Publications by authors named "Helen Stewart"

84 Publications

Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype.

Am J Med Genet A 2021 10 1;185(10):3083-3091. Epub 2021 Jun 1.

Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

KCNT2 variants resulting in substitutions affecting the Arg190 residue have been shown to cause epileptic encephalopathy and a recognizable facial gestalt. We report two additional individuals with intellectual disability, dysmorphic features, hypertrichosis, macrocephaly and the same de novo KCNT2 missense variants affecting the Arg190 residue as previously described. Notably, neither patient has epilepsy. Homology modeling of these missense variants revealed that they are likely to disrupt the stabilization of a closed channel conformation of KCNT2 resulting in a constitutively open state. This is the first report of pathogenic variants in KCNT2 causing a developmental phenotype without epilepsy.
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http://dx.doi.org/10.1002/ajmg.a.62370DOI Listing
October 2021

Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.

Am J Hum Genet 2021 06 21;108(6):1083-1094. Epub 2021 May 21.

Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1RQ, UK; East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.

Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder (DD) cases. The contribution of regulatory variation in non-coding regions to rare disease, including DD, remains very poorly understood. We screened 9,858 probands from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5' untranslated regions (5' UTRs) of genes within which variants have previously been shown to cause DD through a dominant haploinsufficient mechanism. We identified four single-nucleotide variants and two copy-number variants upstream of MEF2C in a total of ten individual probands. We developed multiple bespoke and orthogonal experimental approaches to demonstrate that these variants cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding region variants represent 23% of likely diagnoses identified in MEF2C in the DDD cohort, but these would all be missed in standard clinical genetics approaches. Nonetheless, these variants are readily detectable in exome sequence data, with 30.7% of 5' UTR bases across all genes well covered in the DDD dataset. Our analyses show that non-coding variants upstream of genes within which coding variants are known to cause DD are an important cause of severe disease and demonstrate that analyzing 5' UTRs can increase diagnostic yield. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants and dosage tolerance of the gene.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206381PMC
June 2021

Dissection of contiguous gene effects for deletions around ERF on chromosome 19.

Hum Mutat 2021 Jul 16;42(7):811-817. Epub 2021 May 16.

Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Heterozygous intragenic loss-of-function mutations of ERF, encoding an ETS transcription factor, were previously reported to cause a novel craniosynostosis syndrome, suggesting that ERF is haploinsufficient. We describe six families harboring heterozygous deletions including, or near to, ERF, of which four were characterized by whole-genome sequencing and two by chromosomal microarray. Based on the severity of associated intellectual disability (ID), we identify three categories of ERF-associated deletions. The smallest (32 kb) and only inherited deletion included two additional centromeric genes and was not associated with ID. Three larger deletions (264-314 kb) that included at least five further centromeric genes were associated with moderate ID, suggesting that deletion of one or more of these five genes causes ID. The individual with the most severe ID had a more telomerically extending deletion, including CIC, a known ID gene. Children found to harbor ERF deletions should be referred for craniofacial assessment, to exclude occult raised intracranial pressure.
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http://dx.doi.org/10.1002/humu.24213DOI Listing
July 2021

Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype.

Eur J Hum Genet 2021 Apr 12;29(4):625-636. Epub 2021 Jan 12.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.

Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.
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http://dx.doi.org/10.1038/s41431-020-00769-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115148PMC
April 2021

BRD4-mediated repression of p53 is a target for combination therapy in AML.

Nat Commun 2021 01 11;12(1):241. Epub 2021 Jan 11.

Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Acute myeloid leukemia (AML) is a typically lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, most AML retain wild-type TP53, encoding the pro-apoptotic tumor suppressor p53. MDM2 inhibitors (MDM2i), which activate wild-type p53, and BET inhibitors (BETi), targeting the BET-family co-activator BRD4, both show encouraging pre-clinical activity, but limited clinical activity as single agents. Here, we report enhanced toxicity of combined MDM2i and BETi towards AML cell lines, primary human blasts and mouse models, resulting from BETi's ability to evict an unexpected repressive form of BRD4 from p53 target genes, and hence potentiate MDM2i-induced p53 activation. These results indicate that wild-type TP53 and a transcriptional repressor function of BRD4 together represent a potential broad-spectrum synthetic therapeutic vulnerability for AML.
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http://dx.doi.org/10.1038/s41467-020-20378-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801601PMC
January 2021

Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies.

Am J Med Genet A 2020 12 11;182(12):2877-2886. Epub 2020 Oct 11.

Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.

Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous loss of function variants in the KMT2A (MLL) gene, encoding a lysine N-methyltransferase that mediates a histone methylation pattern specific for epigenetic transcriptional activation. WDSTS is characterized by a distinctive facial phenotype, hypertrichosis, short stature, developmental delay, intellectual disability, congenital malformations, and skeletal anomalies. Recently, a few patients have been reported having abnormal skeletal development of the cervical spine. Here we describe 11 such individuals, all with KMT2A de novo loss-of-function variants: 10 showed craniovertebral junction anomalies, while an 11th patient had a cervical abnormality in C7. By evaluating clinical and diagnostic imaging data we characterized these anomalies, which consist primarily of fused cervical vertebrae, C1 and C2 abnormalities, small foramen magnum and Chiari malformation type I. Craniovertebral anomalies in WDSTS patients have been largely disregarded so far, but the increasing number of reports suggests that they may be an intrinsic feature of this syndrome. Specific investigation strategies should be considered for early identification and prevention of craniovertebral junction complications in WDSTS patients.
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http://dx.doi.org/10.1002/ajmg.a.61859DOI Listing
December 2020

HNRNPH1-related syndromic intellectual disability: Seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome.

Clin Genet 2020 07 15;98(1):91-98. Epub 2020 May 15.

Department of Human and Molecular Genetics, Clinical Genetics Services, VCU Health, Richmond, Virginia, USA.

Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2-related X-linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1-related syndromic intellectual disability.
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http://dx.doi.org/10.1111/cge.13765DOI Listing
July 2020

Effects of - Conformation between Thiophene Rings on Conductance of Oligothiophenes.

J Phys Chem Lett 2019 Sep 27;10(18):5292-5296. Epub 2019 Aug 27.

Graduate School of Engineering Science , Osaka University , 1-3 Machikaneyama , Toyonaka , Osaka 560-8531 , Japan.

Oligothiophenes have been established as important π-conjugated frameworks in organic electronics and molecular electronics. Although oligothiophenes possess the rotational flexibility of thiophene rings, the effects of - conformations on their electrical conductance have not been investigated yet. To investigate the effects of - conformations between thiophene rings on the conductance of oligothiophenes, we performed first-principles transport calculations. The conductance of the oligothiophene was calculated to be higher than that of -oligothiophene, because the highest occupied molecular orbital was closer to the Fermi level of the gold electrode in the isomer than the isomer. This prediction was confirmed through mechanically controllable break junction measurements and fitting of the current-voltage characteristics for the newly synthesized, insulated oligothiophenes with controlled - conformations. This study demonstrates that - and -conformations can affect the electrical properties of oligothiophene frameworks and can potentially be used to control the electronic structure of long oligothiophene molecular wires.
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http://dx.doi.org/10.1021/acs.jpclett.9b02059DOI Listing
September 2019

HIST1H1E heterozygous protein-truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals.

Am J Med Genet A 2019 10 9;179(10):2049-2055. Epub 2019 Aug 9.

Programa de Genética Humans, ICBM, Santiago, Chile.

Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome. Since the initial description of five unrelated individuals with three different heterozygous protein-truncating variants (PTVs) in the HIST1H1E gene in 2017, we have recruited 30 patients, all with HIST1H1E PTVs that result in the same shift in frame and that cluster to a 94-base pair region in the HIST1H1E carboxy terminal domain. The identification of 30 patients with HIST1H1E variants has allowed the clarification of the HIST1H1E syndrome phenotype. Major findings include an ID and a recognizable facial appearance. ID was reported in all patients and is most frequently of moderate severity. The facial gestalt consists of a high frontal hairline and full lower cheeks in early childhood and, in later childhood and adulthood, affected individuals have a strikingly high frontal hairline, frontal bossing, and deep-set eyes. Other associated clinical features include hypothyroidism, abnormal dentition, behavioral issues, cryptorchidism, skeletal anomalies, and cardiac anomalies. Brain magnetic resonance imaging (MRI) is frequently abnormal with a slender corpus callosum a frequent finding.
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http://dx.doi.org/10.1002/ajmg.a.61321DOI Listing
October 2019

Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.

Clin Genet 2019 06 3;95(6):693-703. Epub 2019 Apr 3.

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

Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.
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http://dx.doi.org/10.1111/cge.13533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563422PMC
June 2019

BET Inhibition Suppresses S100A8 and S100A9 Expression in Acute Myeloid Leukemia Cells and Synergises with Daunorubicin in Causing Cell Death.

Bone Marrow Res 2018 31;2018:5742954. Epub 2018 May 31.

Research Building, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PS, UK.

S100A8 and S100A9 are both members of the S100 family and have been shown to play roles in myeloid differentiation, autophagy, apoptosis, and chemotherapy resistance. In this study we demonstrate that the BET-bromodomain inhibitor JQ1 causes rapid suppression of and mRNA and protein in a reversible manner. In addition, we show that JQ1 synergises with daunorubicin in causing AML cell death. Daunorubicin alone causes a dose- and time-dependent increase in S100A8 and S100A9 protein levels in AML cell lines which is overcome by cotreatment with JQ1. This suggests that JQ1 synergises with daunorubicin in causing apoptosis via suppression of S100A8 and S100A9 levels.
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http://dx.doi.org/10.1155/2018/5742954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6000862PMC
May 2018

Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature.

Eur J Hum Genet 2018 09 14;26(9):1272-1281. Epub 2018 Jun 14.

Department of Medical Genetics, University of Calgary, Cumming School of Medicine, Calgary, AB, Canada.

Au-Kline syndrome (AKS, OMIM 616580) is a multiple malformation syndrome, first reported in 2015, associated with intellectual disability. AKS has been associated with de novo loss-of-function variants in HNRNPK (heterogeneous ribonucleoprotein K), and to date, only four of these patients have been described in the literature. Recently, an additional patient with a missense variant in HNRNPK was also reported. These patients have striking facial dysmorphic features, including long palpebral fissures, ptosis, deeply grooved tongue, broad nose, and down-turned mouth. Patients frequently also have skeletal and connective tissue anomalies, craniosynostosis, congenital heart malformations, and renal anomalies. In this report, we describe six new patients and review the clinical information on all reported AKS patients, further delineating the phenotype of AKS. There are now a total of 9 patients with de novo loss-of-function variants in HNRNPK, one individual with a de novo missense variant in addition to 3 patients with de novo deletions of 9q21.32 that encompass HNRNPK. While there is considerable overlap between AKS and Kabuki syndrome (KS), these additional patients demonstrate that AKS does have a distinct facial gestalt and phenotype that can be differentiated from KS. This growing AKS patient cohort also informs an emerging approach to management and health surveillance for these patients.
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http://dx.doi.org/10.1038/s41431-018-0187-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117294PMC
September 2018

"Will she live a long happy life?" Parents' concerns for their children with Fontan circulation.

Int J Cardiol Heart Vasc 2018 Mar 9;18:65-70. Epub 2018 Mar 9.

Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Background: Families of children at the worst end of the congenital heart disease endure a significant burden which is often not clearly delineated in the clinical literature. We examined the greatest concerns of parents whose children have a Fontan circulation.

Methods: Parents ( = 107) of children in the Australian and New Zealand Fontan Registry completed online surveys with open-ended and closed questions. A qualitative method approach incorporating thematic analyses was used.

Results: The greatest concerns for parents of a child with a Fontan circulation were centered on fear of death for their child and psychosocial well-being, followed by lesser themes around anti-coagulation use, pregnancy and financial burdens.

Conclusions: Fear of death and the psychological well-being of their children were the main parental concerns. It highlights the need to clearly communicate information on outcomes to families, and the need for family-focused psychological interventions to improve the psychosocial functioning of both parents and young people.
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http://dx.doi.org/10.1016/j.ijcha.2018.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988481PMC
March 2018

DIS3 isoforms vary in their endoribonuclease activity and are differentially expressed within haematological cancers.

Biochem J 2018 06 29;475(12):2091-2105. Epub 2018 Jun 29.

Medical Research Building, Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton BN1 9PS, U.K.

DIS3 (defective in sister chromatid joining) is the catalytic subunit of the exosome, a protein complex involved in the 3'-5' degradation of RNAs. DIS3 is a highly conserved exoribonuclease, also known as Rrp44. Global sequencing studies have identified DIS3 as being mutated in a range of cancers, with a considerable incidence in multiple myeloma. In this work, we have identified two protein-coding isoforms of DIS3. Both isoforms are functionally relevant and result from alternative splicing. They differ from each other in the size of their N-terminal PIN (PilT N-terminal) domain, which has been shown to have endoribonuclease activity and tether DIS3 to the exosome. Isoform 1 encodes a full-length PIN domain, whereas the PIN domain of isoform 2 is shorter and is missing a segment with conserved amino acids. We have carried out biochemical activity assays on both isoforms of full-length DIS3 and the isolated PIN domains. We find that isoform 2, despite missing part of the PIN domain, has greater endonuclease activity compared with isoform 1. Examination of the available structural information allows us to provide a hypothesis to explain this altered behaviour. Our results also show that multiple myeloma patient cells and all cancer cell lines tested have higher levels of isoform 1 compared with isoform 2, whereas acute myeloid leukaemia and chronic myelomonocytic leukaemia patient cells and samples from healthy donors have similar levels of isoforms 1 and 2. Taken together, our data indicate that significant changes in the ratios of the two isoforms could be symptomatic of haematological cancers.
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http://dx.doi.org/10.1042/BCJ20170962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024818PMC
June 2018

"How long will I continue to be normal?" Adults with a Fontan circulation's greatest concerns.

Int J Cardiol 2018 06;260:54-59

Murdoch Children's Research Institute, Melbourne, Victoria, Australia; Australian and New Zealand Fontan Advisory Committee, Australia and New Zealand; Cardiac Surgery Department, Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Pediatrics, Faculty of Medicine, The University of Melbourne, Melbourne, Victoria, Australia. Electronic address:

Background: Little is known about adults living with a Fontan circulation's concerns outside the scope of their clinical outcomes. We examined adults with a Fontan circulations' greatest concerns, as well as their concerns around anti-coagulation, pregnancy and finances.

Methods: Adults with a Fontan circulation in the Australian and New Zealand Fontan Registry were invited to complete an anonymous online survey, of which 57 participated. A qualitative method approach using thematic analyses was used.

Results: The greatest concerns for adults living with a Fontan circulation were fear of death/uncertainty around life expectancy which for many individuals colored their concerns around physical health, pregnancy and having children, quality of life and finances. Improving information about outcomes to patients with a Fontan circulation might alleviate uncertainties about their future.

Conclusions: Fear of death is the primary concern of adults with a Fontan circulation. It may require improved communication and targeted psychological interventions. Physical exercise incorporated as part of their lifestyle should be encouraged to alleviate physical concerns and also improve psychological well-being.
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http://dx.doi.org/10.1016/j.ijcard.2018.01.098DOI Listing
June 2018

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

Genet Med 2018 10 22;20(10):1175-1185. Epub 2018 Feb 22.

National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

Purpose: To characterize the molecular genetics of autosomal recessive Noonan syndrome.

Methods: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.

Results: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.

Conclusion: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.
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http://dx.doi.org/10.1038/gim.2017.249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105555PMC
October 2018

New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies.

Hum Genet 2019 Sep 20;138(8-9):1027-1042. Epub 2018 Feb 20.

Genetics Service, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.

GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype-phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.
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http://dx.doi.org/10.1007/s00439-018-1875-2DOI Listing
September 2019

Five challenges to ethical communication for interprofessional paediatric practice: A social work perspective.

J Interprof Care 2017 Jul 13;31(4):505-511. Epub 2017 Mar 13.

d Department of Social Work , The University of Melbourne , Melbourne , Victoria , Australia.

In paediatric clinical care, what is said to a parent or carer as well as when, where, and how it is said, directly advances or diminishes parents' capacities to understand available options and to contribute to decisions about treatment for their child. This makes interprofessional and patient communication an ethical endeavour. Social workers are uniquely situated to observe, participate in, and provide an active link in the communication between families and other health team members. This article reports phenomenological research exploring ethical issues encountered by social workers in their everyday practice communicating with families and other health professionals in a paediatric hospital context in Australia. Data were collected via semi-structured interviews with nine social workers and analysed thematically. Participants described two main communication-based roles: to support families through information provision and to contribute collaboratively to the interprofessional team involved in caring for a child and family. We grouped participants' descriptions of conflict between these roles into five main "communication challenges": (1) holding troublesome knowledge; (2) the need for diplomacy; (3) conciliation; (4) every man and his dog in family meetings; and (5) systems and processes presenting a brick wall. The five communication challenges provide empirically derived examples of how communication occurring within interprofessional health teams and between individual clinicians and parents can act to diminish or enhance parents' experience of care for their hospitalised child. Identifying these challenges may help to inform how communication within interprofessional teams and between clinicians and patients can benefit children and their parents.
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http://dx.doi.org/10.1080/13561820.2017.1296419DOI Listing
July 2017

Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts.

Nat Genet 2016 10 29;48(10):1185-92. Epub 2016 Aug 29.

Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.

Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045717PMC
http://dx.doi.org/10.1038/ng.3661DOI Listing
October 2016

De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation.

Cell Rep 2016 06 26;15(10):2251-2265. Epub 2016 May 26.

EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia; The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, WA 6009, Australia. Electronic address:

Disruptions to neuronal mRNA translation are hypothesized to underlie human neurodevelopmental syndromes. Notably, the mRNA translation re-initiation factor DENR is a regulator of eukaryotic translation and cell growth, but its mammalian functions are unknown. Here, we report that Denr influences the migration of murine cerebral cortical neurons in vivo with its binding partner Mcts1, whereas perturbations to Denr impair the long-term positioning, dendritic arborization, and dendritic spine characteristics of postnatal projection neurons. We characterized de novo missense mutations in DENR (p.C37Y and p.P121L) detected in two unrelated human subjects diagnosed with brain developmental disorder to find that each variant impairs the function of DENR in mRNA translation re-initiation and disrupts the migration and terminal branching of cortical neurons in different ways. Thus, our findings link human brain disorders to impaired mRNA translation re-initiation through perturbations in DENR (OMIM: 604550) function in neurons.
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http://dx.doi.org/10.1016/j.celrep.2016.04.090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906373PMC
June 2016

Hepatoblastoma in a mosaic trisomy 18 child with hemihypertrophy.

BMJ Case Rep 2016 Jan 21;2016. Epub 2016 Jan 21.

Department of Clinical Cytogenetics, University of Oxford Hospitals, NHS Trust, Oxford, UK.

To date, there are 12 reported cases of hepatoblastoma in trisomy 18 patients, three of whom had a mosaic chromosome pattern. We report on an 18-month-old child who had hemihypertrophy and developmental delay, was found to have hepatoblastoma on surveillance ultrasound scan, and was subsequently diagnosed with mosaic trisomy 18 on array comparative genomic hybridisation from a peripheral blood sample and molecular cytogenetic analysis of the tumour specimen. Although hemihypertrophy has been associated with mosaic trisomies, there are only a couple of published case reports of hemihypertrophy or asymmetry in mosaic trisomy 18 patients and none in the reported cases of hepatoblastoma in a mosaic trisomy 18 setting. We have reviewed the published case reports of hepatoblastoma in trisomy 18 patients and found that they seem to tolerate the intensive treatment very well if there are no significant comorbidities.
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http://dx.doi.org/10.1136/bcr-2015-211380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735188PMC
January 2016

Acute myeloid leukemia cells exhibit selective down-regulation of DNMT3A isoform 2.

Leuk Lymphoma 2015 19;56(12):3445-8. Epub 2015 Jun 19.

a Brighton and Sussex Medical School , Brighton , UK.

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http://dx.doi.org/10.3109/10428194.2015.1032965DOI Listing
September 2016

Homozygous mutations in the SCN1A gene associated with genetic epilepsy with febrile seizures plus and Dravet syndrome in 2 families.

Eur J Paediatr Neurol 2015 Jul 21;19(4):484-8. Epub 2015 Feb 21.

The Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK; School of Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, UK. Electronic address:

Background: Mutations in the gene encoding the alpha subunit of the voltage-gated sodium channel SCN1A are associated with several epilepsy syndromes. These range from severe phenotypes including Dravet syndrome to milder phenotypes such as genetic epilepsy with febrile seizures plus (GEFS+). To date the sequence variants identified have been heterozygous in nature as one would expect for a disorder that occurs de novo or is dominantly inherited.

Methods And Results: We report the association of two novel homozygous missense mutations of the SCN1A gene in four children with infantile epilepsies from two consanguineous pedigrees. We suggest that the nature and location of the identified amino acid changes allows heterozygous carriers to remain unaffected. However, having such changes on both alleles may have a cumulative and detrimental effect.

Conclusion: The presented cases illustrate how better understanding of the nature and location of SCN1A missense mutations may aid the interpretation of genotype-phenotype associations. SCN1A related epilepsies should be considered in children with infantile onset epilepsies even when an autosomal recessive neurological disorder is suspected.
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http://dx.doi.org/10.1016/j.ejpn.2015.02.001DOI Listing
July 2015

Refinement of genotype-phenotype correlation in 18 patients carrying a 1q24q25 deletion.

Am J Med Genet A 2015 May 25;167A(5):1008-17. Epub 2015 Feb 25.

Hospices Civils de Lyon, Service de Génétique, Laboratoire de Cytogénétique Constitutionnelle, Bron, France.

Interstitial deletion 1q24q25 is a rare rearrangement associated with intellectual disability, growth retardation, abnormal extremities and facial dysmorphism. In this study, we describe the largest series reported to date, including 18 patients (4M/14F) aged from 2 days to 67 years and comprising two familial cases. The patients presented with a characteristic phenotype including mild to moderate intellectual disability (100%), intrauterine (92%) and postnatal (94%) growth retardation, microcephaly (77%), short hands and feet (83%), brachydactyly (70%), fifth finger clinodactyly (78%) and facial dysmorphism with a bulbous nose (72%), abnormal ears (67%) and micrognathia (56%). Other findings were abnormal palate (50%), single transverse palmar crease (53%), renal (38%), cardiac (38%), and genital (23%) malformations. The deletions were characterized by chromosome microarray. They were of different sizes (490 kb to 20.95 Mb) localized within chromosome bands 1q23.3-q31.2 (chr1:160797550-192912120, hg19). The 490 kb deletion is the smallest deletion reported to date associated with this phenotype. We delineated three regions that may contribute to the phenotype: a proximal one (chr1:164,501,003-167,022,133), associated with cardiac and renal anomalies, a distal one (chr1:178,514,910-181,269,712) and an intermediate 490 kb region (chr1:171970575-172460683, hg19), deleted in the most of the patients, and containing DNM3, MIR3120 and MIR214 that may play an important role in the phenotype. However, this genetic region seems complex with multiple regions giving rise to the same phenotype.
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http://dx.doi.org/10.1002/ajmg.a.36856DOI Listing
May 2015

The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.

J Med Genet 2015 Mar 6;52(3):147-56. Epub 2015 Jan 6.

Institute of Genetics & Molecular Medicine, Edinburgh, UK MRC Human Genetics, University of Edinburgh, Edinburgh, UK.

Background: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly.

Methods And Results: Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F.

Conclusions: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.
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http://dx.doi.org/10.1136/jmedgenet-2014-102691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345935PMC
March 2015

Bromodomain inhibition by JQ1 suppresses lipopolysaccharide-stimulated interleukin-6 secretion in multiple myeloma cells.

Cytokine 2015 Feb 4;71(2):415-7. Epub 2014 Dec 4.

Brighton and Sussex Medical School, Medical Research Building, University of Sussex, Falmer, Brighton BN1 9PS, UK. Electronic address:

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http://dx.doi.org/10.1016/j.cyto.2014.11.013DOI Listing
February 2015

Nanog requires BRD4 to maintain murine embryonic stem cell pluripotency and is suppressed by bromodomain inhibitor JQ1 together with Lefty1.

Stem Cells Dev 2015 Apr 17;24(7):879-91. Epub 2014 Dec 17.

1 Brighton and Sussex Medical School, University of Sussex , Brighton, United Kingdom .

Embryonic stem cells (ESCs) are maintained in an undifferentiated state through expression of the core transcriptional factors Nanog, Oct4, and Sox2. However, the epigenetic regulation of pluripotency is poorly understood. Differentiation of ESCs is accompanied by a global reduction of panacetylation of histones H3 and H4 suggesting that histone acetylation plays an important role in maintenance of ESC pluripotency. Acetylated lysine residues on histones are read by members of the bromodomain family that includes BET (bromodomain and extraterminal domain) proteins for which highly potent and selective inhibitors have been developed. In this study we demonstrate that the pan-BET bromodomain inhibitor JQ1 induces rapid spontaneous differentiation of murine ESCs by inducing marked transcriptional downregulation of Nanog as well as the stemness markers Lefty1 and Lefty2, but not Myc, often used as a marker of BET inhibitor activity in cancer. We show that the effects of JQ1 are recapitulated by knockdown of the BET family member BRD4 implicating this protein in Nanog regulation. These data are also supported by chromatin immunoprecipitation experiments which confirm BRD4 binding at the Nanog promoter that is known to require acetylation by the histone acetyltransferase MOF for transcriptional activity. In further support of our findings, we show that JQ1 antagonizes the stem cell-promoting effects of the histone deacetylase inhibitors sodium butyrate and valproic acid. Our data suggest that BRD4 is critical for the maintenance of ESC pluripotency and that this occurs primarily through the maintenance of Nanog expression.
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http://dx.doi.org/10.1089/scd.2014.0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367495PMC
April 2015

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.

Am J Hum Genet 2014 May 10;94(5):734-44. Epub 2014 Apr 10.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.
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http://dx.doi.org/10.1016/j.ajhg.2014.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067551PMC
May 2014

Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.

Hum Mol Genet 2014 Jun 25;23(12):3200-11. Epub 2014 Jan 25.

Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.

In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.
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http://dx.doi.org/10.1093/hmg/ddu030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030775PMC
June 2014
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