Submission Details

The SLC30A9 gene encodes the zinc transporter ZnT9, which is highly expressed in the fetal brain, cerebellum, skeletal muscles, and kidney (PMID: 28334855). The evolutionarily conserved ZnT9 protein is primarily localized in the mitochondria of both invertebrates and vertebrates. ZnT9 functions to export zinc from the mitochondria, thereby maintaining zinc homeostasis and ensuring normal respiratory chain activity (PMID: 34433664, 39158587). SLC30A9 was first reported in relation to autosomal recessive acrodermatitis psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, also known as Birk-Landau-Perez syndrome (BILAPES) in 2017 (Perez et al., PMID: 28334855). This progressive genetic disorder is characterized by severe psychomotor delay or regression, intellectual disability, ataxia or gait abnormality, dystonia, choreoathetosis, axial hypotonia, oculomotor apraxia, ptosis, sensorineural hearing impairment, variable renal symptoms such as echogenic kidney, chronic kidney disease, cystic kidney and renal hypoplasia, and abnormal brain imaging findings. Six unique variants including in-frame small deletion, frameshift, and splicing variants that have been reported in seven unrelated probands are included in this curation (PMIDs: 28334855, 34716203, 37041080, 37576556). The pathogenicity mechanism is loss-of-function. This gene-disease association is supported by expression studies, in vitro assays, and animal models. The gene is highly expressed in the brain, skeletal muscle, and kidney (PMID: 28334855). ZnT9 exports zinc from mitochondria, crucial for maintaining their morphology and function. Loss of ZnT9 leads to swollen mitochondria with an expanded matrix and disappearing cristae, a phenotype rescued by wildtype ZnT9 but not by mutant p.350del. Zinc imbalance due to ZnT9 loss causes defective mitochondrial functions (PMID: 34433664). The number of mitochondria is reduced in mutant worm neural dendrites and axons, indicating SLC30A9's role in mitochondrial transport (PMID: 34433664). Knockdown of SLC30A9 in flies results in abnormal movement and wing posture, with disrupted mitochondrial shapes and increased zinc levels. Introducing wildtype SLC30A9 or reducing zinc transport partially rescues these defects (PMID: 39158587). Mice with brain-specific KO of SLC30A9 show decreased size, weight, movement abnormalities, tremors, and early death, mirroring some patient symptoms. Their mitochondria are enlarged with decreased folding and elevated zinc content. Knockdown in 293T cells or zinc treatment reduces mitochondrial function, ATP content, and membrane potential, linking ZnT9 loss to zinc accumulation and mitochondrial dysfunction (PMID: 39158587). In summary, SLC30A9 is definitively associated with autosomal recessive psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen IEM GCEP on March 14, 2025 (SOP Version 11).