Kabuki Syndrome (KS) is a rare, multisystem congenital disorder with five foremost clinical manifestations encompassing dysmorphic facial characteristics, postnatal growth constraint, craniofacial/skeletal anomalies, mild to moderate intellectual disability, and dermatoglyphic abnormalities. We analyzed two unrelated Iranian patients suspected of having KS using whole-exome sequencing. An in silico analysis was performed to evaluate the potential effects of the discovered variants on the structure and function of the corresponding protein. A novel de novo heterozygous protein-truncating mutation was found in patient 1, NM_003482.4: c.13818C>G (p.Y4606X), and a de novo heterozygous premature stop codon was identified in patient 2, NM_003482.4: c.16360C>T (p.R5454X). These mutations cause haploinsufficiency in KMT2D and are absent in the proband’s parents. Although these mutations provide evidence of the potential pathogenicity of KMT2D in KS, further functional studies are necessary to confirm their impact. Our observations not only provide evidence for the potential pathogenicity of the two identified protein-truncating mutations but also have important implications for the accurate diagnosis and potential treatment of KS. These findings underscore the significance of genetic testing in diagnosing this disorder and expand our understanding of the role of KMT2D mutations in its pathogenesis.

Knobloch Syndrome (KS) is a rare genetic disorder characterized by ocular abnormalities and central nervous system (CNS) defects, which are attributed to collagenopathy. The primary gene implicated in KS is COL18A1, which encodes the alpha chain of type XVIII collagen. This type of collagen functions as a proteoglycan, predominantly located in the basement membrane of human tissues. This study examined an Iranian female presenting with symptoms of horizontal nystagmus, strabismus, and suspected vision loss, with a potential diagnosis of KS. Genomic DNA was subjected to whole-exome sequencing (WES). The identified pathogenic variant was subsequently confirmed using Sanger sequencing. The impact of the identified pathogenic variant on the structure of COL18A1 was assessed using I-TASSER. Analysis of WES data revealed two pathogenic compound heterozygous variants, c.2416C>T (p.Arg806Ter) and c.1698delC (p.Gly567AspfsTer45), in exons 7 and 16, respectively, of the COL18A1 (NM_030582) gene. Furthermore, a standard literature review of clinical data highlighted the heterogeneity of phenotypic manifestations, ranging from mild ocular abnormalities to severe neurodevelopmental impairments. This study and literature search offer valuable insights into the genetic landscape of KS, thereby expanding our understanding of the disease and its clinical implications. The identification of novel variants in key genes sheds light on the underlying molecular mechanisms and potential therapeutic targets.