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.
Highlights
(HPE, MIM 236100) is defined by failed or incomplete division of the forebrain that occurs early in gestation
We evaluated a rare cohort of adolescents and adults with HPE with aims of characterizing genotypic and phenotypic features of the group, identifying factors associated with survival, and providing prognostic and natural history information so that information shared with families might be improved
Prenatal history was significant for uncontrolled maternal type 1 diabetes with ketoacidosis during early gestation
Summary
(HPE, MIM 236100) is defined by failed or incomplete division of the forebrain that occurs early in gestation. 602630) are found in approximately 30% of nonsyndromic cases,[2,10] while mutations in any of over 10 additional genes have been seen at a much lower frequency.[3,11] Familial cases of nonsyndromic HPE with dominant inheritance and variable expressivity or incomplete penetrance have been reported previously in multiple cohorts,[12,13] pointing to the possibility of complex inheritance in these families. Recent case reports of digenic inheritance[14,15] and studies on gene– environment interactions in mice have supported this scenario of complex inheritance in HPE.[16]
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