Dataset Information

Estimated birth prevalence of Menkes disease and ATP7A-related disorders based on the Genome Aggregation Database (gnomAD).

ABSTRACT:

Background

Previous estimates of the prevalence of Menkes disease, a lethal X-linked recessive disorder of copper metabolism, were based on confirmed clinical cases ascertained from specific populations and varied from 1 in 40,000 to 1 in 354,507. With newly available population-based allelic frequencies of DNA sequence variants, the expected birth prevalence of Menkes disease and other ATP7A-related phenotypes can be reconsidered using Hardy-Weinberg theoretical principles.

Methods

We reviewed the canonical ATP7A transcript in the current version of gnomAD (v2.1.1) to evaluate frequency of complete loss-of-function alleles in a diverse normal control population. As a comparator, we used the DMD locus, associated with Duchenne and Becker Muscular Dystrophy, another X-linked recessive trait. We applied Hardy-Weinberg theory and PolyPhen-2 in silico plus REVEL and CADD ensemble analyses to calculate estimated frequencies of normal and predicted deleterious ATP7A alleles.

Results

We identified 1106 total ATP7A variants out of 205,523 alleles in gnomAD, with missense variants most common (43.4%). Complete loss-of-function variants were found in four ATP7A alleles (frequency = 0.0000194), including three frameshift/nonsense mutations and one canonical splice donor site defect. Assuming Harvey-Weinberg equilibrium, this frequency of pathogenic alleles predicts 1 in 34,810 live male births with Menkes disease or other ATP7A-related disorders each year in the US. The same analysis for DMD loss-of-function variants predicted 1 in 7246 newborn males with Duchenne (or Becker) muscular dystrophy. We also identified nine ATP7A missense variants in gnomAD predicted as deleterious by PolyPhen-2 and stringent REVEL/CADD criteria, comprising 12 more disease-causing alleles and raising the estimated birth prevalence to 1 in 8664 and predicting 225 newborns with Menkes disease or other ATP7A-related disorders per year in the US alone.

Conclusions

Assuming Harvey-Weinberg equilibrium, the allelic frequency of deleterious ATP7A variants in a genomic database from a large diverse population predicts a birth prevalence of Menkes disease or ATP7A-related disorders as high as 1 in 8664 live male births. This genome-driven ascertainment of deleterious ATP7A alleles in the population implies a higher birth prevalence of Menkes disease and ATP7A-related conditions than previously appreciated. A population-based newborn screening pilot study for Menkes disease will be instrumental in confirming the prediction.

SUBMITTER: Kaler SG

PROVIDER: S-EPMC7283148 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Estimated birth prevalence of Menkes disease and ATP7A-related disorders based on the Genome Aggregation Database (gnomAD).

Kaler Stephen G SG Ferreira Carlos R CR Yam Lung S LS

Molecular genetics and metabolism reports 20200605

<h4>Background</h4>Previous estimates of the prevalence of Menkes disease, a lethal X-linked recessive disorder of copper metabolism, were based on confirmed clinical cases ascertained from specific populations and varied from 1 in 40,000 to 1 in 354,507. With newly available population-based allelic frequencies of DNA sequence variants, the expected birth prevalence of Menkes disease and other <i>ATP7A</i>-related phenotypes can be reconsidered using Hardy-Weinberg theoretical principles.<h4>Me ...[more]

PMID: 32528851

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Project description:Human aldehyde dehydrogenase (ALDH) is a multigene family with 19 functional members encoding a class of diverse but important enzymes for detoxification or biotransformation of different endogenous and exogenous aldehyde substrates. Genetic mutations in the ALDH genes can cause the accumulation of toxic aldehydes and abnormal carbonyl metabolism and serious human pathologies. However, the physiological functions and substrate specificity of many ALDH genes are still unknown. Although many genetic variants of the ALDH gene family exist in human populations, their phenotype or clinical consequences have not been determined. Using the most comprehensive global human Genome Aggregation Database, gnomAD, we annotated here 1350 common variants in the 19 ALDH genes. These 1350 common variants represent all known genetic polymorphisms with a variant allele frequency of ≥0.1% (or an expected occurrence of ≥1 carrier per 500 individuals) in any of the seven major ethnic groups recorded by gnomAD. We detailed 13 types of DNA sequence variants, their genomic positions, SNP ID numbers, and allele frequencies among the seven major ethnic groups worldwide for each of the 19 ALDH genes. For the 313 missense variants identified in the gnomAD, we used two software algorithms, Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant From Tolerant (SIFT), to predict the consequences of the variants on the structure and function of the enzyme. Finally, gene constraint analysis was used to predict how well genetic mutations were tolerated by selection forces for each of the ALDH genes in humans. Based on the ratio of observed and expected variant numbers in gnomAD, the three ALDH1A gene members, ALDH1A1, ALDH1A2, and ALDH1A3, appeared to have the lowest tolerance for loss-of-function mutations as compared to the other ALDH genes (# observed/# expected ratio 0.15-0.26). These analyses suggest that the ALDH1A1, ALDH1A2, and ALDH1A3 enzymes may serve a more essential function as compared with the other ALDH enzymes; functional loss mutations are much less common in healthy human populations than expected. This informatic analysis may assist the research community in determining the physiological function of ALDH isozymes and associate common variants with clinical phenotypes.

Dataset Information

Estimated birth prevalence of Menkes disease and ATP7A-related disorders based on the Genome Aggregation Database (gnomAD).

Background

Methods

Results

Conclusions

Publications

Estimated birth prevalence of Menkes disease and ATP7A-related disorders based on the Genome Aggregation Database (gnomAD).

Similar Datasets

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