Last modified: 2018-09-09
Abstract
Introduction : Holoprosencephaly is a disorder of failure of prosencephalon to develop into two hemispheres. We describe a case of holoprosencephaly associated with variation of unknown significance (VUS) in GLI2 gene.
Methods: Case report
Case description: A 3-week-old term male was transferred to our hospital for surgical repair of congenital heart disease (CHD). Prenatal ultrasound had shown cleft lip/palate, cardiac anomalies and suspected Trisomy13. He was born by elective C-section, required intubation at birth and prostaglandins for duct dependent CHD. He soon developed seizures, was initiated on anti-epileptic drugs, and continued to have seizures despite maximal doses. MRI brain demonstrated semi lobar holoprosencephaly.
Chromosome analysis and chromosomal micro-array were normal. Whole exome sequencing (WES) showed pathogenic variant in KMT2D gene associated with Kabuki Syndrome. However, WES did not find the variant in parental samples, suggesting a de novo mutation in the patient. There was also a variation of unknown significance in GLI2 gene, known to be associated with holoprosencephaly 9. Mother was heterozygous for this mutation, while father was negative.
Results: Kabuki Syndrome is a genetic syndrome associated with de novo pathogenic variation in KMT2D gene based on previous studies. Kabuki syndrome is associated with seizures, but in our patient was complicated by concurrent holoprosencephaly.
Conclusions: Holoprosencephaly with Kabuki syndrome is extremely rare and may represent a second genetic syndrome in our patient, especially given variation of unknown significance in the GLI2. Defects in GLI2 are associated with holoprosencephaly 9; an autosomal dominant disorder with variable penetrance and expressivity