Dual molecular diagnosis of CEP290 and GLI3 mutations identified in an infant with leber congenital amaurosis and postaxial polydactyly, a Bardet-Biedl syndrome phenocopy.

This study describes a 6-month-old baby girl who was initially thought to have Bardet-Biedl Syndrome (BBS) but actually had two separate genetic conditions. The baby had severe vision problems from birth (unable to track objects visually, with rapid eye movements called nystagmus) and extra fingers on her hands. At first, doctors thought these symptoms together meant she had BBS, which typically causes both vision problems and multiple other health issues throughout the body. However, after following the child for 6 years and doing more comprehensive genetic testing, researchers discovered she actually had two different genetic mutations causing separate problems. One mutation (in the CEP290 gene) caused a severe eye condition called Leber Congenital Amaurosis Type 10 (LCA10), while a second mutation (in the GLI3 gene) inherited from her father caused only the extra fingers. Importantly, the child never developed the other health problems typically seen in BBS, such as kidney issues, obesity, or learning difficulties. This case is significant for families because it shows how important it is to get the right diagnosis. LCA10 has a much better outlook than BBS since it mainly affects vision rather than multiple body systems. Additionally, the researchers note that LCA10 is now being targeted for new gene therapies, which could offer hope for future treatments. The study emphasizes that comprehensive genetic testing and careful long-term observation are crucial for getting accurate diagnoses in complex cases.

Leber congenital amaurosis (LCA) is one of the earliest-onset and most severe forms of inherited retinal disease, and Bardet-Biedl syndrome (BBS) is a rare non-motile primary ciliopathy with a diverse multi-organ phenotype. To our knowledge, we present the first reported genetically confirmed case of LCA10 co-occurring with isolated postaxial polydactyly type A1 harboring CEP290 and GLI3 mutations, which was initially misdiagnosed as BBS. A 6-month-old female infant presented with no visual tracking, nystagmus, and postaxial polydactyly. Targeted gene panel testing identified compound heterozygous pathogenic variants in CEP290, leading to a preliminary diagnosis of BBS. Over a 6-year follow-up, the patient developed progressive pigmentary retinopathy with non-recordable electroretinography but did not develop any other systemic features of BBS. A critical, previously overlooked family history of polydactyly in the father prompted further investigation. Whole-exome sequencing revealed an additional likely pathogenic variant in the GLI3 gene, which was paternally inherited and responsible for the isolated polydactyly. The ocular phenotype was definitively attributed to the CEP290 mutations. A final diagnosis of LCA Type 10 (LCA10) with postaxial polydactyly type A1 was established. This case illustrates the novel co-occurrence of two distinct genetic disorders: CEP290-associated LCA10 and GLI3-associated isolated polydactyly. The initial diagnostic challenge underscores the complexity of pediatric inherited retinal diseases and highlights several critical lessons. The importance of longitudinal phenotyping, the necessity of a detailed family history, and the superior diagnostic utility of comprehensive genetic testing like whole-exome sequencing over targeted panels in complex presentations. Accurate differentiation between LCA and syndromic ciliopathies like BBS is crucial for prognostic counseling and management, as LCA10 carries a more favorable systemic prognosis and is now a target for emerging gene therapies.