Publications by authors named "Graeme Cm Black"

7 Publications

  • Page 1 of 1

High penetrance of myeloid neoplasia with diverse clinical and cytogenetic features in three siblings with a familial GATA2 deficiency.

Cancer Genet 2021 Apr 23;256-257:77-80. Epub 2021 Apr 23.

Manchester Academic Health Science Centre; Department of Paediatric Haematology and Oncology, Royal Manchester Children's Hospital, Manchester NHS Foundation Trust Manchester, UK; Stem Cell and Leukaemia Proteomics Laboratory, Faculty of Medical and Human Sciences, Division of Cancer Studies, University of Manchester, UK; Department of Paediatric and Adolescent Oncology, The Christie NHS Foundation Trust, Manchester, UK. Electronic address:

Pathogenic germ-line variants in GATA2 (GATA2-deficiency) can cause childhood myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and can be associated with distinct clinical syndromic features. However, penetrance and genotype-phenotype correlations are incompletely understood. Here we report on the clinically diverse features of three siblings affected by GATA2c.1021_1031del over an 18-year period, all initially presenting in childhood and adolescence with MDS and AML with monosomy 7 (-7), and one also with trisomy 8 (+8). The siblings inherited a GATA2c.1021_1031del from their father who remains asymptomatic in his sixth decade. The two younger sisters are well after unrelated haematopoietic stem cell transplantation (HSCT), while the first boy died of severe chronic lung disease after sibling HSCT from his youngest sister, who subsequently also developed GATA2-deficiency associated MDS. This family illustrates high penetrance with variable genotype/phenotype correlation within one generation with GATA2-deficiency. We surmise that the lung disease post sibling HSCT was also caused by the GATA2-deficiency. The experience with this family underlines the necessity for GATA2 analysis in all apparently sporadic childhood and teenage MDS and AML with -7 also in the absence of a family history or other clinical features, and rigorous genetic testing in siblings. Moreover, our findings support the arguments for pre-emptive HSCT in variant-carrying siblings.
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http://dx.doi.org/10.1016/j.cancergen.2021.04.002DOI Listing
April 2021

Genomic and healthcare dynamics of nosocomial SARS-CoV-2 transmission.

Elife 2021 03 17;10. Epub 2021 Mar 17.

Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom.

Understanding the effectiveness of infection control methods in reducing and preventing SARS-CoV-2 transmission in healthcare settings is of high importance. We sequenced SARS-CoV-2 genomes for patients and healthcare workers (HCWs) across multiple geographically distinct UK hospitals, obtaining 173 high-quality SARS-CoV-2 genomes. We integrated patient movement and staff location data into the analysis of viral genome data to understand spatial and temporal dynamics of SARS-CoV-2 transmission. We identified eight patient contact clusters (PCC) with significantly increased similarity in genomic variants compared to non-clustered samples. Incorporation of HCW location further increased the number of individuals within PCCs and identified additional links in SARS-CoV-2 transmission pathways. Patients within PCCs carried viruses more genetically identical to HCWs in the same ward location. SARS-CoV-2 genome sequencing integrated with patient and HCW movement data increases identification of outbreak clusters. This dynamic approach can support infection control management strategies within the healthcare setting.
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http://dx.doi.org/10.7554/eLife.65453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009659PMC
March 2021

polyadenylation signal variants cause syndromic microphthalmia.

J Med Genet 2019 07 6;56(7):444-452. Epub 2019 Mar 6.

National Institutes of Health, National Human Genome Research Institute, Bethesda, Maryland, USA.

Background: A single variant in (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia.

Methods: Three families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in were evaluated using quantitative PCR and RNAseq.

Results: Genetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included . Exome sequencing identified a hemizygous polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced mRNA levels and abnormal 3' UTRs in affected individuals. Targeted sequencing of in 376 additional affected individuals failed to identify variants in the PAS.

Conclusion: These data show that PAS variants are the most common variant type in -associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yields.
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http://dx.doi.org/10.1136/jmedgenet-2018-105836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032957PMC
July 2019

Bi-allelic Loss-of-Function Variants in DNMBP Cause Infantile Cataracts.

Am J Hum Genet 2018 10;103(4):568-578

Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva 1205, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, Geneva 1211, Switzerland. Electronic address:

Infantile and childhood-onset cataracts form a heterogeneous group of disorders; among the many genetic causes, numerous pathogenic variants in additional genes associated with autosomal-recessive infantile cataracts remain to be discovered. We identified three consanguineous families affected by bilateral infantile cataracts. Using exome sequencing, we found homozygous loss-of-function variants in DNMBP: nonsense variant c.811C>T (p.Arg271) in large family F385 (nine affected individuals; LOD score = 5.18 at θ = 0), frameshift deletion c.2947_2948del (p.Asp983) in family F372 (two affected individuals), and frameshift variant c.2852_2855del (p.Thr951Metfs41) in family F3 (one affected individual). The phenotypes of all affected individuals include infantile-onset cataracts. RNAi-mediated knockdown of the Drosophila ortholog still life (sif), enriched in lens-secreting cells, affects the development of these cells as well as the localization of E-cadherin, alters the distribution of septate junctions in adjacent cone cells, and leads to a ∼50% reduction in electroretinography amplitudes in young flies. DNMBP regulates the shape of tight junctions, which correspond to the septate junctions in invertebrates, as well as the assembly pattern of E-cadherin in human epithelial cells. E-cadherin has an important role in lens vesicle separation and lens epithelial cell survival in humans. We therefore conclude that DNMBP loss-of-function variants cause infantile-onset cataracts in humans.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174361PMC
October 2018

Next-generation sequencing targeted disease panel in rod-cone retinal dystrophies in Māori and Polynesian reveals novel changes and a common founder mutation.

Clin Exp Ophthalmol 2017 12 13;45(9):901-910. Epub 2017 Jun 13.

Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester, UK.

Importance: This study identifies unique genetic variation observed in a cohort of Māori and Polynesian patients with rod-cone retinal dystrophies using a targeted next-generation sequencing retinal disease gene panel.

Background: With over 250 retinal disease genes identified, genetic diagnosis is still only possible in 60-70% of individuals and even less within unique ethnic groups.

Design: Prospective genetic testing in patients with rod-cone retinal dystrophies identified from the New Zealand Inherited Retinal Disease Database, PARTICIPANTS: Sixteen patients of Māori and Polynesian ancestry.

Methods: Next-generation sequencing of a targeted retinal gene panel. Sanger sequencing for a novel PDE6B mutation in subsequent Māori patients.

Main Outcome Measures: Genetic diagnosis, genotype-phenotype correlation.

Results: Thirteen unique pathogenic variants were identified in 9 of 16 (56.25%) patients in 10 different genes. A definitive genetic diagnosis was made in 7/16 patients (43.7%). Six changes were novel and not in public databases of human variation. In four patients, a homozygous, novel pathogenic variant (c.2197G > C, p.(Ala 733Pro)) in PDE6B was identified and also present in a further five similarly affected Māori patients.

Conclusions And Relevance: Over half of the Māori and Polynesian patients with inherited rod-cone diseases have no pathogenic variant(s) detected with a targeted retinal next-generation sequencing strategy, which is supportive of novel genetic mechanisms in this population. A novel PDE6B founder variant is likely to account for 16% of recessive inherited retinal dystrophy in Māori. Careful characterization of the clinical presentation permits identification of further Māori patients with a similar phenotype and simplifies the diagnostic algorithm.
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http://dx.doi.org/10.1111/ceo.12983DOI Listing
December 2017

Validation of copy number variation analysis for next-generation sequencing diagnostics.

Eur J Hum Genet 2017 06 5;25(6):719-724. Epub 2017 Apr 5.

Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.

Although a common cause of disease, copy number variants (CNVs) have not routinely been identified from next-generation sequencing (NGS) data in a clinical context. This study aimed to examine the sensitivity and specificity of a widely used software package, ExomeDepth, to identify CNVs from targeted NGS data sets. We benchmarked the accuracy of CNV detection using ExomeDepth v1.1.6 applied to targeted NGS data sets by comparison to CNV events detected through whole-genome sequencing for 25 individuals and determined the sensitivity and specificity of ExomeDepth applied to these targeted NGS data sets to be 100% and 99.8%, respectively. To define quality assurance metrics for CNV surveillance through ExomeDepth, we undertook simulation of single-exon (n=1000) and multiple-exon heterozygous deletion events (n=1749), determining a sensitivity of 97% (n=2749). We identified that the extent of sequencing coverage, the inter- and intra-sample variability in the depth of sequencing coverage and the composition of analysis regions are all important determinants of successful CNV surveillance through ExomeDepth. We then applied these quality assurance metrics during CNV surveillance for 140 individuals across 12 distinct clinical areas, encompassing over 500 potential rare disease diagnoses. All 140 individuals lacked molecular diagnoses after routine clinical NGS testing, and by application of ExomeDepth, we identified 17 CNVs contributing to the cause of a Mendelian disorder. Our findings support the integration of CNV detection using ExomeDepth v1.1.6 with routine targeted NGS diagnostic services for Mendelian disorders. Implementation of this strategy increases diagnostic yields and enhances clinical care.
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http://dx.doi.org/10.1038/ejhg.2017.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427176PMC
June 2017

Variation in healthcare services for specialist genetic testing and implications for planning genetic services: the example of inherited retinal dystrophy in the English NHS.

J Community Genet 2015 Apr 9;6(2):157-65. Epub 2015 Jan 9.

Manchester Centre for Health Economics, Institute of Population Health, Faculty of Medical and Human Sciences, MAHSC, The University of Manchester, Manchester, UK.

This study aims to identify and quantify the extent of current variation in service provision of a genetic testing service for dominant and X-linked retinal dystrophies in the English National Health Service (NHS). National audit data (all test requests and results (n = 1839) issued between 2003 and 2011) and survey of English regional genetic testing services were used. Age- and gender-adjusted standardised testing rates were calculated using indirect standardisation, and survey responses were transcribed verbatim and data collated and summarised. The cumulative incidence rate of testing in England was 4.5 per 100,000 population for males and 2.6 per 100,000 population for females. The standardised testing rate (STR) varied widely between regions of England, being particularly low in the North-east (STR 0.485), with half as many tests as expected based on the size and demographic distribution of the population and high in the South-east (STR 1.355), with 36 % more tests than expected. Substantial and significantly different rates of testing were found between regional populations. Specific policy mechanisms to promote, monitor and evaluate the regional distribution of access to genetic and genomic testing are required. However, commissioners will require information on the scope and role of genetic services and the population at risk of the conditions for which patients are tested.
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http://dx.doi.org/10.1007/s12687-014-0210-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356672PMC
April 2015