Colobomatous microphthalmia is a potentially blinding congenital ocular malformation that can present either in isolation or together with other syndromic features. Despite a strong genetic component to disease, many cases lack a molecular diagnosis. We describe an autosomal dominant oculo-vertebral-renal (OVR) syndrome in six independent families characterized by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities. Genome sequencing identified six rare variants in the orphan nuclear receptor gene NR6A1 in these families. We performed in silico, cellular, and zebrafish experiments to demonstrate the NR6A1 variants were pathogenic or likely pathogenic for OVR syndrome. Knockdown of either or both zebrafish paralogs of NR6A1 results in abnormal eye, kidney, and somite development, which was rescued by wild-type but not variant NR6A1 mRNA. Illustrating the power of genomic ascertainment in medicine, our study establishes NR6A1 as a critical factor in eye, kidney, and vertebral development, and a pleiotropic gene responsible for OVR syndrome. Cat eye syndrome (CES), also known as Schmid-Fraccaro syndrome, is a rare genetic disorder named for the vertical iris coloboma observed in some affected individuals. The condition is classically characterized by a triad of features—iris coloboma, anal atresia, and preauricular pits or tags. However, CES can also involve a range of abnormalities affecting the neurodevelopmental, ocular, auricular, nasal, cardiovascular, gastrointestinal, and urogenital systems (see Image. Schematic Diagram Showing Iris Coloboma in Cat Eye Syndrome).  The clinical presentation of CES is variable, with differences in affected organ systems, prognosis, genetics, and heritability among individuals. CES is a rare chromosomal disorder first described in the early 1960s by Schmid and Fraccaro. This condition is characterized by a partial tetrasomy or trisomy of chromosome 22q11.1-q11.2. The name "cat eye" originates from ocular colobomas—iris defects—present in about half of affected individuals, which give the pupil a distinctive keyhole or cat-eye appearance. Although ocular coloboma is the eponymous hallmark, CES is fundamentally a multisystem genomic disorder with highly variable expressivity, spanning a spectrum from nearly asymptomatic to severe anomalies across ocular, cardiac, renal, gastrointestinal, skeletal, and neurodevelopmental domains. The association between ocular coloboma and anal atresia was first described by Haab in 1878. The genetic alteration is due to a small supernumerary marker chromosome (sSMC), which was first described in 1965. Schachenmann et al reported 3 pediatric patients and 1 patient’s mother who carried an additional, abnormally small chromosome featuring a submedian centromere, while the rest of the karyotype appeared normal. This sSMC contains the CES critical region (CESCR), located within the proximal portion of chromosome 22q11.2, between the centromere and the LCR22-A region. Additional genetic conditions related to chromosome 22 include the oculo-auriculo-vertebral spectrum (OAVS), DiGeorge syndrome, and mosaic trisomy 22.  At the genetic level, CES arises from a supernumerary marker chromosome, often dicentric, composed of material from chromosome 22. In approximately 90% of cases, this marker contains 2 extra copies of the proximal 22q11 region (tetrasomy), while a smaller proportion exhibits an additional copy (trisomy). The critical region encompasses approximately 1.5 to 2 Mb and includes multiple dosage-sensitive genes whose overexpression is believed to contribute to the diverse phenotypic features of CES. Molecular cytogenetic techniques, such as fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and, more recently, genome-wide single-nucleotide polymorphism (SNP) microarrays, have replaced traditional karyotyping for precise delineation of the supernumerary chromosome and identification of the breakpoints. This high-resolution genomic mapping is crucial for definitive diagnosis, genotype-phenotype correlations, and recurrence-risk counseling. Clinically, CES is remarkably heterogeneous. The classic triad comprises iris coloboma, preauricular skin tags or pits, and anal atresia or other anorectal malformations. However, no single feature is universally present. Iris coloboma appears in 40% to 60% of cases, preauricular anomalies in up to 70%, and anorectal malformations in about 30% to 50%. Cardiac defects, most commonly total or partial atrioventricular septal defects and tetralogy of Fallot, occur in approximately half of patients and are a major contributor to early morbidity and mortality. Renal anomalies, reported in 20% to 40% of cases, may include unilateral renal agenesis, duplex collecting systems, hydronephrosis, and vesicoureteral reflux. Skeletal abnormalities range from vertebral segmentation defects to limb anomalies. Otolaryngological manifestations may include hearing loss from middle-ear dysplasia. Less commonly, gastrointestinal anomalies beyond anorectal malformations—such as duodenal atresia or Hirschsprung disease—have also been documented. Neurodevelopmental outcomes in CES vary widely. Although some children achieve developmental milestones within normal limits, others present with global developmental delay, intellectual disability, or features consistent with autism spectrum disorder. Hypotonia during infancy and feeding difficulties—often related to underlying gastrointestinal anomalies—may further compromise early growth. Growth parameters can be affected, with some patients exhibiting short stature or failure to thrive; however, many ultimately achieve normal height and weight. Behavioral phenotypes—such as attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders—have also been reported, emphasizing the importance of comprehensive developmental and psychological assessment. Ophthalmic manifestations in CES extend beyond the iris coloboma. Additional anomalies such as chorioretinal colobomas, microphthalmia, cataracts, microcornea, and strabismus can contribute to visual impairment. A comprehensive ophthalmologic evaluation includes slit-lamp biomicroscopy to assess anterior segment abnormalities, indirect ophthalmoscopy for posterior segment examination, and optical coherence tomography (OCT), when available, to delineate the extent of colobomatous defects. Early detection and management of refractive errors, amblyopia, and strabismus are essential to support optimal visual development. Surgical intervention for coloboma is rarely indicated and is typically reserved for cases involving severe aniridia-like photophobia or significant cosmetic concerns (see Image. Schematic Diagram Showing Chorioretinal Coloboma in Cat Eye Syndrome). The management of CES depends on the organ systems involved and the severity of associated malformations. Given the significant clinical heterogeneity, an individualized, interprofessional approach is essential. This activity outlines the genetic and phenotypic spectrum of CES and outlines strategies for tailoring medical care to each patient’s needs. Cardiac evaluation at diagnosis is mandatory. Echocardiography within the first weeks of life is essential for detecting structural heart disease; in moderate-to-severe cases, surgical repair during infancy may be lifesaving. Long-term cardiology follow-up is critical to monitor for residual defects, arrhythmias, and pulmonary hypertension. Similarly, early renal ultrasonography is recommended to identify anatomical anomalies, guide urologic management, and prevent complications such as hypertension or renal insufficiency. Gastroenterological and colorectal management primarily focuses on anorectal malformations. Posterior sagittal anorectoplasty (PSARP) is the standard repair for imperforate anus, with timing and technical details tailored to the patient’s specific anatomy and overall health. Nutritional support—ranging from gavage or gastrostomy feeding in neonates to dietary modifications in older children—is essential, especially when gastrointestinal motility disorders or malabsorption are present. Audiologic and otologic care begins with newborn hearing screening. Conductive hearing loss due to middle ear anomalies may require interventions such as tympanostomy tubes or myringotomy. Speech therapy and educational support, tailored to the child’s developmental needs, are essential for optimizing communication outcomes. Genetic counseling for families includes discussion of recurrence risk, which is generally low (<1%) in de novo cases but higher in familial instances when a parent carries the small supernumerary marker chromosome in a balanced form. Secondary complications may include endocrine disorders, particularly growth hormone deficiency and thyroid dysfunction, necessitating regular endocrinologic screening. Orthopedic evaluations focus on detecting scoliosis and limb-length discrepancies. Dental and orthodontic assessments help identify malocclusion and enamel hypoplasia. Psychosocial support for families—including referrals to patient advocacy groups and peer support networks—promotes coping strategies and shared experiences. From a research perspective, CES provides valuable insights into gene dosage effects in contiguous-gene syndromes. The 22q11 region implicated in CES overlaps with that of DiGeorge syndrome (22q11.2 deletion), yet their phenotypes differ, reflecting divergent consequences of haploinsufficiency versus gene overexpression. Current studies focus on elucidating the roles of candidate genes such as CECR1 (which encodes adenosine deaminase 2) and CECR2 (involved in chromatin remodeling) in contributing to CES manifestations. Animal models with targeted duplications of the 22q11 region are under development to investigate relevant developmental pathways. Additionally, next-generation sequencing techniques show promise in detecting cryptic rearrangements and refining genotype–phenotype correlations, ultimately improving prognostic accuracy and identifying potential therapeutic targets. In summary, CES is a complex, multisystem chromosomal disorder. While its hallmark features include ocular coloboma, ear anomalies, and anorectal malformations, the condition also encompasses a wider phenotypic spectrum affecting the cardiac, renal, skeletal, neurodevelopmental, and endocrine systems. Accurate diagnosis relies on high-resolution cytogenetic and molecular techniques. Effective management requires coordinated multidisciplinary care, involving specialties from neonatology and cardiology to ophthalmology, urology, and developmental pediatrics. As advances in molecular genetics continue, they will enhance personalized prognostic counseling and enable the development of targeted therapies, ultimately improving outcomes for individuals and families affected by this rare but informative genomic syndrome.

Background/Objectives: Heterozygous variants in the heterogeneous nuclear ribonucleoprotein C gene (HNRNPC) have recently been reported to cause intellectual developmental disorder-74 (MRD74), a neurodevelopmental disorder with no recurrent diagnostic handles. Affected individuals show variable, non-specific, and subtle dysmorphic features. The degree of developmental delay (DD)/intellectual disability (ID) is also wide, ranging from mild to severe. The mutational spectrum is relatively broad with exon deletions and splice site and frameshift variants distributed along the entire length of the gene leading to HNRNPC loss of function. Only two missense changes located within the RNA-binding motif (RBM) and adjacent linker region of the more abundant isoform (Arg64Trp and Arg99Gln) have been described. Notably, the Arg99Gln amino acid substitution was reported in a subject presenting with a more complex and unique clinical phenotype characterized by distinctive facial features, DD/ID, cochlear aplasia, and bilateral colobomatous microphthalmia, suggesting the possible occurrence of phenotypic heterogeneity. Results: Here, we report the second individual carrying the Arg99Gln change in HNRNPC and having clinical features with a significant overlap with the peculiar phenotype of the previously described subject, supporting the occurrence of a genotype-phenotype correlation. Conclusions: Due to the concomitant occurrence of ocular and cochlear involvement as recognizable diagnostic handles, we propose that the HNRNPCArg99Gln-related phenotype should be considered as a potential differential diagnosis in subjects with ID and major signs of CHARGE syndrome not fulfilling the minimum criteria for a clinical diagnosis.

Colobomatous microphthalmia is a potentially blinding congenital ocular malformation that can present either in isolation or together with other syndromic features. Despite a strong genetic component to disease, many cases lack a molecular diagnosis. We describe a novel autosomal dominant oculo-vertebral-renal (OVR) syndrome in six independent families characterized by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities. Genome sequencing identified six rare variants in the orphan nuclear receptor gene NR6A1 in these families. We performed in silico, cellular and zebrafish experiments to demonstrate the NR6A1 variants were pathogenic or likely pathogenic for OVR syndrome. Knockdown of either or both zebrafish paralogs of NR6A1 results in abnormal eye and somite development, which was rescued by wild-type but not variant NR6A1 mRNA. Illustrating the power of genomic ascertainment in medicine, our study establishes NR6A1 as a critical factor in eye and vertebral development and a pleiotropic gene responsible for OVR syndrome.

Colobomatous microphthalmia is a potentially blinding congenital ocular malformation that can present either in isolation or together with other syndromic features. Despite a strong genetic component to disease, many cases lack a molecular diagnosis. We describe a novel autosomal dominant oculo-vertebral-renal (OVR) syndrome in six independent families characterized by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities. Genome sequencing identified six rare variants in the orphan nuclear receptor gene NR6A1 in these families. We performed in silico, cellular and zebrafish experiments to demonstrate the NR6A1 variants were pathogenic or likely pathogenic for OVR syndrome. Knockdown of either or both zebrafish paralogs of NR6A1 results in abnormal eye and somite development, which was rescued by wild-type but not variant NR6A1 mRNA. Illustrating the power of genomic ascertainment in medicine, our study establishes NR6A1 as a critical factor in eye and vertebral development and a pleiotropic gene responsible for OVR syndrome.

To describe the clinical characteristics and outcomes of children with posterior segment coloboma (PSC). The medical records of children (age <18 years) with PSC examined at Boston Children's Hospital from May 1997 to May 2023 were reviewed retrospectively. The following data were collected: demographics, ocular and systemic conditions, coloboma type according to the Ida Mann (IM) classification, and best-corrected visual acuity. Rate of retinal detachment (RD) was calculated. A t test was used to compare visual outcomes by coloboma classification. Logistic regression was used to evaluate the association of CHARGE syndrome with coloboma classification and laterality. A total of 501 eyes of 343 patients were included. Differences in the mean best-corrected visual acuity of eyes with large PSC (IM type 1-3) and moderate-to-small PSC (IM type 4-7) were found at initial and final examination (both P < 0.001). RD rate was 5% per eye (95% CI, 3.25-7.28) and 7.3% per patient (95% CI, 4.77-10.57). After adjusting for covariates, children with CHARGE syndrome were at increased odds of having IM type 1, type 2, or type 3 colobomas (OR = 2.5; 95% CI, 1.4-4.8; P = 0.003) and bilateral fundus colobomas (OR = 7.0; 95% CI, 3.4-14.5; P <0.001), regardless of IM type, compared to children with PSC and no CHARGE association. Eyes with large IM colobomas had worse visual outcomes than those with smaller defects; however, both experienced visual impairment. Children with PSC had a low rate of RD. Children with CHARGE syndrome often presented with bilateral and large IM colobomatous defects.