Abstract:
Holoprosencephaly (HPE) is a devastating congenital brain disorder characterized by partial or complete non-separation of the primary prosencephalon along its three major planes. It occurs in as many as 1 in 250 conceptuses and 1 in 10,000 live births. HPE is regarded as a multifactorial disorder, stemming from intricate interactions among diverse genetic elements, the interplay of genetic and environmental factors, and potentially unidentified contributors. Studies in European (including patients from the United Kingdom) and North/South American cohorts have found that two of the most frequently implicated genes in HPE patients include the SHH and ZIC2 genes, respectively. In addition, chromosomal abnormalities (aneuploidy or structural aberrations) are commonly identified in syndromic forms of HPE. To date, there have been no studies to identify the genetic basis of HPE in South African patients.
In this retrospective study, patients with non-chromosomal, non-syndromic HPE, who attended the University of Pretoria Facial Cleft Deformity Clinic, were investigated. A total of 37 patients (33 of African- and 4 of European ancestry) with non-chromosomal HPE and no family history were screened for sequence variants in the SHH and ZIC2 genes, using Sanger sequencing. Overall, 13 variants (of mostly benign clinical significance) were identified, six previously reported variants in ZIC2 and seven variants in SHH, two of which are novel (one nonsynonymous & one intronic variant). Interestingly, all of the variants were detected in patients of self-identified African ancestry, except for one intronic variant (c.301-49G>A) in SHH, that was detected in two patients of European ancestry. Particularly noteworthy is the novel SHH missense variant, p.Leu122Arg (c.365T>G), that is predicted to be disease-causing by various in silico methods and may likely be pathogenic. Until functional studies of the ZIC2 Alanine expansion variant, p.Ala469_Ala470dup, determines the effect of this expansion, it must be classified as a variant of unknown significance.
In conclusion, this study represents the first investigation of both the ZIC2- and SHH-genes in a cohort of South African patients with non-chromosomal, non-syndromic holoprosencephaly. To our knowledge, this is the first study to identify a likely pathogenic variant in the SHH gene that may be responsible for 1/33 of non-chromosomal, non-syndromic South African HPE cases of African ancestry. The results of this study contribute further information on the role of the SHH- and ZIC2-genes in non-syndromic cases of holoprosencephaly, especially in African populations.
