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

• Published in: Genetics in medicine Vol. 20; no. 1; pp. 14 - 23
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.01.2018; Nature Publishing Group US; Elsevier Limited; Nature Publishing Group
• Subjects: 631/208/1516; 631/208/2489/1381; 692/699/375/2764; Adolescent; Adult; Adults; Biomedical and Life Sciences; Biomedicine; DISP1; Facies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; holoprosencephaly; Holoprosencephaly - diagnosis; Holoprosencephaly - genetics; Human Genetics; Humans; Laboratory Medicine; Magnetic Resonance Imaging; Male; natural history; Neuropsychological Tests; Original; original-research-article; Phenotype; Registries; whole-exome sequencing; Young Adult; ZIC2; holoprosencephaly; ZIC2; natural history; whole-exome sequencing; DISP1
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1038/gim.2017.68

With 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. Participants 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. Semilobar 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. Individuals 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.