SLC30A9 – Birk-Landau-Perez Syndrome

Birk-Landau-Perez syndrome is an autosomal recessive cerebro-renal disorder characterized by neurodevelopmental regression, oculomotor abnormalities, movement disorder, and variable renal involvement. Patients typically present with developmental regression, ataxia, hearing impairment, and eye abnormalities. In addition, some individuals demonstrate chronic kidney disease, highlighting a complex and variable clinical spectrum. This syndrome was initially reported in a large Bedouin kindred and subsequently observed in additional consanguineous families, expanding the phenotypic presentation. Multiple case reports across diverse populations underscore the reproducibility of the clinical findings (PMID:37576556).

Genetic investigations have revealed biallelic pathogenic variants in SLC30A9 that segregate with the disease phenotype. In one pivotal case report, whole‐exome sequencing identified a homozygous in-frame deletion, which was confirmed to segregate with disease in the family (PMID:37576556).Another study involving four unrelated families identified additional pathogenic variants, including a recurrent missense change that disrupts the protein structure (PMID:37041080). These findings, spread over multiple independent families, provide robust genetic support for the role of SLC30A9 in this syndrome.

The genetic evidence is further underscored by segregation analysis demonstrating that affected siblings and other relatives harbor the pathogenic alleles, with at least seven additional affected relatives documented in familial studies (PMID:37576556, PMID:37041080). The spectrum of reported variants includes the in‐frame deletion c.1049_1051delCAG (p.Ala350del), which meets stringent HGVS guidelines, and other variant types contributing to disease heterogeneity. This convergence of allelic findings across case reports and multi‐patient studies strengthens the causative link between SLC30A9 and the clinical phenotype.

Functional studies further support the pathogenicity of SLC30A9 disruption by demonstrating impaired zinc transport and altered intracellular zinc homeostasis. Experimental assays in cellular models have consistently shown that the mutant SLC30A9 protein leads to lower cytosolic zinc concentrations and mitochondrial zinc accumulation, phenomena that plausibly underlie the observed neurological and renal features (PMID:28334855). Moreover, animal models and cross‐species functional analyses indicate that loss of SLC30A9 function results in severe developmental abnormalities, thereby offering a mechanistic framework for the human phenotype (PMID:39158587). Such concordant experimental evidence offers moderate support regarding the molecular mechanism of disease.

In summary, the integration of genetic and functional data provides a coherent narrative linking biallelic SLC30A9 variants with Birk-Landau-Perez syndrome. The documented genetic evidence from multiple unrelated probands, combined with rigorous segregation and recurrent variant findings, along with functional assays demonstrating zinc dyshomeostasis, culminate in a strong gene-disease association. While some phenotypic variability exists among patients, the overall data substantiate the clinical utility of testing SLC30A9 in individuals with overlapping cerebro-renal phenotypes. This information aids diagnostic decision-making, supports commercial use in genetic testing panels, and underpins future publication efforts.

Key Take‑home sentence: Definitive genetic and functional evidence for SLC30A9 implicates it as a critical diagnostic marker in patients with complex neurodevelopmental and renal syndromes.

References

• Frontiers in Genetics • 2023 • Case report: Birk-Landau-Perez syndrome linked to the SLC30A9 gene-identification of additional cases and expansion of the phenotypic spectrum PMID:37576556
• Neurology • 2023 • Clinical Phenotype in Individuals With Birk-Landau-Perez Syndrome Associated With Biallelic SLC30A9 Pathogenic Variants PMID:37041080
• Brain : a journal of neurology • 2017 • SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome PMID:28334855
• Cellular and Molecular Life Sciences : CMLS • 2024 • SLC30A9: an evolutionarily conserved mitochondrial zinc transporter essential for mammalian early embryonic development PMID:39158587

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