Publications by authors named "Deborah J G Mackay"

53 Publications

Experiences of adolescents living with Silver-Russell syndrome.

Arch Dis Child 2021 Mar 19. Epub 2021 Mar 19.

Clinical Ethics & Law, Faculty of Medicine, University of Southampton, Southampton, UK.

Objective: The psychosocial impact of growing up with Silver-Russell syndrome (SRS), characterised by growth failure and short stature in adulthood, has been explored in adults; however, there are no accounts of contemporary lived experience in adolescents. Such data could inform current healthcare guidance and transition to adult services. We aimed to explore the lived experience of adolescents with SRS.

Design/setting/patients: In-depth, semi-structured interviews were conducted between January 2015 and October 2016 with a sample of eight adolescents aged 13-18 (five girls) with genetically confirmed SRS from the UK. Qualitative interviews were transcribed and coded to identify similarities and differences using thematic analysis; codes were then grouped to form overarching themes.

Results: We identified four themes from the interview data: (1) the psychosocial challenges of feeling and looking different; (2) pain, disability and fatigue; (3) anticipated stigma; and (4) building resilience and acceptance. Despite adolescents accepting SRS in their lives, they described ongoing psychosocial challenges and anticipated greater problems to come, such as stigma from prospective employers.

Conclusions: Adolescents with SRS may experience psychosocial difficulties from as young as 10 years old related to feeling and looking different; pain, disability and fatigue; anticipated stigma; and future challenges around employment. We discuss these findings in relation to recommendations for the care of adolescents with SRS to prepare them for adult life.
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http://dx.doi.org/10.1136/archdischild-2020-321376DOI Listing
March 2021

Phenotype of genetically confirmed Silver-Russell syndrome beyond childhood.

J Med Genet 2020 10 13;57(10):683-691. Epub 2020 Feb 13.

Human Development and Health, Faculty of Medicine University of Southampton, Southampton, UK

Background: Silver-Russell syndrome is an imprinting disorder that restricts growth, resulting in short adult stature that may be ameliorated by treatment. Approximately 50% of patients have loss of methylation of the imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 and 5%-10% have maternal uniparental disomy of chromosome 7. Most published research focuses on the childhood phenotype. Our aim was to describe the phenotypic characteristics of older patients with SRS.

Methods: A retrospective cohort of 33 individuals with a confirmed molecular diagnosis of SRS aged 13 years or above were carefully phenotyped.

Results: The median age of the cohort was 29.6 years; 60.6% had a height SD score (SDS) ≤-2 SDS despite 70% having received growth hormone treatment. Relative macrocephaly, feeding difficulties and a facial appearance typical of children with SRS were no longer discriminatory diagnostic features. In those aged ≥18 years, impaired glucose tolerance in 25%, hypertension in 33% and hypercholesterolaemia in 52% were noted. While 9/33 accessed special education support, university degrees were completed in 40.0% (>21 years). There was no significant correlation between quality of life and height SDS. 9/25 were parents and none of the 17 offsprings had SRS.

Conclusion: Historical treatment regimens for SRS were not sufficient for normal adult growth and further research to optimise treatment is justified. Clinical childhood diagnostic scoring systems are not applicable to patients presenting in adulthood and SRS diagnosis requires molecular confirmation. Metabolic ill-health warrants further investigation but SRS is compatible with a normal quality of life including normal fertility in many cases.
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http://dx.doi.org/10.1136/jmedgenet-2019-106561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525777PMC
October 2020

The phenotypic variations of multi-locus imprinting disturbances associated with maternal-effect variants of NLRP5 range from overt imprinting disorder to apparently healthy phenotype.

Clin Epigenetics 2019 12 11;11(1):190. Epub 2019 Dec 11.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania "Luigi Vanvitelli", Caserta, Italy.

Background: A subset of individuals affected by imprinting disorders displays multi-locus imprinting disturbances (MLID). MLID has been associated with maternal-effect variants that alter the maintenance of methylation at germline-derived differentially methylated regions (gDMRs) in early embryogenesis. Pedigrees of individuals with MLID also include siblings with healthy phenotype. However, it is unknown if these healthy individuals have MLID themselves or if their methylation patterns differ from those associated with imprinting disorders, and in general, if MLID affects the clinical phenotype.

Methods: We have investigated gDMR methylation by locus-specific and whole-genome analyses in a family with multiple pregnancy losses, a child with Beckwith-Wiedemann syndrome (BWS) and a further child with no clinical diagnosis of imprinting disorder or other pathologies.

Results: We detected MLID with different methylation profiles in the BWS-affected and healthy siblings. Whole-exome sequencing demonstrated the presence of novel loss-of-function variants of NLRP5 in compound heterozygosity in the mother. The methylation profiles of the two siblings were compared with those of other cases with MLID and control groups by principal component analysis and unsupervised hierarchical clustering, but while their patterns were clearly separated from those of controls, we were unable to cluster those associated with specific clinical phenotypes among the MLID cases.

Conclusion: The identification of two novel maternal-effect variants of NLRP5 associated with poly-abortivity and MLID adds further evidence to the role of this gene in the maintenance of genomic imprinting in early embryos. Furthermore, our results demonstrate that within these pedigrees, MLID can also be present in the progeny with healthy phenotype, indicating that some sort of compensation occurs between altered imprinted loci in these individuals. The analysis of larger cohorts of patients with MLID is needed to formulate more accurate epigenotype-phenotype correlations.
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http://dx.doi.org/10.1186/s13148-019-0760-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907351PMC
December 2019

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

Genome Res 2019 07 3;29(7):1057-1066. Epub 2019 Jun 3.

Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon and Exeter NHS Foundation Trust, Exeter, EX2 5DW, United Kingdom.

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha () are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: Sotos syndrome overgrowth disorder and Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.
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http://dx.doi.org/10.1101/gr.243584.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633263PMC
July 2019

Growth Hormone Improves Short-Term Growth in Patients with Temple Syndrome.

Horm Res Paediatr 2018 5;90(6):407-413. Epub 2019 Mar 5.

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Background/aims: Temple syndrome is an imprinting disorder caused by maternal uniparental disomy of chromosome 14 (mat UPD14), paternal deletion of 14q32 or paternal hypomethylation of the intergenic differentially methylated region (MEG3/DLK1 IG-DMR). Patients with Temple syndrome have pre- and postnatal growth restriction, short stature, hypotonia, small hands and feet and precocious puberty. We sought to determine whether treatment with growth hormone improves growth outcomes in patients with Temple syndrome.

Methods: This was a retrospective observational study reviewing the medical records of 14 patients with Temple syndrome, 7 of whom were treated with growth hormone.

Results: After 1 year of growth hormone treatment, the height standard deviation score (SDS) increased a median of 1.31 SDS with a median increased height velocity of 5.30 cm/year.

Conclusions: These results suggest short-term improvement in height SDS with growth hormone treatment similar to the response in patients treated under the small for gestational age indication. We recommend considering growth hormone therapy in all patients with Temple syndrome who have short stature.
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http://dx.doi.org/10.1159/000496700DOI Listing
August 2019

Discrepant molecular and clinical diagnoses in Beckwith-Wiedemann and Silver-Russell syndromes.

Genet Res (Camb) 2019 03 4;101:e3. Epub 2019 Mar 4.

Institute of Human Genetics, University Hospital, Technical University of Aachen,Aachen,Germany.

Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders associated with opposite molecular alterations in the 11p15.5 imprinting centres. Their clinical diagnosis is confirmed by molecular testing in 50-70% of patients. The authors from different reference centres for BWS and SRS have identified single patients with unexpected and even contradictory molecular findings in respect to the clinical diagnosis. These patients clinically do not fit the characteristic phenotypes of SRS or BWS, but illustrate their clinical heterogeneity. Thus, comprehensive molecular testing is essential for accurate diagnosis and appropriate management, to avoid premature clinical diagnosis and anxiety for the families.
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http://dx.doi.org/10.1017/S001667231900003XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044970PMC
March 2019

Genetic diagnosis of subfertility: the impact of meiosis and maternal effects.

J Med Genet 2019 05 6;56(5):271-282. Epub 2019 Feb 6.

Reproduction and Genetics Department, Vrije Universiteit Brussel, Brussels, Belgium.

During reproductive age, approximately one in seven couples are confronted with fertility problems. While the aetiology is diverse, including infections, metabolic diseases, hormonal imbalances and iatrogenic effects, it is becoming increasingly clear that genetic factors have a significant contribution. Due to the complex nature of infertility that often hints at a multifactorial cause, the search for potentially causal gene mutations in idiopathic infertile couples has remained difficult. Idiopathic infertility patients with a suspicion of an underlying genetic cause can be expected to have mutations in genes that do not readily affect general health but are only essential in certain processes connected to fertility. In this review, we specifically focus on genes involved in meiosis and maternal-effect processes, which are of critical importance for reproduction and initial embryonic development. We give an overview of genes that have already been linked to infertility in human, as well as good candidates which have been described in other organisms. Finally, we propose a phenotypic range in which we expect an optimal diagnostic yield of a meiotic/maternal-effect gene panel.
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http://dx.doi.org/10.1136/jmedgenet-2018-105513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581078PMC
May 2019

Genomic imprinting disorders: lessons on how genome, epigenome and environment interact.

Nat Rev Genet 2019 04;20(4):235-248

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', Caserta; Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' CNR, Napoli, Italy.

Genomic imprinting, the monoallelic and parent-of-origin-dependent expression of a subset of genes, is required for normal development, and its disruption leads to human disease. Imprinting defects can involve isolated or multilocus epigenetic changes that may have no evident genetic cause, or imprinting disruption can be traced back to alterations of cis-acting elements or trans-acting factors that control the establishment, maintenance and erasure of germline epigenetic imprints. Recent insights into the dynamics of the epigenome, including the effect of environmental factors, suggest that the developmental outcomes and heritability of imprinting disorders are influenced by interactions between the genome, the epigenome and the environment in germ cells and early embryos.
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http://dx.doi.org/10.1038/s41576-018-0092-0DOI Listing
April 2019

Genetics, molar pregnancies and medieval ideas of monstrous births: the lump of flesh in .

Med Humanit 2019 Mar 7;45(1):2-9. Epub 2018 Aug 7.

Department of Human Genetics and Genomics Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.

The medieval English romance gives an account of a birth of a lump of flesh. This has been considered as fantastic and monstrous in past literature, the horrific union of a Christian and Saracen. However, while the text certainly speaks to miscegenation, we propose that this lump of flesh is actually a hydatidiform mole. We trace the hydatidiform mole from antiquity, surrounding it with contextual medieval examples, from theology, history and medicine, that also describe abnormal births as 'lumps of flesh'. By discussing medieval ideas of monsters as a warning sign, we interpret the lump of flesh in terms of abnormal births, seed transmission, parental contribution and sin. Ideas of warning, blame and intervention present themselves as a response to moles both in medieval texts as well as in modern reactions to hydatidiform moles. We explore the epigenetics of hydatidiform moles and relate them to the medieval text. In , the fault for the lump of flesh could reside with either parent; we find that this is also the case in the genetic formation of the hydatidiform mole; we also argue that the epigenetics supports medieval theories of seed transmission.
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http://dx.doi.org/10.1136/medhum-2017-011387DOI Listing
March 2019

Lived experience of Silver-Russell syndrome: implications for management during childhood and into adulthood.

Arch Dis Child 2019 01 28;104(1):76-82. Epub 2018 Jun 28.

Faculty of Medicine, Clinical Ethics and Law, University of Southampton, Southampton, UK.

Objective: There is limited information on the psychosocial impact of growing up with Silver-Russell syndrome (SRS), characterised by slow growth in utero leading to short stature in adulthood. Such information could aid families in making difficult treatment decisions and guide management strategies for health professionals. We aimed to explore the lived experience of people with SRS across the lifespan.

Design/setting/patients: In-depth, semi-structured interviews were conducted between January 2015 and October 2016 with a sample of 15 adults (six women) with genetically confirmed SRS from the UK. Qualitative interviews were transcribed and coded to identify similarities and differences: codes were then grouped to form overarching themes.

Results: Four themes were identified from participant accounts: (1) appearance-related concerns extending beyond height; (2) strategies to deal with real and perceived threats; (3) women's experiences of pain, disability and feeling older than their years; and (4) feeling overlooked in romantic relationships. These themes show that other factors, beyond short stature, affect patient well-being and indicate a mismatch between patient need and healthcare provision.

Conclusions: Challenges in SRS during childhood and adolescence were central to the psychosocial impact of SRS, and were not limited to height. These challenges, as well as symptoms such as pain and fatigue for women, have not previously been documented. To help individuals with SRS develop strategies to manage psychosocial issues, we recommend clinicians incorporate psychological services as an integral part of multidisciplinary teams managing individuals with SRS during childhood, adolescence and adulthood.
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http://dx.doi.org/10.1136/archdischild-2018-314952DOI Listing
January 2019

Maternal variants in and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring.

J Med Genet 2018 07 24;55(7):497-504. Epub 2018 Mar 24.

Faculty of Medicine, University of Southampton, Southampton, UK.

Background: Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance.

Methods: Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in have previously been found.

Results: We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including , and . As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss.

Conclusion: The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.
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http://dx.doi.org/10.1136/jmedgenet-2017-105190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047157PMC
July 2018

Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.

Nat Rev Endocrinol 2018 04 29;14(4):229-249. Epub 2018 Jan 29.

Department of Medical Genetics, University of Cambridge and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.
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http://dx.doi.org/10.1038/nrendo.2017.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022848PMC
April 2018

Human imprinting disorders: Principles, practice, problems and progress.

Eur J Med Genet 2017 Nov 14;60(11):618-626. Epub 2017 Aug 14.

Faculty of Medicine, University of Southampton, Duthie Building (MP808), Southampton University Hospital, Tremona Road, Southampton SO16 6YD, UK.

Epigenetic regulation orchestrates gene expression with exquisite precision, over a huge dynamic range and across developmental space and time, permitting genomically-homogeneous humans to develop and adapt to their surroundings. Every generation, these epigenetic marks are re-set twice: in the germline, to enable differentiation of sperm and eggs, and at fertilisation, to create the totipotent zygote that then begins growth and differentiation into a new human. A small group of genes evades the second, zygotic wave of epigenetic reprogramming, and these genes retain an epigenetic 'imprint' of the parent from whom they were inherited. Imprinted genes are (as a general rule) expressed from one parental allele only. Some imprinted genes are critical regulators of growth and development, and thus disruption of their normal monoallelic expression causes congenital imprinting disorders, with clinical features impacting growth, development, behaviour and metabolism. Imprinting disorders as a group have characteristics that challenge diagnosis and management, including clinical and molecular heterogeneity, overlapping clinical features, somatic mosaicism, and multi-locus involvement. New insights into the biology and epigenomics of the early embryo offers new clues about the origin and importance of imprinting disorders.
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http://dx.doi.org/10.1016/j.ejmg.2017.08.014DOI Listing
November 2017

Diagnosis and management of Silver-Russell syndrome: first international consensus statement.

Nat Rev Endocrinol 2017 02 2;13(2):105-124. Epub 2016 Sep 2.

AP-HP, Hôpitaux Universitaires Paris Est (AP-HP) Hôpital des Enfants Armand Trousseau, Service d'Explorations Fonctionnelles Endocriniennes, 26 avenue du Dr Arnold Netter, 75012 Paris, France.

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.
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http://dx.doi.org/10.1038/nrendo.2016.138DOI Listing
February 2017

Erratum to: Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci.

Clin Epigenetics 2016 7;8:27. Epub 2016 Mar 7.

Endocrinology and diabetology for children and reference center for rare disorders of calcium and phosphorus metabolism, Bicêtre Paris Sud, APHP, Le Kremlin-Bicêtre, France ; INSERM U986, INSERM, Le Kremlin-Bicêtre, France ; INSERM, UMR_S 938, CDR Saint-Antoine, Paris, F-75012 France.

[This corrects the article DOI: 10.1186/s13148-015-0143-8.].
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http://dx.doi.org/10.1186/s13148-016-0194-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782320PMC
March 2016

Transient Neonatal Diabetes Mellitus followed by recurrent asymptomatic hypoglycaemia: a case report.

BMC Pediatr 2015 Dec 2;15:200. Epub 2015 Dec 2.

Royal Hospital for Women, Randwick, Sydney, Australia.

Background: Transient Neonatal Diabetes Mellitus is the commonest cause of diabetes presenting in the first week of life. Majority of infants recover by 3 months of age but are predisposed to developing type 2 diabetes later on in life. This condition is usually due to genetic aberrations at the 6q24 gene locus, and can be sporadic or inherited. This disorder has three phases: neonatal diabetes, apparent remission, relapse of diabetes.

Case Presentation: Our case, a neonate presented with low birth weight and growth retardation along with the metabolic profile consistent with transient diabetes mellitus at birth. We report a novel clinical observation of recurrent asymptomatic hypoglycaemia detected on pre-feed blood glucose level monitoring in our case with transient neonatal diabetes mellitus at 6 weeks of age, 4 weeks after the remission of diabetes mellitus.

Conclusion: This case demonstrates that neonates in remission following transient diabetes mellitus can present with recurrent asymptomatic hypoglycaemia without any other obvious congenital malformations seen. This asymptomatic hypoglycaemia may persist for weeks and may be missed if pre-feed blood glucose level monitoring is not done in these infants. Also, these infants may require an aggressive enteral feeding regimen with high glucose delivery rate to maintain normoglycemia.
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http://dx.doi.org/10.1186/s12887-015-0512-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667510PMC
December 2015

Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci.

Clin Epigenetics 2015 14;7:123. Epub 2015 Nov 14.

Endocrinology and diabetology for children and reference center for rare disorders of calcium and phosphorus metabolism, Bicêtre Paris Sud, APHP, Le Kremlin-Bicêtre, France ; INSERM U986, INSERM, Le Kremlin-Bicêtre, France ; INSERM, UMR_S 938, CDR Saint-Antoine, Paris, F-75012 France.

Congenital imprinting disorders (IDs) are characterised by molecular changes affecting imprinted chromosomal regions and genes, i.e. genes that are expressed in a parent-of-origin specific manner. Recent years have seen a great expansion in the range of alterations in regulation, dosage or DNA sequence shown to disturb imprinted gene expression, and the correspondingly broad range of resultant clinical syndromes. At the same time, however, it has become clear that this diversity of IDs has common underlying principles, not only in shared molecular mechanisms, but also in interrelated clinical impacts upon growth, development and metabolism. Thus, detailed and systematic analysis of IDs can not only identify unifying principles of molecular epigenetics in health and disease, but also support personalisation of diagnosis and management for individual patients and families.
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http://dx.doi.org/10.1186/s13148-015-0143-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650860PMC
November 2015

Temple syndrome as a result of isolated hypomethylation of the 14q32 imprinted DLK1/MEG3 region.

Am J Med Genet A 2016 Jan 23;170A(1):170-5. Epub 2015 Sep 23.

Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

We present a Caucasian female, who was diagnosed at 13 years of age with Temple syndrome (formerly referred to as "maternal UPD 14 phenotype") due to an epigenetic loss of methylation at IG-DMR/MEG3-DMR at the chromosome 14q32 imprinted locus. Clinical features were typical and included intra-uterine growth retardation (IUGR), low birth weight, hypotonia, and poor feeding in the neonatal period; and failure to thrive and developmental delay--particularly in relation to speech--in early childhood. Premature puberty, with short stature and truncal obesity, but normal intelligence, were the key features in teenage years. To date only eight patients with Temple syndrome due to an epigenetic error have been described and the etiology of the methylation defect is currently undetermined. In view of a tendency towards central obesity, patients are at potential risk of early-onset type 2 diabetes mellitus, as well as cardiovascular disease and they, therefore, require appropriate monitoring.
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http://dx.doi.org/10.1002/ajmg.a.37400DOI Listing
January 2016

Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans.

Nat Commun 2015 Sep 1;6:8086. Epub 2015 Sep 1.

Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.

Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting.
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http://dx.doi.org/10.1038/ncomms9086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568303PMC
September 2015

Maternal uniparental disomy of chromosome 20: a novel imprinting disorder of growth failure.

Genet Med 2016 Apr 6;18(4):309-15. Epub 2015 Aug 6.

Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Purpose: Maternal uniparental disomy of chromosome 20 (UPD(20)mat) has been reported in only four patients, three of whom also had mosaicism for complete or partial trisomy of chromosome 20. We sought to evaluate the clinical significance of isolated UPD(20)mat in eight individuals.

Methods: We evaluated phenotypic and genomic findings of a series of eight new patients with UPD(20)mat.

Results: All eight individuals with UPD(20)mat had intrauterine growth restriction, short stature, and prominent feeding difficulties with failure to thrive. As a common feature, they often required gastric tube feeds. Genomic data in most patients are indicative of UPD as a result of trisomy rescue after meiosis II nondisjunction.

Conclusion: We describe the first natural history of the disorder and the results of therapeutic interventions, including the frequent requirement of direct gastric feedings only during the first few years of life, and propose that growth hormone supplementation is probably safe and effective for this condition. We suggest that UPD(20)mat can be regarded as a new imprinting disorder and its identification requires specialized molecular testing, which should be performed in patients with early-onset idiopathic isolated growth failure.Genet Med 18 4, 309-315.
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http://dx.doi.org/10.1038/gim.2015.103DOI Listing
April 2016

The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study.

Lancet 2015 Sep 28;386(9997):957-63. Epub 2015 Jul 28.

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK. Electronic address:

Background: Traditional genetic testing focusses on analysis of one or a few genes according to clinical features; this approach is changing as improved sequencing methods enable simultaneous analysis of several genes. Neonatal diabetes is the presenting feature of many discrete clinical phenotypes defined by different genetic causes. Genetic subtype defines treatment, with improved glycaemic control on sulfonylurea treatment for most patients with potassium channel mutations. We investigated the effect of early, comprehensive testing of all known genetic causes of neonatal diabetes.

Methods: In this large, international, cohort study, we studied patients with neonatal diabetes diagnosed with diabetes before 6 months of age who were referred from 79 countries. We identified mutations by comprehensive genetic testing including Sanger sequencing, 6q24 methylation analysis, and targeted next-generation sequencing of all known neonatal diabetes genes.

Findings: Between January, 2000, and August, 2013, genetic testing was done in 1020 patients (571 boys, 449 girls). Mutations in the potassium channel genes were the most common cause (n=390) of neonatal diabetes, but were identified less frequently in consanguineous families (12% in consanguineous families vs 46% in non-consanguineous families; p<0·0001). Median duration of diabetes at the time of genetic testing decreased from more than 4 years before 2005 to less than 3 months after 2012. Earlier referral for genetic testing affected the clinical phenotype. In patients with genetically diagnosed Wolcott-Rallison syndrome, 23 (88%) of 26 patients tested within 3 months from diagnosis had isolated diabetes, compared with three (17%) of 18 patients referred later (>4 years; p<0·0001), in whom skeletal and liver involvement was common. Similarly, for patients with genetically diagnosed transient neonatal diabetes, the diabetes had remitted in only ten (10%) of 101 patients tested early (<3 months) compared with 60 (100%) of the 60 later referrals (p<0·0001).

Interpretation: Patients are now referred for genetic testing closer to their presentation with neonatal diabetes. Comprehensive testing of all causes identified causal mutations in more than 80% of cases. The genetic result predicts the best diabetes treatment and development of related features. This model represents a new framework for clinical care with genetic diagnosis preceding development of clinical features and guiding clinical management.

Funding: Wellcome Trust and Diabetes UK.
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http://dx.doi.org/10.1016/S0140-6736(15)60098-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772451PMC
September 2015

Neonatal diabetes in Ukraine: incidence, genetics, clinical phenotype and treatment.

J Pediatr Endocrinol Metab 2015 Nov;28(11-12):1279-86

Background: Neonatal diabetes has not been previously studied in Ukraine. We investigated the genetic etiology in patients with onset of diabetes during the first 9 months of life.

Methods: We established a Pediatric Diabetes Register to identify patients diagnosed with diabetes before 9 months of age. Genetic testing was undertaken for 42 patients with permanent or transient diabetes diagnosed within the first 6 months of life (n=22) or permanent diabetes diagnosed between 6 and 9 months (n=20).

Results: We determined the genetic etiology in 23 of 42 (55%) patients; 86% of the patients diagnosed before 6 months and 20% diagnosed between 6 and 9 months. The incidence of neonatal diabetes in Ukraine was calculated to be 1 in 126,397 live births.

Conclusions: Genetic testing for patients identified through the Ukrainian Pediatric Diabetes Register identified KCNJ11 and ABCC8 mutations as the most common cause (52%) of neonatal diabetes. Transfer to sulfonylureas improved glycemic control in all 11 patients.
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http://dx.doi.org/10.1515/jpem-2015-0170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860009PMC
November 2015

Multilocus methylation defects in imprinting disorders.

Biomol Concepts 2015 Mar;6(1):47-57

Mammals inherit two complete sets of chromosomes, one from the father and one from the mother, and most autosomal genes are expressed from both maternal and paternal alleles. In imprinted genes, the expression of the allele is dependent upon its parental origin. Appropriate regulation of imprinted genes is important for normal development, with several genetic diseases associated with imprinting defects. A common process for controlling gene activity is methylation. The first steps for understanding the functions of DNA methylation and its regulation in mammalian development have led us to identify common (epi)genetic mechanisms involved in the eight human congenital imprinting disorders.
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http://dx.doi.org/10.1515/bmc-2014-0037DOI Listing
March 2015

Very small deletions within the NESP55 gene in pseudohypoparathyroidism type 1b.

Eur J Hum Genet 2015 Apr 9;23(4):494-9. Epub 2014 Jul 9.

1] Human Genetics and Genomic medicine, Faculty of Medicine, University of Southampton, Southampton, UK [2] Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury NHS Foundation Trust, Salisbury, UK.

Pseudohypoparathyroidism (PHP) is caused by reduced expression of genes within the GNAS cluster, resulting in parathormone resistance. The cluster contains multiple imprinted transcripts, including the stimulatory G protein α subunit (Gs-α) and NESP55 transcript preferentially expressed from the maternal allele, and the paternally expressed XLas, A/B and antisense transcripts. PHP1b can be caused by loss of imprinting affecting GNAS A/B alone (associated with STX16 deletion), or the entire GNAS cluster (associated with deletions of NESP55 in a minority of cases). We performed targeted genomic next-generation sequencing (NGS) of the GNAS cluster to seek variants and indels underlying PHP1b. Seven patients were sequenced by hybridisation-based capture and fourteen more by long-range PCR and transposon-mediated insertion and sequencing. A bioinformatic pipeline was developed for variant and indel detection. In one family with two affected siblings, and in a second family with a single affected individual, we detected maternally inherited deletions of 40 and 33 bp, respectively, within the deletion previously reported in rare families with PHP1b. All three affected individuals presented with atypically severe PHP1b; interestingly, the unaffected mother in one family had the detected deletion on her maternally inherited allele. Targeted NGS can reveal sequence changes undetectable by current diagnostic methods. Identification of genetic mutations underlying epigenetic changes can facilitate accurate diagnosis and counselling, and potentially highlight genetic elements critical for normal imprint setting.
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http://dx.doi.org/10.1038/ejhg.2014.133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4247793PMC
April 2015

Temple syndrome: improving the recognition of an underdiagnosed chromosome 14 imprinting disorder: an analysis of 51 published cases.

J Med Genet 2014 Aug 2;51(8):495-501. Epub 2014 Jun 2.

Academic Unit of Human Development and Health, Human Genetics and Genomics Medicine group, Faculty of Medicine, University of Southampton, Southampton, UK Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Princess Anne Hospital, Southampton, UK.

Chromosome 14 harbours an imprinted locus at 14q32. Maternal uniparental disomy of chromosome 14, paternal deletions and loss of methylation at the intergenic differentially methylated region (IG-DMR) result in a human phenotype of low birth weight, hypotonia, early puberty and markedly short adult stature. The analysis of the world literature of 51 cases identifies the key features that will enhance diagnosis and potentially improve treatment. We found a median birth weight SD score (SDS) of -1.88 and median adult final height of -2.04 SDS. Hypotonia and motor delay were reported in 93% and 83% of cases, respectively. Early puberty was reported in 86% of cases with the mean age of menarche at 10 years and 2 months of age. Small hands and feet were reported frequently (87% and 96%, respectively). Premature birth was common (30%) and feeding difficulties frequently reported (n = 22). There was evidence of mildly reduced intellectual ability (measured IQ 75-95). Obesity was reported in 49% of cases, and three patients developed type 2 diabetes mellitus. Two patients were reported to have recurrent hypoglycaemia, and one of these patients was subsequently demonstrated to be growth hormone deficient and started replacement therapy. We propose the use of the name 'Temple syndrome' for this condition and suggest that improved diagnosis and long-term monitoring, especially of growth and cardiovascular risk factors, is required.
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http://dx.doi.org/10.1136/jmedgenet-2014-102396DOI Listing
August 2014

Chromosome 6q24 transient neonatal diabetes mellitus and protein sensitive hyperinsulinaemic hypoglycaemia.

J Pediatr Endocrinol Metab 2014 Nov;27(11-12):1065-9

Aim: We describe the novel clinical observation of protein induced hyperinsulinaemic hypoglycaemia following remission of transient neonatal diabetes mellitus (TNDM) in a patient with 6q24 methylation defect.

Methods: A male infant of non-consanguineous Caucasian parents, born at 40 weeks of gestation with a birth weight of 3330 g (-0.55 standard deviation score) presented with hyperglycaemia in the first week of life and was diagnosed with 6q24 TNDM. At 22 months of age, he developed recurrent hypoglycaemic episodes. Controlled diagnostic fast, oral glucose tolerance test, protein loading test and mixed meal tolerance test were undertaken. Sequencing of ABCC8, KCNJ11, GLUD1 and HADH were performed.

Results: Investigations suggested a diagnosis of protein sensitive hyperinsulinaemic hypoglycaemia with normal serum ammonia, acylcarnitine profile and urine organic acids. Sequencing of ABCC8, KCNJ11, GLUD1 and HADH did not identify a pathogenic mutation to explain his hyperinsulinaemic hypoglycaemia.

Conclusion: This clinical case demonstrates the novel observation of protein sensitive hyperinsulinaemic hypoglycaemia in a patient with 6q24 TNDM. Long-term follow-up of patients with chromosome 6q24 TNDM is warranted following remission.
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http://dx.doi.org/10.1515/jpem-2014-0031DOI Listing
November 2014

A familial disorder of altered DNA-methylation.

J Med Genet 2014 Jun 10;51(6):407-12. Epub 2014 Apr 10.

Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.

Background: In a subset of imprinting disorders caused by epimutations, multiple imprinted loci are affected. Familial occurrence of multilocus imprinting disorders is rare.

Purpose/objective: We have investigated the clinical and molecular features of a familial DNA-methylation disorder.

Methods: Tissues of affected individuals and blood samples of family members were investigated by conventional and molecular karyotyping. Sanger sequencing and RT-PCR of imprinting-associated genes (NLRP2, NLRP7, ZFP57, KHDC3L, DNMT1o), exome sequencing and locus-specific, array-based and genome-wide technologies to determine DNA-methylation were performed.

Results: In three offspring of a healthy couple, we observed prenatal onset of severe growth retardation and dysmorphism associated with altered DNA-methylation at paternally and maternally imprinted loci. Array-based analyses in various tissues of the offspring identified the DNA-methylation of 2.1% of the genes in the genome to be recurrently altered. Despite significant enrichment of imprinted genes (OR 9.49), altered DNA-methylation predominately (90.2%) affected genes not known to be imprinted. Sequencing of genes known to cause comparable conditions and exome sequencing in affected individuals and their ancestors did not unambiguously point to a causative gene.

Conclusions: The family presented herein suggests the existence of a familial disorder of DNA-methylation affecting imprinted but also not imprinted gene loci potentially caused by a maternal effect mutation in a hitherto not identified gene.
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http://dx.doi.org/10.1136/jmedgenet-2013-102149DOI Listing
June 2014

Genome-wide DNA methylation analysis of patients with imprinting disorders identifies differentially methylated regions associated with novel candidate imprinted genes.

J Med Genet 2014 Apr 5;51(4):229-38. Epub 2014 Feb 5.

Faculty of Medicine, University of Southampton, Southampton, UK.

Background: Genomic imprinting is allelic restriction of gene expression potential depending on parent of origin, maintained by epigenetic mechanisms including parent of origin-specific DNA methylation. Among approximately 70 known imprinted genes are some causing disorders affecting growth, metabolism and cancer predisposition. Some imprinting disorder patients have hypomethylation of several imprinted loci (HIL) throughout the genome and may have atypically severe clinical features. Here we used array analysis in HIL patients to define patterns of aberrant methylation throughout the genome.

Design: We developed a novel informatic pipeline capable of small sample number analysis, and profiled 10 HIL patients with two clinical presentations (Beckwith-Wiedemann syndrome and neonatal diabetes) using the Illumina Infinium Human Methylation450 BeadChip array to identify candidate imprinted regions. We used robust statistical criteria to quantify DNA methylation.

Results: We detected hypomethylation at known imprinted loci, and 25 further candidate imprinted regions (nine shared between patient groups) including one in the Down syndrome critical region (WRB) and another previously associated with bipolar disorder (PPIEL). Targeted analysis of three candidate regions (NHP2L1, WRB and PPIEL) showed allelic expression, methylation patterns consistent with allelic maternal methylation and frequent hypomethylation among an additional cohort of HIL patients, including six with Silver-Russell syndrome presentations and one with pseudohypoparathyroidism 1B.

Conclusions: This study identified novel candidate imprinted genes, revealed remarkable epigenetic convergence among clinically divergent patients, and highlights the potential of epigenomic profiling to expand our understanding of the normal methylome and its disruption in human disease.
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http://dx.doi.org/10.1136/jmedgenet-2013-102116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963529PMC
April 2014