Cytogenetics and holoprosencephaly: A chromosomal microarray study of 222 individuals with holoprosencephaly

Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):175-186. doi: 10.1002/ajmg.c.31622.


Holoprosencephaly (HPE), a common developmental forebrain malformation, is characterized by failure of the cerebrum to completely divide into left and right hemispheres. The etiology of HPE is heterogeneous and a number of environmental and genetic factors have been identified. Cytogenetically visible alterations occur in 25% to 45% of HPE patients and cytogenetic techniques have long been used to study copy number variants (CNVs) in this disorder. The karyotype approach initially demonstrated several recurrent chromosomal anomalies, which led to the identification of HPE-specific loci and, eventually, several major HPE genes. More recently, higher-resolution cytogenetic techniques such as subtelomeric multiplex ligation-dependent probe amplification and chromosomal microarray have been used to analyze chromosomal anomalies. By using chromosomal microarray, we sought to identify submicroscopic chromosomal deletions and duplications in patients with HPE. In an analysis of 222 individuals with HPE, a deletion or duplication was detected in 107 individuals. Of these 107 individuals, 23 (21%) had variants that were classified as pathogenic or likely pathogenic by board-certified medical geneticists. We identified multiple patients with deletions in established HPE loci as well as three patients with deletions encompassed by 6q12-q14.3, a CNV previously reported by Bendavid et al. In addition, we identified a new locus, 16p13.2 that warrants further investigation for HPE association. Incidentally, we also found a case of Potocki-Lupski syndrome, a case of Phelan-McDermid syndrome, and multiple cases of 22q11.2 deletion syndrome within our cohort. These data confirm the genetically heterogeneous nature of HPE, and also demonstrate clinical utility of chromosomal microarray in diagnosing patients affected by HPE.

Keywords: CNV; array CGH; chromosomal microarray; copy number variant; holoprosencephaly.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Chromosome Aberrations*
  • Comparative Genomic Hybridization
  • Cytogenetics / methods
  • DNA Copy Number Variations
  • Female
  • Genetic Association Studies*
  • Holoprosencephaly / diagnosis*
  • Holoprosencephaly / genetics*
  • Humans
  • Infant
  • Karyotyping
  • Male
  • Phenotype
  • Young Adult