Syndromic Alobar Holoprosencephaly Associated with a de novo 2p21p16.2 Contiguous Gene Deletion: A Neonatal Case Report

Background: Chromosome 2p21 harbors SIX3, a major driver gene for holoprosencephaly (HPE). Large copy number variants (CNVs) overlapping 2p21p16.2 are rare and may present with pleiotropic congenital anomalies. Case Presentation: A female neonate born at 27 weeks (1,000 g) after placental abruption was diagnosed with distinguishable craniofacial features, alobar HPE, agenesis of the corpus collosum (ACC), and a 6-mm atrial septal defect. Chromosomal microarray analysis revealed a heterozygous 11.3 Mb interstitial deletion at arr[GRCh38] 2p21p16.2(43075433_54379379)x1, containing entire SIX3, EPCAM, and a cluster of mismatch repair (MMR) genes such as MSH2 and MSH6. The parents do not have dysmorphic features, their karyotype analysis was normal, and based on the available data, the CNV was considered de novo. Conclusion: The patient’s phenotype is consistent with SIX3 haploinsufficiency leading to severe forebrain division insufficiency; the adjacent MMR deletion defines the Lynch susceptibility locus. We emphasize the need to consider the risk of cancer in later life, in addition to the currently available findings.