First Report of Mexican Patients with <b><i>PACS1</i></b>-Related Neurodevelopmental Disorder and Review of the <b><i>PACS1</i></b>-, <b><i>PACS2</i></b>-, and <b><i>WDR37</i></b>-Related Ophthalmological Manifestations

Abstract

<b><i>Introduction:</i></b> <i>PACS1</i>-related neurodevelopmental disorder (<i>PACS1-</i>related NDD) is caused by pathogenic variants in the <i>PACS1</i> 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 <i>WDR37</i> and <i>PACS2</i> genes, although they vary in terms of severity and eye involvement. <b><i>Case Presentation:</i></b> Here, we describe 4 individuals with <i>PACS1</i>-related NDD from Mexico, all of them carrying a de novo <i>PACS1</i> variant c.607C&#x3e;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 <i>PACS1</i>-related NDD. <b><i>Discussion:</i></b> We reviewed the ocular phenotypes reported in 74 individuals with <i>PACS1</i>-related NDD and the overlaps with <i>WDR37-</i> and <i>PACS2</i>-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 <i>PACS1</i>-related NDD and <i>WDR37</i> syndrome, being more severe in the latter. This supports the previous statement that the so-called <i>WDR37</i>-<i>PACS1</i>-<i>PACS2</i> 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.