The researchers classified the variants of the CDD gene that causes AADC deficiency based on its pathogenic potential, study finds, first study to identify and characterize hitherto unknown CDD variants.
“Since genetic testing is a core diagnostic test for AADC deficiency, a comprehensive catalog of genetic variants associated with the disorder is essential for interpreting genetic test results,” the researchers wrote.
The study of the variant, “Spectrum of CDD variants causing aromatic l-amino acid decarboxylase (AADC) deficiency and interpretation of pathogenicity using ACMG-AMP/ACGS recommendationswas published in the journal Molecular genetics and metabolism.
AADC deficiency is caused by variants of CDD gene that causes reduced activity of the AADC enzyme, which is vital for producing several neurotransmitters, molecules that nerve cells use to communicate.
CDD variants can result in an inactive AADC enzyme, or too little enzyme, ultimately reducing neurotransmitter production. Because different variants lead to enzymes with different activities, and in turn a range of neurotransmitter levels, symptoms and their severity, vary greatly from person to person.
Therefore, understanding the molecular characteristics associated with different CDD the variants will help support an accurate diagnosis of AADC deficiency.
“The ability to accurately diagnose aromatic l-amino acid decarboxylase (AADC) deficiency depends on a more complete understanding of CDD gene variants, their molecular effects and their link to AADC deficiency [characteristics]wrote a research team in Europe and the United States
422 variants identified and located
The researchers first identified 422 variants from three databases and mapped them to their location in the human CDD embarrassed. Variants were found throughout the gene, including in segments containing instructions for proteins, called exons, and introns, segments deleted before protein production. Variants also occurred immediately next to the start and end of the gene.
All variants were then ranked according to their pathogenic potential, or pathogenicity, according to the modified American College of Medical Genetics and Genomics/Association for Molecular Pathology/Association for Clinical Genomic Science (ACMG-AMP/ACGS) criteria.
The largest number of variants, totaling 348, were classified as having moderate pathogenicity by the ACMG and were not found in a healthy population. This was followed by 176 variants considered to support pathogenicity by computational analysis.
According to published reports, 108 CDD variants cause confirmed AADC deficiency. At least one allele was classified in this study as a pathogen or probable pathogen in 101 of the 108 different gene types (genotypes). An allele is a variation of the same gene present at the same part of DNA. People inherit one allele from each parent.
At the same time, the others were a combination of two so-called variants of uncertain significance. No variant was judged to be benign or probably benign.
Of the 422 variants, 204 (48%) were missense variants, where a single change in the CDD leads to an AADC enzyme marked by a single change in an amino acid, a building block of protein. Sixty-two variants (15%) were synonymous, meaning they do not change amino acids but can nevertheless affect protein function, and 53 (13%) were considered to be intronic splice site variants . These changes occur at the boundary of an exon and an intron.
The impact of 68 variants (16%) on AADC enzyme production was unknown, and of these, 47 (69%) were deep intronic variants that occur far from the exon-intron boundary.
Frame, Extend, Nonsense, and Inframe Shift Variants
The remaining variants in this group have been categorized into frameshift variants due to DNA insertion or deletion, and extension variants, which extend the size of the protein. There were also some nonsensical variants, leading to a shortened enzyme, and in-frame variants, resulting in an enzyme with missing or altered sections.
Computer algorithms (CADD, PolyPhen2 and SIFT) were used to predict the impact of CDD missense variants, which modify single amino acids, on AADC enzyme function. This included analysis of the three-dimensional (3D) structure of the porcine kidney AADC enzyme to map these amino acid changes.
Among the 204 missense variants, 14 (7%) were classified as pathogenic and 66 (32%) as probably pathogenic.
Uncharacterized variants considered “hot” variants of uncertain significance (VUS), which were expected to be more pathogenic, occurred in 11 variants (5%), with 32 (16%) as hot VUS and 36 (18%) like lukewarm SUVs. Cold SUVs were also categorized in 25 (12%), 10 (5%) as cold SUVs, five (2%) as icy SUVs, and two (1%) as probably mild and mild.
Statistical analysis revealed that ACMG classification was strongly associated with SUV severity. Computational tools, including CADD and the three-dimensional enzyme structure of AADC, were more correlated with probably benign or probably pathogenic classifications. Finally, the PolyPhen2 and SIFT algorithms were mostly associated with benign or pathogenic classifications.
“The use of [computer] variant interpretation tools, combined with 3D structural modeling of variant proteins and applied benchmarking, have improved current CDD interpretation recommendations for variants, especially SUVs,” the researchers concluded.
#Classification #DDC #variants #interpreting #results #genetic #testing..