Molecular Genetic Testing and the Future of Clinical Genomics

Katsanis, Sara Huston; Katsanis, Nicholas

doi:10.1016/b978-0-12-800681-8.00018-9

Cited by 45 publications

(51 citation statements)

References 54 publications

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“…Progresses in the elucidation of these molecular pathways could help for diagnosis and treatment of patients affected by iron‐related disorders, particularly those with IO in whom no causative mutation in the known HH genes can be identified . NGS is emerging as a useful approach in this setting, although patients with evidence of iron overload must to be treated to remove excess iron regardless of if a specific genetic defect can be identified. Cellular and animal models have identified BMPs, particularly BMP6, as compelling candidates, but until recently, evidence in humans was limited to the possible role of common SNPs in BMP2 and BMP4 as modifiers of classical HFE ‐related HH .…”

Section: Discussionmentioning

confidence: 99%

Identification of new BMP6 pro‐peptide mutations in patients with iron overload

et al. 2017

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Hereditary Hemochromatosis (HH) is a genetically heterogeneous disorder caused by mutations in at least five different genes (HFE, HJV, TFR2, SLC40A1, HAMP) involved in the production or activity of the liver hormone hepcidin, a key regulator of systemic iron homeostasis. Nevertheless, patients with an HH-like phenotype that remains completely/partially unexplained despite extensive sequencing of known genes are not infrequently seen at referral centers, suggesting a role of still unknown genetic factors. A compelling candidate is Bone Morphogenetic Protein 6 (BMP6), which acts as a major activator of the BMP-SMAD signaling pathway, ultimately leading to the upregulation of hepcidin gene transcription. A recent seminal study by French authors has described three heterozygous missense mutations in BMP6 associated with mild to moderate lateonset iron overload (IO). Using an updated next-generation sequencing (NGS)-based genetic test in IO patients negative for the classical HFE p.Cys282Tyr mutation, we found three BMP6 heterozygous missense mutations in four patients from three different families. One mutation (p. Leu96Pro) has already been described and proven to be functional. The other two (p.Glu112Gln, p.Arg257His) were novel, and both were located in the pro-peptide domain known to be crucial for appropriate BMP6 processing and secretion. In silico modeling also showed results consistent with their pathogenetic role. The patients' clinical phenotypes were similar to that of other patients with BMP6-related IO recently described. Our results independently add further evidence to the role of BMP6 mutations as likely contributing factors to late-onset moderate IO unrelated to mutations in the established five HH genes.

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Section: Discussionmentioning

confidence: 99%

Identification of new BMP6 pro‐peptide mutations in patients with iron overload

et al. 2017

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“…Only relatively few cases have been molecularly characterized at referral centers through traditional sequencing, which was hampered by time‐consuming and costs, until recently. Recent breakthrough in the development of novel genomic technologies for high‐throughput DNA sequencing, collectively known as “next generation sequencing” (NGS), have now the potential of revolutionizing the molecular diagnosis of inherited diseases . This holds the promise of a significant impact on clinical care , with unprecedented accuracy, rapidity, and at constantly declining costs .…”

Section: Introductionmentioning

confidence: 99%

Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload

et al. 2016

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Hereditary hemochromatosis, one of the commonest genetic disorder in Caucasians, is mainly associated to homozygosity for the C282Y mutation in the HFE gene, which is highly prevalent (allele frequency up to near 10% in Northern Europe) and easily detectable through a widely available "first level" molecular test. However, in certain geographical regions like the Mediterranean area, up to 30% of patients with a HH phenotype has a negative or non-diagnostic (i.e. simple heterozygosity) test, because of a known heterogeneity involving at least four other genes (HAMP, HJV, TFR2, and SLC40A1). Mutations in such genes are generally rare/private, making the diagnosis of atypical HH essentially a matter of exclusion in clinical practice (from here the term of "non-HFE" HH), unless cumbersome traditional sequencing is applied. We developed a Next Generation Sequencing (NGS)-based test targeting the five HH genes, and applied it to patients with clinically relevant iron overload (IO) and a non-diagnostic first level genetic test. We identified several mutations, some of which were novel (i.e. HFE W163X, HAMP R59X, and TFR2 D555N) and allowed molecular reclassification of "non-HFE" HH clinical diagnosis, particularly in some highly selected IO patients without concurring acquired risk factors. This NGS-based "second level" genetic test may represent a useful tool for molecular diagnosis of HH in patients in whom HH phenotype remains unexplained after the search of common HFE mutations.

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“…This example underscores the importance of performing molecular studies for the diagnosis of Wilson's disease, and in the absence of bi‐allelic mutations in ATP7B , an alternative diagnosis should be considered. It is important to recognize the known limitations of WES, which are primarily 3‐fold: (1) false negatives (some segments of the genome are not amenable to capture); (2) failure to detect large genomic deletions and/or insertions; and (3) failure to detect structural or chromosomal abnormalities. Thus, for specific cases in which these limitations are known barriers to diagnosis, whole‐genome sequencing is being evaluated as an alternative to fill in these gaps.…”

Section: When Should Wes Be Used In Adult Hepatology Clinical Practice?mentioning

confidence: 99%

Exome Sequencing in Clinical Hepatology

Vilarinho¹,

Mistry

2019

Hepatology

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The clinical relevance of the Human Genome Project and next‐generation sequencing technology was demonstrated for the first time in 2009, when whole‐exome sequencing (WES) provided the definitive diagnosis of congenital chloride diarrhea in an infant with presumed renal salt‐wasting disease. Over the past decade, numerous studies have shown the utility of WES for clinical diagnosis as well as for discovery of novel genetic disorders through analysis of a single or a handful of informative pedigrees. Hence, advances in improving the speed, accuracy, and computational analysis combined with exponential decrease in the cost of sequencing the human genome is transforming the practice of medicine. The impact of WES has been most noticeable in pediatric disorders and oncology, but its utility in the liver clinic is recently emerging. Here, we assess the current status of WES for clinical diagnosis and acceleration of translation research to enhance care of patients with liver disease.

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Molecular Genetic Testing and the Future of Clinical Genomics

Cited by 45 publications

References 54 publications

Identification of new BMP6 pro‐peptide mutations in patients with iron overload

Identification of new BMP6 pro‐peptide mutations in patients with iron overload

Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload

Exome Sequencing in Clinical Hepatology

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