Publications by authors named "Esther Kinning"

28 Publications

  • Page 1 of 1

A child with congenital short gut associated with DYNC2LI1 ciliopathy.

Clin Dysmorphol 2021 Jan;30(1):66-68

West of Scotland Genomic Medicine Service, Queen Elizabeth University Hospital, Glasgow, UK.

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http://dx.doi.org/10.1097/MCD.0000000000000341DOI Listing
January 2021

Phenotype delineation of ZNF462 related syndrome.

Am J Med Genet A 2019 10 30;179(10):2075-2082. Epub 2019 Jul 30.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.
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http://dx.doi.org/10.1002/ajmg.a.61306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935050PMC
October 2019

Heterozygous CTNNB1 and TBX4 variants in a patient with abnormal lung growth, pulmonary hypertension, microcephaly, and spasticity.

Clin Genet 2019 10 22;96(4):366-370. Epub 2019 Jul 22.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

The canonical wingless (Wnt) and fibroblast growth factor (FGF) signaling pathways involving CTNNB1 and TBX4, respectively, are crucial for the regulation of human development. Perturbations of these pathways and disruptions from biological homeostasis have been associated with abnormal morphogenesis of multiple organs, including the lung. The aim of this study was to identify the underlying genetic cause of abnormal lung growth, pulmonary hypertension (PAH), severe microcephaly, and muscle spasticity in a full-term newborn, who died at 4 months of age due to progressively worsening PAH and respiratory failure. Family trio exome sequencing showed a de novo heterozygous nonsense c.1603C>T (p.Arg535*) variant in CTNNB1 and a paternally inherited heterozygous missense c.1198G>A (p.Glu400Lys) variant in TBX4, both predicted to be likely deleterious. We expand the phenotypic spectrum associated with CTNNB1 and TBX4 variants and indicate that they could act synergistically to produce a distinct more severe phenotype. Our findings further support a recently proposed complex compound inheritance model in lethal lung developmental diseases and the contention that dual molecular diagnoses can parsimoniously explain blended phenotypes.
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http://dx.doi.org/10.1111/cge.13605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953252PMC
October 2019

Pathogenicity and selective constraint on variation near splice sites.

Genome Res 2019 02 26;29(2):159-170. Epub 2018 Dec 26.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.

Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. By using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking noncanonical positions (27%), and calculate the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at noncanonical positions in splice sites. We estimate 35%-40% of pathogenic variants in noncanonical splice site positions are missing from public databases.
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http://dx.doi.org/10.1101/gr.238444.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360807PMC
February 2019

Proteomic Evidence of Biological Aging in a Child with a Compound Heterozygous ZMPSTE24 Mutation.

Proteomics Clin Appl 2019 03 27;13(2):e1800135. Epub 2018 Dec 27.

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.

Background: Progeria-like syndromes offer a unique insight into aging. Here the case of a boy affected with mandibuloacral dysplasia and compound heterozygous mutations in ZMPSTE24 is presented.

Methods: Capillary electrophoresis-mass spectroscopy is used for proteome analysis to analyze peptides previously found to be differentially regulated in chronic kidney disease (273 peptides defining the CKD273 classifier), coronary artery disease (238 peptides defining the CAD238 classifier), and aging (116 peptides defining the AGE116 classifier).

Results: No evidence of renal disease is identified. Although the boy has no overt cardiovascular disease other than a raised carotid intima media thickness relative to his age, a proteomic classifier for the diagnosis of coronary artery disease is mildly raised. The biological age based on the proteomic AGE116 classifier is 24 years compared to the chronological ages of 5 and 10 years. In contrast, a control group of healthy children has a significantly lower (p < 0.0001) calculated mean age of 13.

Conclusion: Urinary proteomic analysis is effective in confirming advanced biological age and to identify early evidence of renal or cardiovascular damage. This case highlights the value of proteomic approaches in aging research and may represent a method for non-invasive monitoring of the effects of early aging.
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http://dx.doi.org/10.1002/prca.201800135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492098PMC
March 2019

Expanding the phenotypic spectrum of variants in PDE4D/PRKAR1A: from acrodysostosis to acroscyphodysplasia.

Eur J Hum Genet 2018 11 13;26(11):1611-1622. Epub 2018 Jul 13.

Department of Medical Genetics, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, IMAGINE Institute, Necker Enfants Malades Hospital, Paris, France.

Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.
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http://dx.doi.org/10.1038/s41431-018-0135-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189044PMC
November 2018

Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome.

Am J Med Genet A 2018 04 20;176(4):862-876. Epub 2018 Feb 20.

Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.

In 2016, we described that missense variants in parts of exons 30 and 31 of CREBBP can cause a phenotype that differs from Rubinstein-Taybi syndrome (RSTS). Here we report on another 11 patients with variants in this region of CREBBP (between bp 5,128 and 5,614) and two with variants in the homologous region of EP300. None of the patients show characteristics typical for RSTS. The variants were detected by exome sequencing using a panel for intellectual disability in all but one individual, in whom Sanger sequencing was performed upon clinical recognition of the entity. The main characteristics of the patients are developmental delay (90%), autistic behavior (65%), short stature (42%), and microcephaly (43%). Medical problems include feeding problems (75%), vision (50%), and hearing (54%) impairments, recurrent upper airway infections (42%), and epilepsy (21%). Major malformations are less common except for cryptorchidism (46% of males), and cerebral anomalies (70%). Individuals with variants between bp 5,595 and 5,614 of CREBBP show a specific phenotype (ptosis, telecanthi, short and upslanted palpebral fissures, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum). 3D face shape demonstrated resemblance to individuals with a duplication of 16p13.3 (the region that includes CREBBP), possibly indicating a gain of function. The other affected individuals show a less specific phenotype. We conclude that there is now more firm evidence that variants in these specific regions of CREBBP and EP300 result in a phenotype that differs from RSTS, and that this phenotype may be heterogeneous.
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http://dx.doi.org/10.1002/ajmg.a.38626DOI Listing
April 2018

A novel COL1A1 mutation causing a variant of osteogenesis imperfecta.

Clin Dysmorphol 2017 Oct;26(4):243-246

aDevelopmental Endocrinology Research Group, Child Health, School of Medicine, University of Glasgow, Royal Hospital for Children bWest of Scotland Genetics Service, Laboratory Medicine Building, Queen Elizabeth Hospitals, Glasgow cSheffield Diagnostics Genetics Service, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield, UK.

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http://dx.doi.org/10.1097/MCD.0000000000000201DOI Listing
October 2017

WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features.

Am J Hum Genet 2017 Jul;101(1):139-148

Division of Medical Genetics, Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.

We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.
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http://dx.doi.org/10.1016/j.ajhg.2017.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501873PMC
July 2017

Clinical features associated with CTNNB1 de novo loss of function mutations in ten individuals.

Eur J Med Genet 2017 Feb 30;60(2):130-135. Epub 2016 Nov 30.

DDD Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

Loss of function mutations in CTNNB1 have been reported in individuals with intellectual disability [MIM #615075] associated with peripheral spasticity, microcephaly and central hypotonia, suggesting a recognisable phenotype associated with haploinsufficiency for this gene. Trio based whole exome sequencing via the Deciphering Developmental Disorders (DDD) study has identified eleven further individuals with de novo loss of function mutations in CTNNB1. Here we report detailed phenotypic information on ten of these. We confirm the features that have been previously described and further delineate the skin and hair findings, including fair skin and fair and sparse hair with unusual patterning.
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http://dx.doi.org/10.1016/j.ejmg.2016.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070129PMC
February 2017

An Unbalanced Rearrangement of Chromosomes 4:20 is Associated with Childhood Osteoporosis and Reduced Caspase-3 Levels.

J Pediatr Genet 2016 Sep 3;5(3):167-73. Epub 2016 Jun 3.

Child Health, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland.

The purpose of this study was to investigate the association of a chromosome 4:20 imbalance with osteoporosis in three related children. Bone biochemistry, bone turnover markers, and dual-energy X-ray absorptiometry (DXA) scanning were performed in all three cases and bone biopsy and histomorphometry in one. The chromosome imbalance was delineated by array comparative genomic hybridization (aCGH) and analyzed for candidate genes. A potential candidate gene within the deleted region is caspase-3, previously linked to low bone mineral density (BMD) in heterozygous mice thus caspase-3 activity was measured in cases and controls. Routine bone biochemistry and markers of bone turnover did not reveal any abnormality. DXA showed reduced total and lumbar spine bone mineral content. aCGH showed an 8 megabase (Mb) deletion of terminal chromosome 4q incorporating a region previously linked to low BMD and a 15 Mb duplication of terminal chromosome 20p. Bone biopsy showed a high bone turnover state, trabecularisation of cortical bone and numerous small osteoclasts coupled with normal bone formation. Basal serum caspase-3 activity was lower in cases compared with controls. We conclude that the early-onset osteoporosis with low basal levels of caspase-3 and abnormal osteoclasts is a feature of this chromosomal translocation. Further investigation of the role of the deleted and duplicated genes and especially caspase-3 is required.
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http://dx.doi.org/10.1055/s-0036-1584359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999330PMC
September 2016

Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 domain.

Hum Mol Genet 2016 Mar 5;25(5):927-35. Epub 2016 Jan 5.

Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK,

We present a generic, multidisciplinary approach for improving our understanding of novel missense variants in recently discovered disease genes exhibiting genetic heterogeneity, by combining clinical and population genetics with protein structural analysis. Using six new de novo missense diagnoses in TBL1XR1 from the Deciphering Developmental Disorders study, together with population variation data, we show that the β-propeller structure of the ubiquitous WD40 domain provides a convincing way to discriminate between pathogenic and benign variation. Children with likely pathogenic mutations in this gene have severely delayed language development, often accompanied by intellectual disability, autism, dysmorphology and gastrointestinal problems. Amino acids affected by likely pathogenic missense mutations are either crucial for the stability of the fold, forming part of a highly conserved symmetrically repeating hydrogen-bonded tetrad, or located at the top face of the β-propeller, where 'hotspot' residues affect the binding of β-catenin to the TBLR1 protein. In contrast, those altered by population variation are significantly less likely to be spatially clustered towards the top face or to be at buried or highly conserved residues. This result is useful not only for interpreting benign and pathogenic missense variants in this gene, but also in other WD40 domains, many of which are associated with disease.
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http://dx.doi.org/10.1093/hmg/ddv625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754046PMC
March 2016

A case of functional growth hormone deficiency and early growth retardation in a child with IFT172 mutations.

J Clin Endocrinol Metab 2015 Apr 9;100(4):1221-4. Epub 2015 Feb 9.

Developmental Endocrinology Research Group (A.K.L.-H., S.F.A.), School of Medicine, University of Glasgow, Royal Hospital for Sick Children (RHSC), Yorkhill, Glasgow, G3 8SJ United Kingdom; Department of Clinical Genetics (E.K.), Southern General Hospital, Glasgow, G51 4TF United Kingdom; Laboratory of Bone and Joint Diseases (A.I., Z.W., S.I.), Center for Integrative Medical Sciences, RIKEN, Tokyo 108-8639, Japan; Department of Human Genetics (N.M.), Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; and Department of Biochemistry (J.M.), Southern General Hospital, 1345 Govan Rd, Glasgow, G51 4TF United Kingdom.

Context: Ciliopathies are a group of rare conditions that present through a wide range of manifestations. Given the relative common occurrence of defects of the GH/IGF-I axis in children with short stature and growth retardation, the association between ciliopathies and these defects needs further attention.

Case: Our patient is a boy who was born at term and noted to have early growth retardation and weight gain within the first 18 months of life. Biochemical tests demonstrated low IGF-I but a normal peak GH on stimulation and an adequate increase in IGF-I on administration of recombinant human growth hormone (rhGH). A magnetic resonance imaging scan revealed pituitary hypoplasia and an ectopic posterior pituitary. His growth responded well to rhGH therapy. Subsequently he also developed a retinopathy of his rods and cones, metaphyseal dysplasia, and hypertension with renal failure requiring renal replacement therapy. Whole-exome sequencing demonstrated compound heterozygous mutations of IFT172, thus consistent with a ciliopathy.

Conclusions: This is the first reported case of a child with a mutation in IFT172 who presented with growth retardation in early childhood and was initially managed as a case of functional GH deficiency that responded to rhGH therapy. This case highlights the importance of ciliary function in pituitary development and the link between early onset growth failure and ciliopathies.
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http://dx.doi.org/10.1210/jc.2014-3852DOI Listing
April 2015

De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.

Hum Mutat 2015 Apr 17;36(4):454-62. Epub 2015 Mar 17.

Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, Medical School, University of Zaragoza, CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.

Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼ 1%-2% of CdLS-like phenotypes.
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http://dx.doi.org/10.1002/humu.22761DOI Listing
April 2015

A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype.

Am J Med Genet A 2015 Mar 21;167A(3):461-75. Epub 2015 Jan 21.

Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n = 64), others having SEMD (n = 5), Kniest dysplasia (n = 7), spondyloperipheral dysplasia (n = 2), or Torrance-like dysplasia (n = 2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders.
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http://dx.doi.org/10.1002/ajmg.a.36922DOI Listing
March 2015

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.

J Med Genet 2014 Oct 14;51(10):659-68. Epub 2014 Aug 14.

Clinical Genetics, Yorkshire Regional Genetics Service, Leeds, UK.

Background: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.

Methods: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing.

Results: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as 'NIPBL-like'. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases.

Conclusions: Future diagnostic testing in 'mutation-negative' CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.
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http://dx.doi.org/10.1136/jmedgenet-2014-102573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173748PMC
October 2014

Germline FH mutations presenting with pheochromocytoma.

J Clin Endocrinol Metab 2014 Oct 8;99(10):E2046-50. Epub 2014 Jul 8.

Department of Medical Genetics (G.R.C., E.R.M.), University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, United Kingdom; Medical Research Council (MRC) Cancer Unit (M.S., E.G., C.F.), University of Cambridge, Hutchison/MRC Research Centre, Cambridge CB2 0XZ, United Kingdom; Centre for Rare Diseases and Personalized Medicine (D.M.W., G.K., E.R.W.), University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; West Midlands Regional Genetics Service (G.K., E.R.W.), Birmingham Women's Hospital, Birmingham B15 2TG, United Kingdom; Division of Genetics and Molecular Medicine (M.A.S., R.C.T.), King's College London School of Medicine, Guy's Hospital, London WC2R 2LS, United Kingdom; Department of Clinical Genetics (J.N.B.), University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom; Department of Clinical Genetics (E.K.), Royal Hospital for Sick Children (Yorkhill), Glasgow G3 8SJ, United Kingdom; and Department of Medical Genetics (P.J.M.), Queen's University Belfast, Belfast Health and Social Care Trust, Belfast BT9 7AB, United Kingdom.

Context: At least a third of the patients with pheochromocytoma (PCC) or paraganglioma (PGL) harbor an underlying germline mutation in a known PCC/PGL gene. Mutations in genes (SDHB, SDHD, SDHC, and SDHA) encoding a component of the tricarboxylic acid cycle, succinate dehydrogenase (SDH), are a major cause of inherited PCC and PGL. SDHB mutations are also, albeit less frequently, associated with inherited renal cell carcinoma. Inactivation of SDH and another tricarboxylic acid cycle component, fumarate hydratase (FH), have both been associated with abnormalities of cellular metabolism, responsible for the activation of hypoxic gene response pathways and epigenetic alterations (eg, DNA methylation). However, the clinical phenotype of germline mutations in SDHx genes and FH is usually distinct, with FH mutations classically associated with hereditary cutaneous and uterine leiomyomatosis and renal cell carcinoma, although recently an association with PCC/PGL has been reported.

Objective And Design: To identify potential novel PCC/PGL predisposition genes, we initially undertook exome resequencing studies in a case of childhood PCC, and subsequently FH mutation analysis in a further 71 patients with PCC, PGL, or head and neck PGL.

Results: After identifying a candidate FH missense mutation in the exome study, we then detected a further candidate missense mutation (p.Glu53Lys) by candidate gene sequencing. In vitro analyses demonstrated that both missense mutations (p.Cys434Tyr and p.Glu53Lys) were catalytically inactive.

Conclusions: These findings 1) confirm that germline FH mutations may present, albeit rarely with PCC or PGL; and 2) extend the clinical phenotype associated with FH mutations to pediatric PCC.
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http://dx.doi.org/10.1210/jc.2014-1659DOI Listing
October 2014

Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

Am J Med Genet A 2013 12 8;161A(12):2972-80. Epub 2013 Nov 8.

Division of Genetics & Epidemiology, Institute of Cancer Research, Sutton, UK.

Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.
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http://dx.doi.org/10.1002/ajmg.a.36229DOI Listing
December 2013

Mutation-based growth charts for SEDC and other COL2A1 related dysplasias.

Am J Med Genet C Semin Med Genet 2012 Aug 12;160C(3):205-16. Epub 2012 Jul 12.

Department of Biomedical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.

From data collected via a large international collaborative study, we have constructed a growth chart for patients with molecularly confirmed congenital spondylo-epiphyseal dysplasia (SEDC) and other COL2A1 related dysplasias. The growth chart is based on longitudinal height measurements of 79 patients with glycine substitutions in the triple-helical domain of COL2A1. In addition, measurements of 27 patients with other molecular defects, such as arginine to cysteine substitutions, splice mutations, and mutations in the C-terminal propeptide have been plotted on the chart. Height of the patients progressively deviate from that of normal children: compared to normal WHO charts, the mean length/height is -2.6 SD at birth, -4.2 SD at 5 years, and -5.8 SD in adulthood. The mean adult height (male and female combined) of patients with glycine substitutions in the triple-helical region is 138.2 cm but there is a large variation. Patients with glycine to cysteine substitutions tend to cluster within the upper part of the chart, while patients with glycine to serine or valine substitutions are situated between +1 SD and -1 SD. Patients with carboxy-terminal glycine substitutions tend to be shorter than patients with amino-terminal substitutions, while patients with splice mutations are relatively tall. However, there are exceptions and specific mutations can have a strong or a relatively mild negative effect on growth. The observation of significant difference in adult height between affected members of the same family indicates that height remains a multifactorial trait even in the presence of a mutation with a strong dominant effect.
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http://dx.doi.org/10.1002/ajmg.c.31332DOI Listing
August 2012

Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis.

Am J Hum Genet 2012 Apr 29;90(4):740-5. Epub 2012 Mar 29.

INSERM U781, Département de Génétique, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker Enfants Malades, Paris, France.

Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368*]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368(∗)] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis.
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http://dx.doi.org/10.1016/j.ajhg.2012.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322219PMC
April 2012

A multidisciplinary approach to understanding skeletal dysplasias.

Expert Rev Endocrinol Metab 2011 Sep;6(5):731-743

d Department of Child Health, University of Glasgow, Royal Hospital for Sick Children (Yorkhill), Dalnair Street, Glasgow, G3 8SJ, UK.

The skeletal dysplasias are a heterogeneous group of conditions of abnormal cartilage and bone development, resulting in a wide range of phenotypes of variable severity from perinatal lethality to mild short stature. Elucidation of the molecular mechanisms underlying these disorders is allowing us to understand more about the etiology of these conditions and classify them based upon the underlying gene defect. This article will discuss the development of bone and cartilage in relation to these conditions, present a clinical approach to their diagnosis and management, and consider new avenues of therapy.
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http://dx.doi.org/10.1586/eem.11.61DOI Listing
September 2011

Novel features in auriculo-condylar syndrome.

Clin Dysmorphol 2011 Jan;20(1):1-10

Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospital, Glasgow, UK.

Auriculo-condylar syndrome (ACS, OMIM 602483) is an autosomal dominant condition with marked phenotypic variability. In some patients, the condition may be limited to the auricular deformity which can vary from auricular cleft, cupped helix to the 'question mark' ear, where there is constriction between the middle and lower thirds of the ear. The latter has also been reported in isolation. Other clinical features are; facial asymmetry, round faces with prominent cheeks, microstomia, micrognathia, dental malocclusion and hearing loss. Radiological findings include abnormalities of the temporomandibular joint and/or the mandibular condyle. We describe nine ACS patients (five familial, four singleton) with novel clinical signs including facial clefts, pre-auricular and cheek pits further delineating the features of this highly variable condition. Delayed diagnosis is a common feature suggesting that ACS is largely unrecognized and may be more common than the literature suggests.
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http://dx.doi.org/10.1097/MCD.0b013e32833e56f5DOI Listing
January 2011

Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish.

Neurogenetics 2010 Oct;11(4):379-89

Department of Medical and Molecular Genetics, King's College London, School of Medicine, Floor 8 Tower Wing, Guy's Hospital, London, SE1 9RT, UK.

Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) maps to the SPG11 locus in the majority of cases. Mutations in the KIAA1840 gene, encoding spatacsin, have been shown to underlie SPG11-linked HSP-TCC. The aim of this study was to perform candidate gene analysis in HSP-TCC subjects from Asian families and to characterize disruption of spatacsin function during zebrafish development. Homozygosity mapping and direct sequencing were used to assess the ACCPN, SPG11, and SPG21 loci in four inbred kindreds originating from the Indian subcontinent. Four novel homozygous SPG11 mutations (c.442+1G>A, c.2146C>T, c.3602_3603delAT, and c.4846C>T) were identified, predicting a loss of spatacsin function in each case. To investigate the role of spatacsin during development, we additionally ascertained the complete zebrafish spg11 ortholog by reverse transcriptase PCR and 5′ RACE. Analysis of transcript expression through whole-mount in situ hybridization demonstrated ubiquitous distribution, with highest levels detected in the brain. Morpholino antisense oligonucleotide injection was used to knock down spatacsin function in zebrafish embryos. Examination of spg11 morphant embryos revealed a range of developmental defects and CNS abnormalities, and analysis of axon pathway formation demonstrated an overall perturbation of neuronal differentiation. These data confirm loss of spatacsin as the cause of SPG11-linked HSP-TCC in Asian kindreds, expanding the mutation spectrum recognized in this disorder. This study represents the first investigation in zebrafish addressing the function of a causative gene in autosomal recessive HSP and identifies a critical role for spatacsin during early neural development in vivo.
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http://dx.doi.org/10.1007/s10048-010-0243-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944959PMC
October 2010

Arthrogryposis in association with Peters' anomaly.

Clin Dysmorphol 2008 Jul;17(3):177-9

Department of Clinical Genetics, Leicester Royal Infirmary, Infirmary Square, Leicester, UK.

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http://dx.doi.org/10.1097/MCD.0b013e3282f4a127DOI Listing
July 2008

Mutations in the pericentrin (PCNT) gene cause primordial dwarfism.

Science 2008 Feb 3;319(5864):816-9. Epub 2008 Jan 3.

Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).
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http://dx.doi.org/10.1126/science.1151174DOI Listing
February 2008

8p23.1 duplication syndrome; a novel genomic condition with unexpected complexity revealed by array CGH.

Eur J Hum Genet 2008 Jan 17;16(1):18-27. Epub 2007 Oct 17.

National Genetics Reference Laboratory (Wessex), Salisbury NHS Foundation Trust, Salisbury, Wiltshire, UK.

The 8p23.1 deletion syndrome is established but not an equivalent duplication syndrome. Here, we report five patients; a de novo prenatal case and two families in which 8p23.1 duplications have been directly transmitted from mothers to children. Dual-colour fluorescent in situ hybridisation, multiplex ligation-dependent probe amplification analysis and customised oligonucleotide array comparative genomic hybridisation (oaCGH) indicated an approximately 3.75 Mb duplication of most of band 8p23.1 between the olfactory receptor/defensin repeats (ORDRs) in all cases. However, oaCGH revealed an additional duplication of 500 kb adjacent to the proximal ORDR in Family 1 and an additional deletion of 3.14 Mb within the Nablus Mask-Like Facial Syndrome region of 8q22.1 in Family 2. Copy number variation at introns 4-5 of the GATA4 gene was also identified. This 8p23.1 duplication syndrome is associated with a characteristic facial phenotype including a prominent forehead and arched eyebrows. Adrenal insufficiency, Tetralogy of Fallot, partial 2/3 syndactyly of the toes and cleft palate in some individuals may be explained by ascertainment bias, incomplete penetrance and/or the presence of the microdeletion in Family 2. The duplication is compatible with normal early childhood development but, although our adult cases live independent lives with varying degrees of support, learning difficulties have been experienced by some family members. We conclude that the 8p23.1 duplication syndrome is a genomic condition with an emerging but variable phenotype that may be under-diagnosed. Our results demonstrate that direct transmission does not distinguish genuine duplications from euchromatic variants and illustrate the power of array CGH to reveal unexpected additional imbalances in affected patients.
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http://dx.doi.org/10.1038/sj.ejhg.5201932DOI Listing
January 2008

An early-onset autosomal dominant macular dystrophy (MCDR3) resembling North Carolina macular dystrophy maps to chromosome 5.

Invest Ophthalmol Vis Sci 2003 May;44(5):2178-83

Institute of Ophthalmology, University College London, London, United Kingdom.

Purpose: To characterize the phenotype of an autosomal dominant macular dystrophy and identify the chromosomal locus.

Methods: Thirteen members of a four-generation, nonconsanguineous British family were examined clinically and also underwent automated perimetry, fundus fluorescein angiography, and fundus autofluorescence imaging. After informed consent was obtained, blood samples were taken for DNA extraction, and genetic linkage analysis was performed.

Results: The retinal changes have an early age of onset and are confined to the macular region. The macular abnormalities vary from mild retinal pigment epithelium (RPE) pigmentary change to atrophy. Drusen-like deposits are present to various degrees and are characteristic of the phenotype. Subretinal neovascular membrane (SRNVM) is an established complication. Genetic linkage analysis established linkage to chromosome 5, region p13.1-p15.33 with a maximum LOD score of 3.61 at a recombination fraction of 0.00 for marker D5S630. The locus for this autosomal dominant macular dystrophy lies between flanking markers D5S1981 and D5S2031.

Conclusions: A novel locus has been identified for early-onset autosomal dominant macular dystrophy on chromosome 5.
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http://dx.doi.org/10.1167/iovs.02-1094DOI Listing
May 2003

Mutations in a novel gene Dymeclin (FLJ20071) are responsible for Dyggve-Melchior-Clausen syndrome.

Hum Mol Genet 2003 Feb;12(3):357-64

Department of Medical Genetics and INSERM U393, Hôpital Necker Enfants Malades, 75015 Paris, France.

Dyggve-Melchior-Clausen syndrome (DMC) is a rare autosomal-recessive disorder, the gene for which maps to chromosome 18q21.1. DMC is characterized by the association of a spondylo-epi-metaphyseal dysplasia and mental retardation. Electron microscopic study of cutaneous cells of an affected child showed dilated rough endoplasmic reticulum, enlarged and aberrant vacuoles and numerous vesicles. As the etiology of the disorder is unknown, we have used a positional cloning strategy to identify the DMC gene. We detected seven deleterious mutations within a gene predicted from a human transcript (FLJ20071) in 10 DMC families. The mutations were nonsense mutations (R194X, R204X, L219X, Q483X), splice site or frameshift mutations (K626N+92aa to stop). The DMC gene transcript is widely distributed but appears abundant in chondrocytes and fetal brain. The predicted protein product of the DMC gene yields little insight into its likely function, showing no significant homology to any known protein family. However, the carboxy terminal end comprises a cluster of dileucine motifs, highly conserved across species. We conclude that DMC syndrome is consequent upon loss of function of a gene that we propose to name Dymeclin, which may have a role in process of intracellular digestion of proteins.
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http://dx.doi.org/10.1093/hmg/ddg029DOI Listing
February 2003