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

Kaler, Stephen G.; Ferreira, Carlos R.; Yam, Lung S.

doi:10.1016/j.ymgmr.2020.100602

Cited by 29 publications

(25 citation statements)

References 27 publications

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“…As a result, the estimated prevalence of MPS II is not as reliable as it is for the other types of MPS. It is worth mentioning that the other study that uses a similar method for two X-linked diseases (Menkes disease and ATP7A -related disorders) [ 41 ] also found a very low number of variants, which could suggest that this strategy is not the best approach for X-linked disorders.…”

Section: Discussionmentioning

confidence: 99%

Estimated prevalence of mucopolysaccharidoses from population-based exomes and genomes

Borges

Pasqualim

Giugliani

et al. 2020

Orphanet J Rare Dis

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Background In this study, the prevalence of different types of mucopolysaccharidoses (MPS) was estimated based on data from the exome aggregation consortium (ExAC) and the genome aggregation database (gnomAD). The population-based allele frequencies were used to identify potential disease-causing variants on each gene related to MPS I to IX (except MPS II). Methods We evaluated the canonical transcripts and excluded homozygous, intronic, 3′, and 5′ UTR variants. Frameshift and in-frame insertions and deletions were evaluated using the SIFT Indel tool. Splice variants were evaluated using SpliceAI and Human Splice Finder 3.0 (HSF). Loss-of-function single nucleotide variants in coding regions were classified as potentially pathogenic, while synonymous variants outside the exon–intron boundaries were deemed non-pathogenic. Missense variants were evaluated by five in silico prediction tools, and only those predicted to be damaging by at least three different algorithms were considered disease-causing. Results The combined frequencies of selected variants (ranged from 127 in GNS to 259 in IDUA) were used to calculate prevalence based on Hardy–Weinberg's equilibrium. The maximum estimated prevalence ranged from 0.46 per 100,000 for MPSIIID to 7.1 per 100,000 for MPS I. Overall, the estimated prevalence of all types of MPS was higher than what has been published in the literature. This difference may be due to misdiagnoses and/or underdiagnoses, especially of the attenuated forms of MPS. However, overestimation of the number of disease-causing variants by in silico predictors cannot be ruled out. Even so, the disease prevalences are similar to those reported in diagnosis-based prevalence studies. Conclusion We report on an approach to estimate the prevalence of different types of MPS based on publicly available population-based genomic data, which may help health systems to be better prepared to deal with these conditions and provide support to initiatives on diagnosis and management of MPS.

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Section: Discussionmentioning

confidence: 99%

Estimated prevalence of mucopolysaccharidoses from population-based exomes and genomes

Borges

Pasqualim

Giugliani

et al. 2020

Orphanet J Rare Dis

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“…Concern about generating false-positive results exists for all NBS algorithms. A review of ATP7A SNVs in the gnomAD database of 141,456 unrelated individuals revealed 452 singleton ATP7A missense variants that could be construed as possibly deleterious (VUS) if found during NBS [ 15 , 26 ]. Based on these data, we estimate the maximum probability of a false-positive from an ATP7A singleton variant to be approximately 0.2%, as is supported by the absence of findings in newborns screened with whole exome sequencing in the BabySeq Project (Genomic Sequencing for Childhood Risk and Newborn Illness, U19 HD077671) [ 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…Menkes disease is a X-linked recessive disorder of copper metabolism with a predicted minimum birth prevalence of 1 in 34,810 live male births based on loss-of-function variant frequencies in the Genome Aggregation Database (gnomAD) [ 15 ] for ATP7A , which encodes an essential copper-transporting ATPase [ [16] , [17] , [18] ]. While onset of this medically-actionable condition occurs in early infancy, population-based NBS by biochemical analyte testing is not currently available or feasible.…”

Section: Introductionmentioning

confidence: 99%

Targeted next generation sequencing for newborn screening of Menkes disease

Parad

Kaler

Mauceli

et al. 2020

Molecular Genetics and Metabolism Reports

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Purpose Population-based newborn screening (NBS) allows early detection and treatment of inherited disorders. For certain medically-actionable conditions, however, NBS is limited by the absence of reliable biochemical signatures amenable to detection by current platforms. We sought to assess the analytic validity of an ATP7A targeted next generation DNA sequencing assay as a potential newborn screen for one such disorder, Menkes disease. Methods Dried blood spots from control or Menkes disease subjects ( n = 22) were blindly analyzed for pathogenic variants in the copper transport gene, ATP7A. The analytical method was optimized to minimize cost and provide rapid turnaround time . Results The algorithm correctly identified pathogenic ATP7A variants, including missense, nonsense, small insertions/deletions, and large copy number variants, in 21/22 (95.5%) of subjects, one of whom had inconclusive diagnostic sequencing previously. For one false negative that also had not been detected by commercial molecular laboratories, we identified a deep intronic variant that impaired ATP7A mRNA splicing. Conclusions Our results support proof-of-concept that primary DNA-based NBS would accurately detect Menkes disease, a disorder that fulfills Wilson and Jungner screening criteria and for which biochemical NBS is unavailable. Targeted next generation sequencing for NBS would enable improved Menkes disease clinical outcomes, establish a platform for early identification of other unscreened disorders, and complement current NBS by providing immediate data for molecular confirmation of numerous biochemically screened condition.

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“…Other features associated with the clinical phenotype include abnormalities in the intracranial vasculature, such as increased intracranial vessel tortuosity, variable abnormalities of white matter signal, transient temporal lobe changes, Purkinje cell degeneration in the cerebellum, cerebral and cerebellar atrophy, basal ganglia malformations, and subdural collections. Menkes disease arises as a consequence of loss-of-function mutations in the ATP7A gene, which encodes ATPase Copper Transporting Alpha, causing the impaired absorption and cellular metabolism of copper [88,89]. Early treatment of Menkes disease is essential, starting within 28 days of birth.…”

Section: X-linked Inheritancementioning

confidence: 99%

The Genetic Basis of Strokes in Pediatric Populations and Insight into New Therapeutic Options

Janković

Petrović²,

Novaković

et al. 2022

IJMS

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Strokes within pediatric populations are considered to be the 10th leading cause of death in the United States of America, with over half of such events occurring in children younger than one year of life. The multifactorial etiopathology that has an influence on stroke development and occurrence signify the importance of the timely recognition of both modifiable and non-modifiable factors for adequate diagnostic and treatment approaches. The early recognition of a stroke and stroke risk in children has the potential to advance the application of neuroprotective, thrombolytic, and antithrombotic interventions and rehabilitation strategies to the earliest possible timepoints after the onset of a stroke, improving the outcomes and quality of life for affected children and their families. The recent development of molecular genetic methods has greatly facilitated the analysis and diagnosis of single-gene disorders. In this review, the most significant single gene disorders associated with pediatric stroke are presented, along with specific therapeutic options whenever they exist. Besides monogenic disorders that may present with stroke as a first symptom, genetic polymorphisms may contribute to the risk of pediatric and perinatal stroke. The most frequently studied genetic risk factors are several common polymorphisms in genes associated with thrombophilia; these genes code for proteins that are part of the coagulation cascade, fibrolysis, homocystein metabolism, lipid metabolism, or platelets. Single polymorphism frequencies may not be sufficient to completely explain the stroke causality and an analysis of several genotype combinations is a more promising approach. The recent steps forward in our understanding of the disorders underlying strokes has given us a next generation of therapeutics and therapeutic targets by which to improve stroke survival, protect or rebuild neuronal connections in the brain, and enhance neural function. Advances in DNA sequencing and the development of new tools to correct human gene mutations have brought genetic analysis and gene therapy into the focus of investigations for new therapeutic options for stroke patients.

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

Cited by 29 publications

References 27 publications

Estimated prevalence of mucopolysaccharidoses from population-based exomes and genomes

Estimated prevalence of mucopolysaccharidoses from population-based exomes and genomes

Targeted next generation sequencing for newborn screening of Menkes disease

The Genetic Basis of Strokes in Pediatric Populations and Insight into New Therapeutic Options

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