Submission of genetic variant information of the human ZNT7 gene and updating the ClinVar database

Authors: Huang, Liping; ZIEGLER, ALBAN - University Of Angers

Submitted to: Clin Var
Publication Type: Database / Dataset
Publication Acceptance Date: 11/4/2023
Publication Date: 11/4/2023
Citation: Huang, L., Ziegler, A. 2023. Submission of genetic variant information of the human ZNT7 gene and updating the ClinVar database. Clin Var. VCV001711192.3. https://www.ncbi.nlm.nih.gov/clinvar/variation/1711192/?oq=SCV002578244&m=NM_133496.5(SLC30A7):c.21dup%20(p.Asp8fs)

Interpretive Summary: Zinc is an essential trace mineral and zinc deficiency results in stunted growth, skin lesions, hypogonadism (when the sex glands don't produce enough sex hormones during puberty), and frequent infections in humans. Disease-causing variants or mutations in the human SLC30A7 (ZNT7, a zinc transporter) gene have not been previously discovered. We identified two genetic variants of ZNT7 associated with clinical symptoms of stunted growth, delayed onset of puberty in teenage boys, and decreased blood cell counts, including white blood cells, red blood cells, and platelets, leading to anemia, infection, and bleeding. Genomic DNA sequencing from the affected patients and their parents revealed that the patients carried two different genetic variants in ZNT7 inherited from their unaffected parents. One of the variants led to a premature ending of the ZNT7 protein synthesis and the other variant affected functional message RNA generation (a process preceded protein synthesis in the cell). As the result, the level of ZNT7 protein in the cells of affected patients was significantly reduced by 80-96%. These findings strongly indicate that the biallelic variants in SLC30A7 should be considered as the cause for this inherited genetic disease, namely, the Zieglar-Huang Syndrome. Identification of mutations in the ZNT7 gene led to the first report describing zinc as essential for bone marrow health in humans. The findings were novel and greatly advanced knowledge of how zinc deficiency causes a weakened immune system and/or increased premature mortality due to bone marrow failure-induced severe pancytopenia (all blood cells in circulation are reduced) if not treated.

Technical Abstract: Zinc is an essential trace mineral and zinc deficiency results in stunted growth, skin lesions, hypogonadism and frequent infections in humans. Disease-causing variants or mutations in the human SLC30A7 (ZNT7, a zinc transporter) gene have not been previously discovered. We identified two genetic variants of ZNT7 associated with clinical symptoms of stunted growth, delayed onset of puberty in teenage boys, and decreased blood cell counts, including white blood cells, red blood cells, and platelets, leading to macrocytic anemia, infection, and bleeding. Genomic DNA sequencing from the affected patients and their parents revealed compound heterozygous variants in ZNT7 consisting of NM_133496.5:c.21dup; p.Asp8ArgfsTer3 and c.842 + 15 T > C inherited from their unaffected mother and father, respectively. The c.21dup variant led to a premature stop codon in exon 1 of the ZNT7 coding sequence. The c.842 + 15 T > C variant resulted in a leaky mRNA splicing event generating a premature stop codon right after the splicing donor site of exon 8. Due to the variants/mutations, the expression of ZNT7 protein was significantly reduced by 80-96% in the affected patients. These findings strongly indicate that the biallelic variants in SLC30A7 should be considered as the cause for this inherited genetic disease, namely, the Zieglar-Huang Syndrome. Identification of mutations in the ZNT7 gene led to the first report describing zinc as essential for bone marrow health in humans. The findings were novel and greatly advanced knowledge of how zinc deficiency causes a weakened immune system and/or increased premature mortality due to bone marrow failure-induced severe pancytopenia if not treated.