Intragenic loss-of-function variants in transcription factors <i>MAZ</i> , <i>FOXP1</i> and <i>SIN3B</i> in colobomatous microphthalmia

Despite the identification of many genes involved in developmental eye phenotypes, a large percentage of families lack genetic diagnoses, suggesting novel mechanisms remain to be discovered. Large deletions of 16p11.2, 3p14 or 19p13.11 regions involving transcription factors <i>MAZ</i>, <i>FOXP1</i> and <i>SIN3B,</i> correspondingly, along with other genes, have been previously reported in individuals with neurodevelopmental and variable other features, including ocular coloboma and/or microphthalmia; recently, intragenic variants in <i>FOXP1</i> and <i>SIN3B</i> have also been shown to cause neurodevelopmental phenotypes, with developmental eye defects reported in a small number of individuals with <i>FOXP1</i> variants. Through exome sequencing analysis we identified novel splicing variants in <i>MAZ</i> and <i>SIN3B,</i> and a recurrent nonsense allele in <i>FOXP1</i> in unrelated families affected with colobomatous microphthalmia, all with predicted loss-of-function effects; additionally, we report two new families with coloboma and 16p11.2 genomic deletions including <i>MAZ,</i> one de novo and another inherited from an affected parent. These findings provide further support for a role for <i>FOXP1</i> in structural eye phenotypes, expanding its spectrum to include colobomatous microphthalmia, and suggest a role for <i>MAZ</i> and <i>SIN3B</i> in human eye development and disease.