Per Criteria outlined by the ClinGen Lumping and Splitting working group, we found no difference in molecular mechanism or inheritance pattern underlying the disease entities: (1) Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), (MIM:616084) and (2) Retinitis pigmentosa and erythrocytic microcytosis, (MIM:616959). Therefore, evidence favor lumping the entities (MIM:616084 and MIM:616959) to a single disease spectrum.
TRNT1 (CCA-adding tRNA nucleotidyl transferase enzyme) performs an essential post- transcriptional modification by adding on the cytosine- cytosine-adenine (CCA) trinucleotide sequence to the 3′ end of all newly produced tRNAs. This TRNT1- dependent tRNA modification is essential for both cytosolic and mitochondrial tRNAs (mt-tRNAs) to participate in protein biosynthesis.
Mutations in TRNT1 were first reported to cause a syndrome characterized by congenital sideroblastic anemia, B-cell immunodeficiency, recurrent fevers and developmental delay (referred to as SIFD) in 2014 (PMID: 25193871). Retinitis pigmentosa and erythrocytic microcytosis were also reported in SIFD patients (PMID: 27370603).
2 frameshift , 2 splicing , and 3 missense TRNT1 variants are used in this curation. Mechanism of pathogenicity seems to be loss of function resulting in impaired ability of TRNT1 to catalyze the formation of the CCA trinucleotide (PMID: 25193871)
Experimental evidence also supports this gene-disease relationship. Phenotypes of the lumped diseases could be recapitulated in Zebrafish model system through the same molecular pathway. Morphological analysis of the MO-injected embryos (morphants) revealed cardiovascular defects and reduced eye size in addition to reduced staining of hemoglobin-containing red blood cells and significantly reduced touch response. RNA sequencing confirmed that Morphants had a significantly lower CCA incorporation efficiency than controls (PMID: 26494905). Mt-tRNAs lacking CCA are also detected in patients’ fibroblasts compared to controls (PMID: 27370603).
In summary, TRNT1 is definitively associated with the disease spectrum Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) and Retinitis pigmentosa and erythrocytic microcytosis. 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 Antibody Deficiencies GCEP on October 7, 2022.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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