Publications by authors named "Lesley C Adès"

29 Publications

  • Page 1 of 1

Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System.

JAMA 2020 06;323(24):2503-2511

Monash Genetics, Monash Health, Melbourne, Australia.

Importance: Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems.

Objective: To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system.

Design, Setting, And Participants: Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption.

Exposures: Ultra-rapid exome sequencing.

Main Outcomes And Measures: The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge.

Results: The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%).

Conclusions And Relevance: This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.
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http://dx.doi.org/10.1001/jama.2020.7671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312414PMC
June 2020

Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity.

Hum Mutat 2019 Oct 23. Epub 2019 Oct 23.

Center for Medical Genetics Dr. Jacinto de Magalhães, Hospital and University Center of Porto, Porto, Portugal.

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/humu.23936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187541PMC
October 2019

Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection.

J Am Coll Cardiol 2018 08;72(6):605-615

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Cardiology, Ghent University Hospital, Ghent, Belgium. Electronic address:

Background: Thoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events.

Objectives: The purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework.

Methods: We applied the semiquantitative ClinGen framework to assess presumed gene-disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel.

Results: Genes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as "HTAAD genes" (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD.

Conclusions: The ClinGen framework is useful to semiquantitatively assess the strength of gene-disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.
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http://dx.doi.org/10.1016/j.jacc.2018.04.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378369PMC
August 2018

Hemophagocytic Lymphohistiocytosis in Loeys-Dietz Syndrome.

J Clin Immunol 2018 04 9;38(3):234-236. Epub 2018 Mar 9.

Discipline of Child and Adolescent Health, University of Sydney, Westmead, NSW, 2145, Australia.

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http://dx.doi.org/10.1007/s10875-018-0484-0DOI Listing
April 2018

A novel mutation in GMPPA in siblings with apparent intellectual disability, epilepsy, dysmorphism, and autonomic dysfunction.

Am J Med Genet A 2017 Aug 2;173(8):2246-2250. Epub 2017 Jun 2.

Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.

GMPPA encodes the GDP-mannose pyrophosphorylase A protein (GMPPA). The function of GMPPA is not well defined, however it is a homolog of GMPPB which catalyzes the reaction that converts mannose-1-phosphate and guanosine-5'-triphosphate to GDP-mannose. Previously, biallelic mutations in GMPPA were reported to cause a disorder characterized by achalasia, alacrima, neurological deficits, and intellectual disability. In this study, we report a female proband with achalasia, alacrima, hypohydrosis, apparent intellectual disability, seizures, microcephaly, esotropia, and craniofacial dysmorphism. Exome sequencing identified a previously unreported homozygous c.853+1G>A variant in GMPPA in the proband and her affected sister. Their unaffected parents were heterozygous, and unaffected brother homozygous wild type for this variant. Lymphoblast cells from the affected sisters showed complete loss of the GMPPA protein by Western blotting, and increased levels of GDP-mannose in lymphoblasts on high performance liquid chromatography. Based on our findings and the previous report describing patients with an overlapping phenotype, we conclude that this novel variant in GMPPA, identified by exome sequencing in the proband and her affected sister, is the genetic cause of their phenotype and may expand the known phenotype of this recently described glycosylation disorder.
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http://dx.doi.org/10.1002/ajmg.a.38292DOI Listing
August 2017

Autosomal dominant frontometaphyseal dysplasia: Delineation of the clinical phenotype.

Am J Med Genet A 2017 Jul 12;173(7):1739-1746. Epub 2017 May 12.

Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGFβ-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.
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http://dx.doi.org/10.1002/ajmg.a.38267DOI Listing
July 2017

Update on the Diagnosis and Management of Inherited Aortopathies, Including Marfan Syndrome.

Heart Lung Circ 2017 Jun 24;26(6):536-544. Epub 2016 Dec 24.

Children's Hospital at Westmead, Sydney, NSW, Australia.

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http://dx.doi.org/10.1016/j.hlc.2016.10.023DOI Listing
June 2017

Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia.

Am J Hum Genet 2016 08 15;99(2):392-406. Epub 2016 Jul 15.

Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand. Electronic address:

Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor β (TGF-β)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C [p.Glu70Gln], c.299T>A [p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex.
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http://dx.doi.org/10.1016/j.ajhg.2016.05.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974064PMC
August 2016

HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study.

BMJ Open 2016 Apr 29;6(4):e009537. Epub 2016 Apr 29.

Greenwood Genetic Center, Greenwood, South Carolina, USA.

Background: X linked intellectual disability (XLID) syndromes account for a substantial number of males with ID. Much progress has been made in identifying the genetic cause in many of the syndromes described 20-40 years ago. Next generation sequencing (NGS) has contributed to the rapid discovery of XLID genes and identifying novel mutations in known XLID genes for many of these syndromes.

Methods: 2 NGS approaches were employed to identify mutations in X linked genes in families with XLID disorders. 1 involved exome sequencing of genes on the X chromosome using the Agilent SureSelect Human X Chromosome Kit. The second approach was to conduct targeted NGS sequencing of 90 known XLID genes.

Results: We identified the same mutation, a c.12928 G>C transversion in the HUWE1 gene, which gives rise to a p.G4310R missense mutation in 2 XLID disorders: Juberg-Marsidi syndrome (JMS) and Brooks syndrome. Although the original families with these disorders were considered separate entities, they indeed overlap clinically. A third family was also found to have a novel HUWE1 mutation.

Conclusions: As we identified a HUWE1 mutation in an affected male from the original family reported by Juberg and Marsidi, it is evident the syndrome does not result from a mutation in ATRX as reported in the literature. Additionally, our data indicate that JMS and Brooks syndromes are allelic having the same HUWE1 mutation.
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http://dx.doi.org/10.1136/bmjopen-2015-009537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854010PMC
April 2016

The Cardiac Genetics Clinic: a model for multidisciplinary genomic medicine.

Med J Aust 2015 Sep;203(6):261.e1-6

Melbourne Health, Melbourne, VIC.

Objectives: To describe patient characteristics, standard operating procedure, and uptake of genetic testing at the multidisciplinary Cardiac Genetics Clinic (CGC) at the Royal Melbourne Hospital during its first 6 years.

Design: Database exploration of referral diagnoses, sex, number of clinic visits and incidence of genetic testing in a population of individuals attending the CGC.

Setting: Tertiary referral hospital (Royal Melbourne Hospital) providing cardiac genetics services to the state of Victoria.

Participants: All individuals initially attending the clinic between July 2007 and July 2013, either as the proband or as an at-risk family member.

Main Outcome Measures: Classification of patients into diagnostic categories, number of probands and at-risk relatives assessed, incidence and outcomes of genetic testing.

Results: 1170 individuals were seen for the first time over the 6-year period; 57.5% made only one visit. The median age was 39 years. Most were encompassed within four broad diagnostic categories: cardiomyopathy (315 patients), aortopathy (303 patients), arrhythmia disorders (203 patients) and resuscitated cardiac arrest and/or family history of sudden cardiac death (341 patients); eight patients had "other" diagnoses. Genetic testing (mutation detection or predictive testing) was undertaken in 381 individuals (32.6%), and a pathogenic mutation was identified in 47.6% of tests, representing 15.3% of the total population.

Conclusion: The CGC fulfils an important role in assisting clinicians and patients by reviewing genetic cardiac diagnoses. Clinical practice during the study period moved from a selected candidate gene approach to broader gene panel-based testing. This move to next-generation sequencing may increase the detection of mutations and variants of unknown significance. A major contribution by the clinic to the care of these individuals and their families is the provision (or negating) of a diagnosis, and of a plan for managing risks of predictable cardiac disease.
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http://dx.doi.org/10.5694/mja14.01674DOI Listing
September 2015

Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder.

Am J Hum Genet 2011 Oct;89(4):551-63

Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.

Persons with neurodevelopmental disorders or autism spectrum disorder (ASD) often harbor chromosomal microdeletions, yet the individual genetic contributors within these regions have not been systematically evaluated. We established a consortium of clinical diagnostic and research laboratories to accumulate a large cohort with genetic alterations of chromosomal region 2q23.1 and acquired 65 subjects with microdeletion or translocation. We sequenced translocation breakpoints; aligned microdeletions to determine the critical region; assessed effects on mRNA expression; and examined medical records, photos, and clinical evaluations. We identified a single gene, methyl-CpG-binding domain 5 (MBD5), as the only locus that defined the critical region. Partial or complete deletion of MBD5 was associated with haploinsufficiency of mRNA expression, intellectual disability, epilepsy, and autistic features. Fourteen alterations, including partial deletions of noncoding regions not typically captured or considered pathogenic by current diagnostic screening, disrupted MBD5 alone. Expression profiles and clinical characteristics were largely indistinguishable between MBD5-specific alteration and deletion of the entire 2q23.1 interval. No copy-number alterations of MBD5 were observed in 7878 controls, suggesting MBD5 alterations are highly penetrant. We surveyed MBD5 coding variations among 747 ASD subjects compared to 2043 non-ASD subjects analyzed by whole-exome sequencing and detected an association with a highly conserved methyl-CpG-binding domain missense variant, p.79Gly>Glu (c.236G>A) (p = 0.012). These results suggest that genetic alterations of MBD5 cause features of 2q23.1 microdeletion syndrome and that this epigenetic regulator significantly contributes to ASD risk, warranting further consideration in research and clinical diagnostic screening and highlighting the importance of chromatin remodeling in the etiology of these complex disorders.
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http://dx.doi.org/10.1016/j.ajhg.2011.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188839PMC
October 2011

Prognosis factors in probands with an FBN1 mutation diagnosed before the age of 1 year.

Pediatr Res 2011 Mar;69(3):265-70

Service de Pédiatrie, Hôpital Ambroise Paré, Boulogne, 92100 France.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder. Diagnostic criteria of neonatal MFS (nMFS), the most severe form, are still debated. The aim of our study was to search for clinical and molecular prognostic factors that could be associated with length of survival. Probands ascertained via the framework of the Universal Marfan database-FBN1, diagnosed before the age of 1 y and presenting with cardiovascular features (aortic root dilatation or valvular insufficiency) were included in this study. Clinical and molecular data were correlated to survival. Among the 60 individuals, 38 had died, 82% died before the age of 1 y, mostly because of congestive heart failure. Three probands reached adulthood. Valvular insufficiencies and diaphragmatic hernia were predictive of shorter life expectancy. Two FBN1 mutations were found outside of the exon 24-32 region (in exons 4 and 21). Mutations in exons 25-26 were overrepresented and were associated with shorter survival (p = 0.03). We report the largest genotyped series of probands with MFS diagnosed before 1 y of life. In this population, factors significantly associated with shorter survival are presence of valvular insufficiencies or diaphragmatic hernia in addition to a mutation in exons 25 or 26.
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http://dx.doi.org/10.1203/PDR.0b013e3182097219DOI Listing
March 2011

Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency.

Eur J Hum Genet 2010 Aug 14;18(8):895-901. Epub 2010 Apr 14.

Center for Medical Genetics, University Hospital Ghent, De Pintelaan 185, Ghent, Belgium.

Fibulin-4 is a member of the fibulin family, a group of extracellular matrix proteins prominently expressed in medial layers of large veins and arteries. Involvement of the FBLN4 gene in cardiovascular pathology was shown in a murine model and in three patients affected with cutis laxa in association with systemic involvement. To elucidate the contribution of FBLN4 in human disease, we investigated two cohorts of patients. Direct sequencing of 17 patients with cutis laxa revealed no FBLN4 mutations. In a second group of 22 patients presenting with arterial tortuosity, stenosis and aneurysms, FBLN4 mutations were identified in three patients, two homozygous missense mutations (p.Glu126Lys and p.Ala397Thr) and compound heterozygosity for missense mutation p.Glu126Val and frameshift mutation c.577delC. Immunoblotting analysis showed a decreased amount of fibulin-4 protein in the fibroblast culture media of two patients, a finding sustained by diminished fibulin-4 in the extracellular matrix of the aortic wall on immunohistochemistry. pSmad2 and CTGF immunostaining of aortic and lung tissue revealed an increase in transforming growth factor (TGF)beta signaling. This was confirmed by pSmad2 immunoblotting of fibroblast cultures. In conclusion, patients with recessive FBLN4 mutations are predominantly characterized by aortic aneurysms, arterial tortuosity and stenosis. This confirms the important role of fibulin-4 in vascular elastic fiber assembly. Furthermore, we provide the first evidence for the involvement of altered TGFbeta signaling in the pathogenesis of FBLN4 mutations in humans.
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http://dx.doi.org/10.1038/ejhg.2010.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987390PMC
August 2010

The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype.

Eur J Hum Genet 2010 Feb 7;18(2):163-70. Epub 2009 Oct 7.

Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic features in these patients. In this study, we report the molecular and clinical characterisation of nine new 2q23.1 deletion patients and a clinical update on two previously reported patients. All patients were mentally retarded with pronounced speech delay and additional abnormalities including short stature, seizures, microcephaly and coarse facies. The majority of cases presented with stereotypic repetitive behaviour, a disturbed sleep pattern and a broad-based gait. These features led to the initial clinical impression of Angelman, Rett or Smith-Magenis syndromes in several patients. The overlapping 2q23.1 deletion region in all 15 patients comprises only one gene, namely, MBD5. Interestingly, MBD5 is a member of the methyl CpG-binding domain protein family, which also comprises MECP2, mutated in Rett's syndrome. Another gene in the 2q23.1 region, EPC2, was deleted in 12 patients who had a broader phenotype than those with a deletion of MBD5 only. EPC2 is a member of the polycomb protein family, involved in heterochromatin formation and might be involved in causing MR. Patients with a 2q23.1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems.
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http://dx.doi.org/10.1038/ejhg.2009.152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987180PMC
February 2010

FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation.

Nat Genet 2009 Sep 9;41(9):1037-42. Epub 2009 Aug 9.

Committee on Neurobiology, University of Chicago, Chicago, Illinois, USA.

Dandy-Walker malformation (DWM), the most common human cerebellar malformation, has only one characterized associated locus. Here we characterize a second DWM-linked locus on 6p25.3, showing that deletions or duplications encompassing FOXC1 are associated with cerebellar and posterior fossa malformations including cerebellar vermis hypoplasia (CVH), mega-cisterna magna (MCM) and DWM. Foxc1-null mice have embryonic abnormalities of the rhombic lip due to loss of mesenchyme-secreted signaling molecules with subsequent loss of Atoh1 expression in vermis. Foxc1 homozygous hypomorphs have CVH with medial fusion and foliation defects. Human FOXC1 heterozygous mutations are known to affect eye development, causing a spectrum of glaucoma-associated anomalies (Axenfeld-Rieger syndrome, ARS; MIM no. 601631). We report the first brain imaging data from humans with FOXC1 mutations and show that these individuals also have CVH. We conclude that alteration of FOXC1 function alone causes CVH and contributes to MCM and DWM. Our results highlight a previously unrecognized role for mesenchyme-neuroepithelium interactions in the mid-hindbrain during early embryogenesis.
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http://dx.doi.org/10.1038/ng.422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2843139PMC
September 2009

Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis.

Nat Genet 2009 Jan 14;41(1):95-100. Epub 2008 Dec 14.

Departments of Paediatrics, Dunedin School of Medicine, Otago University, Dunedin 9054, New Zealand.

Abnormalities in WNT signaling are implicated in a broad range of developmental anomalies and also in tumorigenesis. Here we demonstrate that germline mutations in WTX (FAM123B), a gene that encodes a repressor of canonical WNT signaling, cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (OSCS; MIM300373). This condition is typically characterized by increased bone density and craniofacial malformations in females and lethality in males. The mouse homolog of WTX is expressed in the fetal skeleton, and alternative splicing implicates plasma membrane localization of WTX as a factor associated with survival in males with OSCS. WTX has also been shown to be somatically inactivated in 11-29% of cases of Wilms tumor. Despite being germline for such mutations, individuals with OSCS are not predisposed to tumor development. The observed phenotypic discordance dependent upon whether a mutation is germline or occurs somatically suggests the existence of temporal or spatial constraints on the action of WTX during tumorigenesis.
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http://dx.doi.org/10.1038/ng.270DOI Listing
January 2009

Evolution of the face in Loeys-Dietz syndrome type II: longitudinal observations from infancy in seven cases.

Authors:
Lesley C Adès

Clin Dysmorphol 2008 Oct;17(4):243-8

Department of Clinical Genetics Marfan Research Group, The Children's Hospital at Westmead Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia.

Loeys-Dietz syndrome (LDS) is a recently recognized arterial aneurysm syndrome because of heterozygous mutations in TGFBR1 or TGFBR2. Two subtypes have been delineated: LDS I, with features including craniosynostosis, hypertelorism and cleft palate and/or bifid uvula, and LDS II, wherein the face is reportedly normal. The most salient feature in LDS, whether type I or II, is of a generalized arteriopathy. The craniofacial features of LDS I are recognizable. No particular craniofacial phenotype has been reported in LDS II. We describe the evolution of facial features with age in seven LDS II patients harbouring a TGFBR1 or TGFBR2 mutation. Most patients had dolichocephaly, a tall broad forehead, frontal bossing, a high anterior hairline, hypoplastic supraorbital margins, a 'jowly' appearance (particularly in the first 3 years of life), translucent and redundant facial skin (often most pronounced in the periorbital region), prominent upper central incisors in late childhood/adulthood, and an open-mouthed myopathic face. The adult faces appeared prematurely aged. Although not exclusive to LDS II alone, recognition of these facial features may assist in the differentiation of LDS II from closely related conditions, and facilitate diagnosis and appropriate investigations and management.
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http://dx.doi.org/10.1097/MCD.0b013e328303e5d3DOI Listing
October 2008

Refined mapping of X-linked reticulate pigmentary disorder and sequencing of candidate genes.

Hum Genet 2008 Jun 11;123(5):469-76. Epub 2008 Apr 11.

McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390-8591, USA.

X-linked reticulate pigmentary disorder with systemic manifestations in males (PDR) is very rare. Affected males are characterized by cutaneous and visceral symptoms suggestive of abnormally regulated inflammation. A genetic linkage study of a large Canadian kindred previously mapped the PDR gene to a greater than 40 Mb interval of Xp22-p21. The aim of this study was to identify the causative gene for PDR. The Canadian pedigree was expanded and additional PDR families recruited. Genetic linkage was performed using newer microsatellite markers. Positional and functional candidate genes were screened by PCR and sequencing of coding exons in affected males. The location of the PDR gene was narrowed to a approximately 4.9 Mb interval of Xp22.11-p21.3 between markers DXS1052 and DXS1061. All annotated coding exons within this interval were sequenced in one affected male from each of the three multiplex families as well as one singleton, but no causative mutation was identified. Sequencing of other X-linked genes outside of the linked interval also failed to identify the cause of PDR but revealed a novel nonsynonymous cSNP in the GRPR gene in the Maltese population. PDR is most likely due to a mutation within the linked interval not affecting currently annotated coding exons.
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http://dx.doi.org/10.1007/s00439-008-0498-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714970PMC
June 2008

Deletion 22q11.2 syndrome--implications for the intensive care physician.

Pediatr Crit Care Med 2007 Sep;8(5):459-63; quiz 464

Paediatric Intensive Care Unit, The Children's Hospital at Westmead, New South Wales, Australia.

Objective: To report on the experience of a pediatric intensive care unit (PICU) with patients with deletion 22q11.2 syndrome: 1) to delineate the clinical characteristics and management of these patients; 2) to assess whether these patients were managed appropriately, especially in terms of blood transfusion; and 3) to make recommendations for PICU management.

Design: Retrospective assessment of medical records of patients with fluorescent in situ hybridization-proven 22q11 deletion admitted to the PICU at the Children's Hospital at Westmead, Sydney.

Setting: PICU in a tertiary university-affiliated children's hospital.

Patients: Sixty-five consecutive admissions in 40 patients with diagnosis of 22q11 deletion over a 4-yr period.

Interventions: None.

Measurements And Main Results: Thirty-seven (57%) of 65 admissions were postoperative cardiac surgical and accounted for the most common reason for admission to the PICU. Thirteen (20%) admissions were for velopharyngeal/laryngeal problems. Four (6%) admissions were associated with hypocalcemia, with two being first presentations. Five (12.5%) of 40 patients had immune dysfunction, one of whom developed cytomegalovirus pneumonitis. Twenty-nine (72.5%) patients received blood products either immediately before PICU admission or in the PICU. Of these, 16 received nonirradiated cellular blood products. There were two deaths from complications of congenital heart disease.

Conclusions: PICUs need to be familiar with deletion 22q11.2 syndrome, especially the recommended use of irradiated and cytomegalovirus-seronegative blood components in these immunocompromised patients. The guidelines were inconsistently followed in the cohort of patients reported here. The extent of this problem may be more widespread in PICUs, and we recommend that individual units review their practice in this regard. Hypocalcemia may manifest at any time, and a regular survey of the calcium status is required in the intensive care setting. Admission to PICU should afford the opportunity to invite subspecialty referral and optimize extended care.
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http://dx.doi.org/10.1097/01.pcc.0000290023.89437.58DOI Listing
September 2007

EEC syndrome, Arg227Gln TP63 mutation and micturition difficulties: Is there a genotype-phenotype correlation?

Am J Med Genet A 2007 May;143A(10):1114-9

Department of Clinical Genetics, Children's Hospital at Westmead (CHW), Sydney, Australia.

We report on two unrelated families with EEC syndrome (ectrodactyly, ectodermal dysplasia, cleft lip/palate), each with an Arg227Gln TP63 gene mutation, where the phenotype overlapped extensively with the allelic disorder, limb-mammary syndrome (LMS). Features common to both families were an ectodermal dysplasia principally affecting tooth, breast and nipple development, dacryostenosis and severe micturition difficulties. Additional findings included post-axial digital hypoplasia, cleft uvula, anal stenosis, hypoplasia of the perineal body and biopsy-proven interstitial cystitis. No individual had cleft lip. Split hand-split foot malformation (SHFM) occurred in one child-born after the molecular diagnosis was established. Unlike previous reports, the urinary symptoms were refractory to treatment with oral Fibrase and persisted into adulthood. Of the six cases/families now reported with EEC syndrome and Arg227Gln TP63 mutation, four have manifested this distinct urological abnormality, indicative of a genotype-phenotype correlation.
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http://dx.doi.org/10.1002/ajmg.a.31664DOI Listing
May 2007

Axenfeld-Rieger malformation and distinctive facial features: Clues to a recognizable 6p25 microdeletion syndrome.

Am J Med Genet A 2005 Feb;132A(4):381-5

Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

Deletion of distal 6p is associated with a distinctive clinical phenotype including Axenfeld-Rieger malformation, hearing loss, congenital heart disease, dental anomalies, developmental delay, and a characteristic facial appearance. We report the case of a child where recognition of the specific ocular and facial phenotype, led to identification of a 6p microdeletion arising from a de novo 6:18 translocation. Detailed analysis confirmed deletion of the FOXC1 forkhead gene cluster at 6p25. CNS anomalies included hydrocephalus and hypoplasia of the cerebellum, brainstem, and corpus callosum with mild to moderate developmental delay. Unlike previous reports, hearing was normal.
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http://dx.doi.org/10.1002/ajmg.a.30274DOI Listing
February 2005

Out of captivity.

Authors:
Lesley C Adès

Med J Aust 2004 Dec 6-20;181(11-12):628-30

Clinical Genetics, Children's Hospital at Westmead, Sydney, NSW.

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http://dx.doi.org/10.5694/j.1326-5377.2004.tb06493.xDOI Listing
March 2005

Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene.

J Invest Dermatol 2004 Oct;123(4):656-63

Laboratory of Connective Tissues Biology, GIGA Research Center, University of Liège, Liège, Belgium.

Ehlers-Danlos syndrome (EDS) type VIIC, or dermatosparactic type, is a recessively inherited connective tissue disorder characterized, among other symptoms, by an extreme skin fragility resulting from mutations inactivating ADAMTS-2, an enzyme excising the aminopropeptide of procollagens type I, II, and III. All previously described mutations create premature stop codons leading to a marked reduction in the level of mRNA. In this study, we analyzed the ADAMTS2 cDNA sequences from five patients displaying clinical and/or biochemical features consistent with a diagnosis of either typical or potentially mild form of EDS type VIIC. Three different alterations were detected in the two patients with typical EDS type VIIC. The first patient was homozygous for a genomic deletion causing an in-frame skipping of exons 3-5 in the transcript. In the second patient, the allele inherited from the mother lacks exon 3, generating a premature stop codon, whereas the paternal allele has a genomic deletion resulting in an in-frame skipping of exons 14-16 at the mRNA level. Although the exons 3-5 or 14-16 encode protein domains that have not been previously recognized as crucial for ADAMTS-2 activity, the aminoprocollagen processing was strongly impaired in vitro and in vivo, providing evidence for the requirement of these domains for proper enzyme function. The three other patients with a phenotype with some resemblance to EDS type VIIC only had silent and functionally neutral variations also frequently found in a normal population.
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http://dx.doi.org/10.1111/j.0022-202X.2004.23406.xDOI Listing
October 2004

Primary trabeculodysgenesis in association with neonatal Marfan syndrome.

Am J Med Genet A 2004 Aug;128A(4):418-21

Genetic Health Services Victoria, Royal Children's Hospital, Melbourne, Australia.

We present the clinical and ophthalmological findings in two infants with neonatal Marfan syndrome (nMFS) and primary trabeculodysgenesis (PT). Fibrillin 1 (FBN1) mutations were confirmed in both cases. Numerous eye anomalies have been recognized in infants with nMFS, but PT has not been reported previously. Our report expands the phenotype of nMFS, and highlights the importance of early and careful ophthalmological assessment of these infants.
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http://dx.doi.org/10.1002/ajmg.a.30139DOI Listing
August 2004

Short stature, sensorineural deafness, ocular abnormalities and severe mental retardation in two siblings. A new syndrome?

Clin Dysmorphol 2004 Jul;13(3):173-7

Department of Clinical Genetics, The Western Sydney Genetics Program, The Children's Hospital at Westmead, Randwick NSW, Sydney, Australia.

We describe a brother and sister with craniofacial dysmorphism, short stature, relative obesity, sensorineural deafness, multiple pigmented naevi and severe mental retardation. One sibling had keratoconus and the other had an iris coloboma. Dysmorphic features included brachycephaly, hypotelorism, small mouth, thin lips, pterygium colli, broad chest, widely spaced nipples and cutaneous second and third toe syndactyly. The children demonstrate some features of Noonan syndrome, but we believe that they have a different and distinctive phenotype. We have reviewed similar cases in the literature and discuss these in the context of our cases, who may have a previously undescribed syndrome.
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http://dx.doi.org/10.1097/01.mcd.0000115200.74297.cfDOI Listing
July 2004

Ectopia lentis phenotypes and the FBN1 gene.

Am J Med Genet A 2004 Apr;126A(3):284-9

Marfan Research Group, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.

Mutations of the fibrillin-1 (FBN1) gene on chromosome 15 have been described in patients with classical Marfan syndrome (MFS), neonatal MFS, the "MASS" phenotype, autosomal dominant ascending aortic aneurysms, autosomal dominant ectopia lentis (EL), Marfanoid skeletal features [Milewicz et al., 1995: J Clin Invest 95:2373-2378], familial arachnodactyly, Shprintzen-Goldberg syndrome [Hayward et al., 1994: Mol Cell Probes 8:325-327; Furthmayr and Francke, 1997: Semin Thorac Cardiovasc Surg 9:191-205], and severe progressive kyphoscoliosis [Adès et al., 2002: Am J Med Genet 109:261-270]. We report the use of denaturing high performance liquid chromatography (DHPLC) to facilitate the characterization of a previously elusive FBN1 mutation in the large autosomal dominant EL kindred described by Edwards et al. [1994: Am J Med Genet 53:65-71]. This isolated EL kindred remains the largest for which detailed clinical data is available. Nine years on, we present an update of the clinical status of the family. We report a recurrent FBN1 mutation, R240C, in the kindred. This mutation has been reported three times before, once in a family with classic MFS [Loeys et al., 2001: Arch Intern Med 161:2447-2454], once in one member of a multi-generation EL kindred, [Körkkö et al., 2002: J Med Genet 39:34-41], and once in an adult from a familial EL kindred who had EL, and involvement of the integument, without cardiovascular involvement [Comeglio et al., 2002: Br J Ophthalmol 86:1359-1362]. This is the second report of the R240C mutation in association with isolated EL, and supports the existing evidence that the R240C mutation can result in two quite distinct, yet related, phenotypes. It also raises the possibility that R240C may prove to be a relative mutational "hot-spot" for isolated EL. We review the current literature regarding EL (isolated and other) and FBN1 mutations.
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http://dx.doi.org/10.1002/ajmg.a.20605DOI Listing
April 2004

A case of partial trisomy 4p syndrome presenting as severe hydronephrosis in utero.

Clin Dysmorphol 2003 Jul;12(3):179-81

Department of Clinical Genetics, The Children's Hospital at Westmead, NSW, Australia.

We describe the phenotypic features in a newborn infant with an unbalanced translocation 46,XY, der(22) inv(4) (p14p16.1) t(4;22) (p15.1;q13.31)pat. The phenotype was consistent with partial trisomy 4p syndrome. Severe bilateral hydronephrosis was diagnosed at a 31 week prenatal ultrasound scan. Both the patient phenotype and the partial trisomy are unusual, the latter due to the complex nature of the chromosomal rearrangement.
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http://dx.doi.org/10.1097/01.mcd.0000072162.33788.8dDOI Listing
July 2003

Segregation of a novel FBN1 gene mutation, G1796E, with kyphoscoliosis and radiographic evidence of vertebral dysplasia in three generations.

Am J Med Genet 2002 May;109(4):261-70

Marfan Research Group, Department of Clinical Genetics, The Children's Hospital at Westmead, LB 4001, Westmead, NSW 2145, Australia.

Skeletal and spinal radiographic findings are described in five individuals of a three-generation kindred with kyphoscoliosis. The affected individuals have a novel FBN1 gene mutation, G1796E. To our knowledge, this is the first report of a family with an FBN1 gene mutation cosegregating with an unusual autosomal dominant progressive kyphoscoliosis of variable severity, together with radiological abnormalities of the spine, and some skeletal but no ocular or cardiac manifestations of Marfan syndrome. This previously undescribed phenotype represents yet another in the widening spectrum of fibrillinopathies caused by an FBN1 gene mutation.
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http://dx.doi.org/10.1002/ajmg.10333DOI Listing
May 2002

Ten novel FBN2 mutations in congenital contractural arachnodactyly: delineation of the molecular pathogenesis and clinical phenotype.

Hum Mutat 2002 Jan;19(1):39-48

Department of Internal Medicine, University of Texas-Houston Medical School, Houston, Texas, USA.

Congenital contractural arachnodactyly (CCA) is an autosomal dominant condition that shares skeletal features with Marfan syndrome (MFS), but does not have the ocular and cardiovascular complications that characterize MFS. CCA and MFS result from mutations in highly similar genes, FBN2 and FBN1, respectively. All the identified CCA mutations in FBN2 cluster in a limited region similar to where severe MFS mutations cluster in FBN1, specifically between exons 23 and 34. We screened exons 22 through 36 of FBN2 for mutations in 13 patients with classic CCA by single stranded conformational polymorphism analysis (SSCP) and then by direct sequencing. We successfully identified 10 novel mutations in this critical region of FBN2 in these patients, indicating a mutation detection rate of 75% in this limited region. Interestingly, none of these identified FBN2 mutations alter amino acids in the calcium binding consensus sequence in the EGF-like domains, whereas many of the FBN1 mutations alter the consensus sequence. Furthermore, analysis of the clinical data of the CCA patients with characterized FBN2 mutation indicate that CCA patients have aortic root dilatation and the vast majority lack evidence of congenital heart disease. These studies have implications for our understanding of the molecular basis of CCA, along with the diagnosis and genetic counseling of CCA patients.
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http://dx.doi.org/10.1002/humu.10017DOI Listing
January 2002