First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations

Abstract

Introduction: PACS1-related neurodevelopmental disorder (PACS1-related NDD) is caused by pathogenic variants in the PACS1 gene and is characterized by a distinctive facial appearance, intellectual disability, speech delay, seizures, feeding difficulties, cryptorchidism, hernias, and structural anomalies of the brain, heart, eye, and kidney. There is a marked facial resemblance and a common multisystem affectation with patients carrying pathogenic variants in the WDR37 and PACS2 genes, although they vary in terms of severity and eye involvement.

Case presentation: Here, we describe 4 individuals with PACS1-related NDD from Mexico, all of them carrying a de novo PACS1 variant c.607C>T; p.(Arg203Trp) identified by exome sequencing. In addition to eye colobomata, this report identified corneal leukoma, cataracts, and tortuosity of retinal vessels as ophthalmic manifestations not previously reported in patients with PACS1-related NDD.

Discussion: We reviewed the ocular phenotypes reported in 74 individuals with PACS1-related NDD and the overlaps with WDR37- and PACS2-related syndromes. We found that the 3 syndromes have in common the presence of colobomata, ptosis, nystagmus, strabismus, and refractive errors, whereas microphthalmia, microcornea, and Peters anomaly are found only among individuals with PACS1-related NDD and WDR37 syndrome, being more severe in the latter. This supports the previous statement that the so-called WDR37-PACS1-PACS2 axis might have an important role in ocular development and also that the specific ocular findings could be useful in the clinical differentiation between these related syndromes.

Keywords: Coloboma; PACS1; PACS2; Peters anomaly; WDR37.