LZTFL1 was first reported in relation to an autosomal recessive ciliopathy, Bardet-Biedl syndrome 17 (BBS17), in 2012 (Marion et al, PMID: 22510444). Bardet-Biedl syndrome is a multisystem disorder characterized by retinopathy, obesity, polydactyly, intellectual disability, hypogonadotropic hypogonadism and/or genitourinary malformations, and renal malformations and/or renal disease Biallelic loss-of-function variants in at least 26 genes have been described in affected individuals. LZTFL1 is thought to cause <1% of BBS cases (Forsyth and Gunay-Aygun, 2023, PMID: 20301537).
LZTFL1 encodes “leucine zipper transcription factor-like 1”, a ubiquitously expressed cytoplasmic protein that interacts with the BBSome and regulates protein trafficking to the ciliary membrane. Together with the BBSome, LZTFL1 controls the ciliary trafficking of smoothened (SMO) and contributes to the sonic hedgehog (SHH) pathway regulation.
Six variants (two nonsense, two frameshift, one missense, and one synonymous predicted to impact splicing) have been reported in six probands in five publications (Marion et al, 2012, PMID: 22510444; Schaeffer et al, 2014, PMID: 23692385; Gumus et al, 2021, PMID: 32686083; Nawaz et al, 2023, PMID: 37239474; Gnanasekaran et al, 2023, PMID: 37431782). The individuals reported have typical features of BBS but the polydactyly of the hands is mesoaxial rather than postaxial. The mechanism of pathogenicity appears to be loss of function. Total points for genetic evidence = 11.6 points.
This gene-disease relationship is also supported by experimental evidence, including the biochemical function of the gene product, which is consistent with the clinical features observed in patients (Seo et al, 2011, PMID: 22072986; Eguether et al, 2014, PMID: 25446516), observations in cells from a patient (Marion et al, 2012, PMID: 22510444), the features observed in a knock out mouse model (Datta et al, 2015, PMID: 26216965), and results of a rescue experiment (Datta et al, 2020, PMID: 32568387). More experimental evidence is available in the literature but the maximum (6 points) has already been reached.
In summary, there is definitive evidence supporting the relationship between LZTFL1 and autosomal recessive LZTFL1-related ciliopathy. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on January 4th, 2024 (SOP version 10).
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