Publications by authors named "Gabriela Jones"

15 Publications

  • Page 1 of 1

Estimating the clinical prevalence of Wilson's disease in the UK.

JHEP Rep 2021 Oct 7;3(5):100329. Epub 2021 Jul 7.

NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, UK.

Background & Aims: The clinical prevalence of Wilson's disease (WD) in the UK remains unknown. The estimated genetic prevalence in the UK, 142/million, is higher than the clinical prevalence (15/million) reported in other European studies. The aim of this study was to estimate the clinical prevalence of WD utilising readily available laboratory and clinical data.

Method: Patients with WD who attended Nottingham University Hospital NHS Trust (NUH) between 2011 and 2018 were identified using multiple sources of case ascertainment: serum ceruloplasmin, 24-hour urinary copper, 'Wilson' in liver biopsy report, hospital prescription for penicillamine/trientine/zinc and admission coded with ICD-10 Code E83.0 (disorder of copper metabolism). Potential cases were identified using the Leipzig score, diagnosis was confirmed in hospital records and the point prevalence was calculated using the Office for National Statistics mid-2017 population estimates.

Results: A total of 1,794 patients were identified from ≥1 source; 19 patients had WD, of whom 11 were from within the study catchment area and alive at the time of point prevalence estimation. Twenty-nine patients had a Leipzig score ≥2 without a diagnosis of WD, but none had WD on screening (n = 16). The overall prevalence of WD was 15.5/million; males 16.9/million and females 14.1/million.

Conclusion: This is the first UK population-based study to assess the clinical prevalence of WD. The reported clinical prevalence is lower than the UK genetic prevalence, but comparable to the clinical prevalence reported in Europe. The case ascertainment approach used in this study may be cost-effective, and similar practises could be adopted nationally.

Lay Summary: Our study estimates the clinical prevalence of Wilson's disease, a rare genetic disorder of copper metabolism, in the UK. The estimated clinical prevalence is this study is markedly lower than the estimated UK genetic prevalence.
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http://dx.doi.org/10.1016/j.jhepr.2021.100329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335649PMC
October 2021

Genetic testing in motor neuron disease and frontotemporal dementia: a 5-year multicentre evaluation.

J Med Genet 2021 May 7. Epub 2021 May 7.

Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK

Introduction: Motor neuron disease (MND) and frontotemporal dementia (FTD) comprise a neurodegenerative disease spectrum. Genetic testing and counselling is complex in MND/FTD owing to incomplete penetrance, variable phenotype and variants of uncertain significance. Affected patients and unaffected relatives are commonly referred to clinical genetics to consider genetic testing. However, no consensus exists regarding how such genetic testing should best be undertaken and on which patients.

Objective: We sought to ascertain UK clinical genetics testing practice in MND/FTD referrals, with the aim of helping inform guideline development.

Methods: MND/FTD clinical genetics referrals comprising both affected patients and unaffected relatives between 2012 and 2016 were identified and a standardised proforma used to collate data from clinical records.

Results: 301 referrals (70 affected, 231 unaffected) were reviewed across 10 genetics centres. Previously identified familial variants were known in 107 cases and 58% subsequently underwent testing (8 of 8 diagnostic and 54 of 99 predictive). The median number of genetic counselling appointments was 2 for diagnostic and 4 for predictive testing. Importantly, application of current UK Genomic Test Directory eligibility criteria would not have resulted in detection of all pathogenic variants observed in this cohort.

Conclusion: We propose pragmatic MND/FTD genetic testing guidelines based on appropriate genetic counselling.
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http://dx.doi.org/10.1136/jmedgenet-2021-107776DOI Listing
May 2021

Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.

Am J Hum Genet 2019 08 27;105(2):384-394. Epub 2019 Jun 27.

Department of Paediatric Neurology, Leicester Royal Infirmary, Leicester LE1 5WW, UK.

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698938PMC
August 2019

Correction: The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature.

Genet Med 2019 Jul;21(7):1667-1671

Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

The article has been corrected to account for one patient being investigated through genome sequencing rather than exome sequencing as originally published; thus amendments to the Abstract and Methods have been made as well as addition of the relevant authors and acknowledgment.
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http://dx.doi.org/10.1038/s41436-019-0460-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608131PMC
July 2019

The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature.

Genet Med 2019 06 25;21(6):1308-1318. Epub 2018 Oct 25.

Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Purpose: Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations.

Methods: We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing), genome sequencing.

Results: Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes.

Conclusion: Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.
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http://dx.doi.org/10.1038/s41436-018-0339-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752669PMC
June 2019

Correction to: A meta-analysis of consanguinity and breast cancer.

Ir J Med Sci 2019 02;188(1):353

Department of Clinical Genetics, Nottingham City Hospital, Nottingham, UK.

The original version of this article contained an author name error. Gabiella Jones has been corrected to Gabriela Jones. The original article has been corrected.
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http://dx.doi.org/10.1007/s11845-018-1824-zDOI Listing
February 2019

A meta-analysis of consanguinity and breast cancer.

Ir J Med Sci 2018 Nov 24;187(4):895-899. Epub 2018 Mar 24.

Department of Clinical Genetics, Nottingham City Hospital, Nottingham, UK.

Background: There have been various publications stating that consanguinity both increases and decreases the risk of breast cancer.

Aims: The objective of this study was to determine the impact of consanguinity upon breast cancer. We conducted a systematic review of the literature and meta-analysis.

Methods: Eligible studies were identified on Medline and EMBASE updated to the 19 of September 2017. Studies with sufficient comparative data were included in a meta-analysis. Analyses were carried out using RevMan software.

Results: Three comparative studies with a total of 317 individuals with breast cancer and 1459 controls. Reviewing the literature demonstrated conflicting conclusions of the influence of consanguinity upon breast cancer. The meta-analysis showed that there were no statistically significant associations between consanguinity and breast cancer though there was a trend protection from a history of consanguinity.

Conclusion: Though there is limited literature published on the effects of parental consanguinity, the available data does not demonstrate that it is a risk factor for breast cancer.
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http://dx.doi.org/10.1007/s11845-018-1791-4DOI Listing
November 2018

An approach to familial lymphoedema.

Clin Med (Lond) 2017 Dec;17(6):552-557

Department of Clinical Genetics, St Georges Hospital and St George's, University of London, London, UK.

Lymphoedema is the build-up of lymphatic fluid leading to swelling in the tissues. Most commonly it affects the peripheries. Diagnosis is based on clinical assessment and imaging with lymphoscintigraphy. Treatment is supportive with compression garments, massage, good skin hygiene and prompt use of antibiotics to avoid the complication of cellulitis. Most commonly, lymphoedema occurs as a result of damage to the lymphatic system following surgery, trauma, radiation or infection. However, it can be primary, often associated with a genetic defect that causes disruption to the development of the lymphatic system. Common genetic conditions associated with lymphoedema include Turner syndrome and Noonan syndrome; however, there are numerous others that can be classified based on their clinical presentation and associated features. Herein we discuss how to diagnose and classify the known primary lymphoedema conditions and how best to investigate and manage this group of patients.
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http://dx.doi.org/10.7861/clinmedicine.17-6-552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297692PMC
December 2017

Renal anomalies and lymphedema distichiasis syndrome. A rare association?

Am J Med Genet A 2017 Aug 23;173(8):2251-2256. Epub 2017 May 23.

Department of Clinical Genetics, University Hospitals Leicester NHS Trust, Leicester, United Kingdom.

Lymphedema distichiasis syndrome (LDS) is a rare, autosomal dominant genetic condition, characterized by lower limb lymphedema and distichiasis. Other associated features that have been reported include varicose veins, cleft palate, congenital heart defects, and ptosis. We update a previously reported family with a pathogenic variant in FOXC2 (c.412-413insT) where five affected individuals from the youngest generation had congenital renal anomalies detected on prenatal ultrasound scan. These included four fetuses with hydronephrosis and one with bilateral renal agenesis. A further child with LDS had prominence of the left renal pelvis on postnatal renal ultrasound. We also describe a second family in whom the proband and his affected son had congenital renal anomalies; left ectopic kidney, right duplex kidney, and bilateral duplex collecting systems with partial duplex kidney with mild degree of malrotation, respectively. Foxc2 is expressed in the developing kidney and therefore congenital renal anomalies may well be associated, potentially as a low penetrance feature. We propose that all individuals diagnosed with LDS should have a baseline renal ultrasound scan at diagnosis. It would also be important to consider the possibility of renal anomalies during prenatal ultrasound of at risk pregnancies, and that the presence of hydronephrosis may be an indication that the baby is affected with LDS.
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http://dx.doi.org/10.1002/ajmg.a.38293DOI Listing
August 2017

14q22.3 Microdeletion encompassing OTX2 in a five-generation family with microphthalmia, pituitary abnormalities, and intellectual disability.

Ophthalmic Genet 2016 09 9;37(3):352-3. Epub 2016 Feb 9.

a Clinical Genetics Department , University Hospitals Leicester NHS Trust , Leicester , UK.

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http://dx.doi.org/10.3109/13816810.2015.1059463DOI Listing
September 2016

Microform holoprosencephaly with bilateral congenital elbow dislocation; increasing the phenotypic spectrum of Steinfeld syndrome.

Am J Med Genet A 2016 Mar 5;170(3):754-9. Epub 2016 Jan 5.

Clinical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.

Steinfeld syndrome (MIM #184705) was first reported in 1982. It is characterised by holoprosencephaly and limb defects, however other anomalies may also be present. Following the initial description, three further cases have been reported in the literature. We report on a 23-year-old girl, with features of microform holoprosencephaly and bilateral congenital elbow dislocation in association with hypoplastic radial heads. She was identified to have a variant in the CDON gene inherited from her father who had ocular hypotelorism, but no other clinical features. We discuss the clinical features of Steinfeld syndrome, and broaden the phenotypic spectrum of this condition. Structural analysis suggests that this variant could lead to destabilisation of binding of CDON with hedgehog proteins. Further work needs to be done to confirm whether mutations in the CDON gene are the cause of Steinfeld syndrome.
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http://dx.doi.org/10.1002/ajmg.a.37511DOI Listing
March 2016

Should we offer prenatal testing for 17q12 microdeletion syndrome to all cases with prenatally diagnosed echogenic kidneys? Prenatal findings in two families with 17q12 microdeletion syndrome and review of the literature.

Prenat Diagn 2015 Dec 9;35(13):1336-41. Epub 2015 Nov 9.

Clinical Genetics Department, University Hospitals Leicester NHS Trust, Leicester, UK.

Objective: The objective of this study is to report the prenatal ultrasound scan findings in four fetuses from two families postnatally diagnosed with 17q12 microdeletion syndrome on microarray CGH and review the literature.

Methods: We report two families presenting with prenatally detected hyperechogenic kidneys. In family 1, the mother had three pregnancies complicated by anhydramnios with bilateral hyperechogenic kidneys, hyperechogenic enlarged cystic kidneys, and bilateral hyperechogenic kidneys with polyhydramnios respectively. In family 2, prenatal ultrasound scans detected hyperechogenic kidneys. A pubmed search for all reported cases of 17q12 deletion between 2005 and 2015 was performed. All publications were reviewed, and findings summarised.

Results: Fourteen publications were deemed suitable for literature review; there was a diagnosis of 17q12 deletion with documented prenatal findings in 25 cases. Prenatal renal anomalies were reported in 88% of these cases. Anomalies were documented from 15 weeks, and most common presentation was hyperechogenic, muticystic, or enlarged kidneys. Both oligohydramnios and polyhydramnios were seen. Postnatal renal ultrasound scan findings were of muticystic or multicystic dysplastic kidney. There did not appear to be correlation of prenatal presentation and severity of renal disease.

Conclusion: Prenatal testing should be offered to all cases of hyperechogenic kidneys, with unknown cause.
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http://dx.doi.org/10.1002/pd.4701DOI Listing
December 2015

Steroid-resistant nephrotic syndrome with mutations in NPHS2 (podocin): report from a three-generation family.

Clin Kidney J 2014 Jun 2;7(3):303-5. Epub 2014 Apr 2.

Department of Clinical Genetics , Leicester Royal Infirmary, University Hospitals of Leicester , Leicester , UK.

Genetic causes of steroid-resistant nephrotic syndrome are being increasingly recognized. Mutations in NPHS2, which encodes the glomerular protein podocin, account for up to 17% of sporadic and 40% of familial cases, where they display an autosomal-recessive pattern of inheritance. This report describes a non-consanguineous family with three generations of individuals who are either compound heterozygotes for mutations in NPHS2 or who have inherited a mutation and a non-neutral polymorphism (R229Q). As well as providing an aetiological explanation, identifying pathogenic mutations and considering genotype-phenotype correlations can provide prognostic information and lead to changes in genetic counselling and management.
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http://dx.doi.org/10.1093/ckj/sfu028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377750PMC
June 2014

Somatic mosaicism in ACVRL1 with transmission to several offspring affected with severe pulmonary arterial hypertension.

Am J Med Genet A 2014 Aug 21;164A(8):2121-3. Epub 2014 Apr 21.

Clinical Genetics Department, University Hospitals Leicester NHS Trust, Leicester, United Kingdom.

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http://dx.doi.org/10.1002/ajmg.a.36568DOI Listing
August 2014

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations.

Eur J Hum Genet 2014 Jul 27;22(7):881-7. Epub 2013 Nov 27.

South West Thames Regional Genetics Service, St George's Healthcare NHS Trust, London, UK.

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR) (MIM No.152950) is a rare autosomal dominant condition for which a causative gene has recently been identified. Mutations in the kinesin family member 11 (KIF11) gene have now been described in 16 families worldwide. This is a review of the condition based on the clinical features of 37 individuals from 22 families. This report includes nine previously unreported families and additional information for some of those reported previously. The condition arose de novo in 8/20 families (40%). The parental results were not available for two probands. The mutations were varied and include missense, nonsense, frameshift, and splice site and are distributed evenly throughout the KIF11 gene. In our cohort, 86% had microcephaly, 78% had an ocular abnormality consistent with the diagnosis, 46% had lymphoedema, 73% had mild-moderate learning difficulties, 8% had epilepsy, and 8% had a cardiac anomaly. We identified three individuals with KIF11 mutations but no clinical features of MCLMR demonstrating reduced penetrance. The variable expression of the phenotype and the presence of mildly affected individuals indicates that the prevalence may be higher than expected, and we would therefore recommend a low threshold for genetic testing.
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http://dx.doi.org/10.1038/ejhg.2013.263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938398PMC
July 2014
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