Bethany ; Hu, Ping ; Roessler, Erich ; Solomon, Beth ; Wiggs, Edythe ; Thurm, Audrey ; Hufnagel, Robert B. ; Zein, Wadih M. ; Hahn, Jin S. ; Stashinko, Elaine ; Levey, Eric ; Baldwin, Debbie ; Clegg, Nancy J. ; Delgado, Mauricio R. ; Muenke, Maximilian. / In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics. In: Genetics in Medicine. 2018 ; Vol. 20, No. 1. pp. 14-23.
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AU - Hadley, Donald W.

AU - Hadsall, Casey K.

AU - Stokes, Bethany

AU - Hu, Ping

AU - Roessler, Erich

AU - Solomon, Beth

AU - Wiggs, Edythe

AU - Thurm, Audrey

AU - Hufnagel, Robert B.

AU - Zein, Wadih M.

AU - Hahn, Jin S.

AU - Stashinko, Elaine

AU - Levey, Eric

AU - Baldwin, Debbie

AU - Clegg, Nancy J.

AU - Delgado, Mauricio R.

AU - Muenke, Maximilian

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N2 - 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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