Pitfalls of whole exome sequencing in undefined clinical conditions with a suspected genetic etiology

Moresco, Giada; Rondinone, Ornella; Mauri, Alessia; Costanza, Jole; Santaniello, Carlo; Colapietro, Patrizia; Micaglio, Emanuele; Marfia, Giovanni; Pesenti, Chiara; Grilli, Federico; Rinaldi, Berardo; Prada, Elisabetta; Scuvera, Giulietta; Villa, Roberta; Bedeschi, Maria Francesca; Miozzo, Monica; Milani, Donatella; Fontana, Laura

doi:10.1007/s13258-022-01341-x

Cited by 2 publications

(1 citation statement)

References 63 publications

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“…This highlights the importance of immediate diagnosis, and the need of efficient newborn screening methods for prompt treatment, as well as the utility of WES as first-tier genomic test for phenotypes with a suspected genetic etiology. Compared to traditional genetic testing (Karyotype, aCGH) and multigene panels sequencing, WES-based diagnosis may represent a powerful agnostic tool to solve complex cases such as ours, avoiding missing a second diagnosis and delaying any possible treatments, and allowing an efficient and rapid identification of the genetic cause in rare and ultra-rare conditions (Mergnac et al, 2022;Moresco et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Menkes disease complicated by concurrent ACY1 deficiency: A case report

Mauri

Saielli²,

Alfei³

et al. 2023

Front. Genet.

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Introduction: Menkes disease is an X‐linked recessive condition caused by mutations in the ATP7A gene, which leads to severe copper deficiency. Aminoacylase-1 deficiency is a rare inborn error of metabolism caused by homozygous or compound heterozygous variant in the ACY1 gene, characterized by increased urinary excretion of specific N-acetyl amino acids.Case presentation: We report an infant with neurological findings such as seizures, neurodevelopmental delay and hypotonia. Metabolic screening showed low serum copper and ceruloplasmin, and increased urinary excretion of several N-acetylated amino acids. Whole-exome sequencing analysis (WES) revealed the novel de novo variant c.3642_3649dup (p.Ala1217Aspfs*2) in the ATP7A gene, leading to a diagnosis of Menkes disease, and the simultaneous presence of the homozygous ACY1 variant c.1057C>T (p.Arg353Cys) causative of Aminoacylase-1 deficiency.Conclusion: Our patient had two rare conditions with different treatment courses but overlapping clinical features. The identified novel ATP7A mutation associated with Menkes disease expands the ATP7A gene spectrum.

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Section: Discussionmentioning

confidence: 99%

Menkes disease complicated by concurrent ACY1 deficiency: A case report

Mauri

Saielli²,

Alfei³

et al. 2023

Front. Genet.

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Exploring the Impact of Genetics in a Large Cohort of Moebius Patients by Trio Whole Exome Sequencing

Moresco,

Bedeschi,

Venturin

et al. 2024

Genes

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Moebius syndrome (MBS) is a rare congenital disorder characterized by non-progressive facial palsy and ocular abduction paralysis. Most cases are sporadic, but also rare familial cases with autosomal dominant transmission and incomplete penetrance/variable expressivity have been described. The genetic etiology of MBS is still unclear: de novo pathogenic variants in REV3L and PLXND1 are reported in only a minority of cases, suggesting the involvement of additional causative genes. With the aim to uncover the molecular causative defect and identify a potential genetic basis of this condition, we performed trio-WES on a cohort of 37 MBS and MBS-like patients. No de novo variants emerged in REV3L and PLXND1. We then proceeded with a cohort analysis to identify possible common causative genes among all patients and a trio-based analysis using an in silico panel of candidate genes. However, identified variants emerging from both approaches were considered unlikely to be causative of MBS, mainly due to the lack of clinical overlap. In conclusion, despite this large cohort, WES failed to identify mutations possibly associated with MBS, further supporting the heterogeneity of this syndrome, and suggesting the need for integrated omics approaches to identify the molecular causes underlying MBS development.

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Pitfalls of whole exome sequencing in undefined clinical conditions with a suspected genetic etiology

Cited by 2 publications

References 63 publications

Menkes disease complicated by concurrent ACY1 deficiency: A case report

Menkes disease complicated by concurrent ACY1 deficiency: A case report

Exploring the Impact of Genetics in a Large Cohort of Moebius Patients by Trio Whole Exome Sequencing

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