Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

Cooper, David Neil; Chen, Jian‐Min; Ball, Edward V.; Howells, Katy; Mort, Matthew; Phillips, Andrew David; Chuzhanova, Nadia; Krawczak, Michael; Kehrer‐Sawatzki, Hildegard; Stenson, Peter D.

doi:10.1002/humu.21260

Cited by 167 publications

(133 citation statements)

References 360 publications

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“…Heterozygous MUTYH mutations were not identified in the remaining 84 index patients, for which somatic mutations or further germline pathomechanisms, for example, large genomic rearrangements such as inversions in the MMR genes have to be considered. 3,[26][27][28] In the control cohort the MUTYH mutation frequency of 1.24% was comparable to the frequencies of 0%-4.8% reported in the general population. 12,22,29 As MAP can manifest in an extremely variable phenotype, MUTYH mutation analysis should also be considered in patients with a low number of adenomas, early-onset or synchronous or metachronous CRC and in patients with MSS tumours.…”

Section: Discussionsupporting

confidence: 71%

Biallelic MUTYH mutations can mimic Lynch syndrome

et al. 2014

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The hallmarks of Lynch syndrome (LS) include a positive family history of colorectal cancer (CRC), germline mutations in the DNA mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression. However, in B10-15% of clinically suspected LS cases, MMR mutation analyses cannot explain MSI-H and abnormal immunohistochemistry (IHC) results. The highly variable phenotype of MUTYH-associated polyposis (MAP) can overlap with the LS phenotype, but is inherited recessively. We analysed the MUTYH gene in 85 'unresolved' patients with tumours showing IHC MMR-deficiency without detectable germline mutation. Biallelic p.(Tyr179Cys) MUTYH germline mutations were found in one patient (frequency 1.18%) with CRC, urothelial carcinoma and a sebaceous gland carcinoma. LS was suspected due to a positive family history of CRC and because of MSI-H and MSH2-MSH6 deficiency on IHC in the sebaceous gland carcinoma. Sequencing of this tumour revealed two somatic MSH2 mutations, thus explaining MSI-H and IHC results, and mimicking LS-like histopathology. This is the first report of two somatic MSH2 mutations leading to an MSI-H tumour lacking MSH2-MSH6 protein expression in a patient with MAP. In addition to typical transversion mutations in KRAS and APC, MAP can also induce tumourigenesis via the MSI-pathway.

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Section: Discussionsupporting

confidence: 71%

Biallelic MUTYH mutations can mimic Lynch syndrome

et al. 2014

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“…Thus, another mutation in the OPLAH gene is improbable except located in a deep intronic region. Splicing mutations account for around 10 % of all reported mutations and deep intronic mutations represent less than 1 % of known splicing mutations (Cooper et al 2010). All these data together suggest that these two probands seem to be carriers of only one defect in the OPLAH gene.…”

Section: Discussionmentioning

confidence: 88%

5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

et al. 2012

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The inherited 5-oxoprolinuria is primarily suggestive of genetic defects in two enzymes belonging to the gamma-glutamyl cycle in the glutathione (GSH) metabolism: the glutathione synthetase (GSS) and the 5-oxoprolinase (OPLAH). The GSS deficiency is the best characterized of the inborn errors of GSH metabolism, whereas the OPLAH deficiency is questioned whether it is a disorder or just a biochemical condition with no adverse clinical effects. Recently, the first human OPLAH mutation (p.H870Pfs) was reported in homozygosis in two siblings who suffered from 5-oxoprolinuria with a benign clinical course. We report two unrelated patients who manifested massive excretion of 5-oxoproline in urine. In both probands, the blood GSH levels were normal and no mutations were found in the GSS gene. The mutational screening of the OPLAH gene, which included the codified sequences, the intronic flanking sequences, the promoter sequence, and a genetic analysis in order to detect large deletions and/or duplications, showed that each patient only harbors one missense mutation in heterozygosis. The in silico analyses revealed that each one of these OPLAH mutations, p.S323R and p.V1089I, could alter the proper function of this homodimeric enzyme. In addition, clinical symptoms manifest in these two probands were not related to GSH cycle defects and, therefore, this study provides further evidence that oxoprolinuria may present as epiphenomenon in several pathological conditions and confound the final diagnosis.

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“…This difficulty is most clearly reflected in the distribution of mutations listed in databases of Mendelian disorders, such as the Human Gene Mutation Database, where most mutations are found within coding regions (86%) or at intronic splice sites (11%), with only a small fraction (3%) identified in regulatory regions (14). Newer methods for annotating and predicting the impact of noncoding (NC) variants have provided substantial improvements (15,16), but experimental validation of the presumed effects remains critical for the determination of pathogenicity and elucidation of the mechanism of action (13,17).…”

Section: Mendelian Erythroid Disordersmentioning

confidence: 99%

Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders

Wakabayashi

Ulirsch

Ludwig

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptional cis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders.GATA1 | cis-regulatory elements | noncoding mutations | Mendelian erythroid disorders W hole-exome sequencing (WES) and targeted sequencing approaches have greatly accelerated our ability to identify causal genetic lesions in both previously implicated and novel genes underlying monogenic disorders (1, 2). In hematology, WES has been extremely useful for identifying unknown genetic etiologies for various disorders, such as those affecting red blood cell (RBC) production, including Diamond-Blackfan anemia and congenital dyserythropoietic anemia (3-5), disorders of RBC structure and function (6, 7), and disorders affecting other aspects of hematologic function (2, 8). Despite this considerable success, however, more than 50% of cases of presumed monogenic diseases are refractory to current WES approaches (9). Although resolving these remaining cases will benefit from improvements in exome capture (10), read alignment (11), and variant annotation methodologies (11), the importance of genetic variation occurring within regulatory elements (REs) outside of the traditionally investigated coding sequences in hematologic and other diseases is being increasingly appreciated (12).Whole-genome sequencing (WGS) approaches are becoming progressively more available and affordable, but separating pathogenic genetic variation from benign or unrelated mutations remains especially difficult outside of protein-coding gen...

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Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

Cited by 167 publications

References 360 publications

Biallelic MUTYH mutations can mimic Lynch syndrome

Biallelic MUTYH mutations can mimic Lynch syndrome

5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders

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