Publications by authors named "Susan Holder"

31 Publications

The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction.

Genet Med 2021 02 27;23(2):352-362. Epub 2020 Oct 27.

All Wales Medical Genomics Service, University Hospital of Wales, Cardiff, UK.

Purpose: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit.

Methods: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits.

Results: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly.

Conclusion: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.
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http://dx.doi.org/10.1038/s41436-020-00981-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862067PMC
February 2021

Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes.

Arch Dis Child 2020 04 3;105(4):384-389. Epub 2019 Sep 3.

Genetic Medicine, Central Manchester University Hospitals Foundation Trust, Manchester, UK.

Introduction: Fetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential.

Methods: We reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service.

Results: Seven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10).

Conclusions: This study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.
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http://dx.doi.org/10.1136/archdischild-2018-316547DOI Listing
April 2020

The clinical presentation caused by truncating CHD8 variants.

Clin Genet 2019 07 14;96(1):72-84. Epub 2019 May 14.

Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.

Variants in the chromodomain helicase DNA-binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth and CHD8 is one of the causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (81%), ASDs (84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate-to-severe ID, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were non-ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex-dependent penetrance of CHD8 PTVs in humans.
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http://dx.doi.org/10.1111/cge.13554DOI Listing
July 2019

De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism.

Am J Hum Genet 2019 02 17;104(2):246-259. Epub 2019 Jan 17.

Department of Surgery/Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address:

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369454PMC
February 2019

Clinical and genetic aspects of KBG syndrome.

Am J Med Genet A 2016 11 26;170(11):2835-2846. Epub 2016 Sep 26.

Wellcome Trust Sanger Institute, Cambridgeshire, United Kingdom.

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. We describe 32 KBG patients aged 2-47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half the patients. We identified 20 ANKRD11 mutations (18 novel: all truncating) confirmed by Sanger sequencing in 32 patients. Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. There were no conclusive phenotype-genotype correlations. Our findings suggest that mutation of ANKRD11 is a common Mendelian cause of developmental delay. Affected patients may not show the characteristic KBG phenotype and the diagnosis is therefore easily missed. We propose updated diagnostic criteria/clinical recommendations for KBG syndrome and suggest that inclusion of ANKRD11 will increase the utility of gene panels designed to investigate developmental delay. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435101PMC
November 2016

BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription.

Am J Hum Genet 2016 08 21;99(2):253-74. Epub 2016 Jul 21.

Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK. Electronic address:

Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.
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http://dx.doi.org/10.1016/j.ajhg.2016.05.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974071PMC
August 2016

Ultrasound diagnosis of bilateral cataracts in a fetus with possible cerebro-ocular congential muscular dystrophy during the routine second trimester anomaly scan.

Ultrasound 2015 Aug 27;23(3):181-5. Epub 2015 Mar 27.

Centre for Fetal Care, Queen Charlottes and Chelsea Hospital for Women, London, UK.

The finding of bilateral congenital cataracts in the fetus is rare. We report bilateral congenital cataracts detected during the routine second trimester anomaly scan, which subsequently were found to be associated with other congenital anomalies and the parents opted for a termination of pregnancy. At post-mortem, Muscle-Eye Brain disease or Walker-Warburg Syndrome was considered likely, which are autosomal recessive congenital muscular dystrophy disorders associated with cerebral, cerebellar, muscle and eye anomalies. On ultrasound, bilateral cataracts appear as echogenic, solid areas within the fetal orbits. The examination of the fetal face and orbits plays an important role in confirming fetal well-being antenatally. We propose that it should become a routine part of the structural survey of fetal anatomy during the obstetric anomaly scan. This is especially important in pregnancies previously affected by fetal cataracts or pregnancies at risk of rare genetic syndromes.
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http://dx.doi.org/10.1177/1742271X15579479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760586PMC
August 2015

CCDC88A mutations cause PEHO-like syndrome in humans and mouse.

Brain 2016 Apr 25;139(Pt 4):1036-44. Epub 2016 Feb 25.

Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK

Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a rare Mendelian phenotype comprising severe retardation, early onset epileptic seizures, optic nerve/cerebellar atrophy, pedal oedema, and early death. Atypical cases are often known as PEHO-like, and there is an overlap with 'early infantile epileptic encephalopathy'. PEHO is considered to be recessive, but surprisingly since initial description in 1991, no causative recessive gene(s) have been described. Hence, we report a multiplex consanguineous family with the PEHO phenotype where affected individuals had a homozygous frame-shift deletion in CCDC88A (c.2313delT, p.Leu772*ter). Analysis of cDNA extracted from patient lymphocytes unexpectedly failed to show non-sense mediated decay, and we demonstrate that the mutation produces a truncated protein lacking the crucial C-terminal half of CCDC88A (girdin). To further investigate the possible role of CCDC88A in human neurodevelopment we re-examined the behaviour and neuroanatomy of Ccdc88a knockout pups. These mice had mesial-temporal lobe epilepsy, microcephaly and corpus callosum deficiency, and by postnatal Day 21, microcephaly; the mice died at an early age. As the mouse knockout phenotype mimics the human PEHO phenotype this suggests that loss of CCDC88A is a cause of the PEHO phenotype, and that CCDC88A is essential for multiple aspects of normal human neurodevelopment.
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http://dx.doi.org/10.1093/brain/aww014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806221PMC
April 2016

Truncating Homozygous Mutation of Carboxypeptidase E (CPE) in a Morbidly Obese Female with Type 2 Diabetes Mellitus, Intellectual Disability and Hypogonadotrophic Hypogonadism.

PLoS One 2015 29;10(6):e0131417. Epub 2015 Jun 29.

Section of Investigative Medicine, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom.

Carboxypeptidase E is a peptide processing enzyme, involved in cleaving numerous peptide precursors, including neuropeptides and hormones involved in appetite control and glucose metabolism. Exome sequencing of a morbidly obese female from a consanguineous family revealed homozygosity for a truncating mutation of the CPE gene (c.76_98del; p.E26RfsX68). Analysis detected no CPE expression in whole blood-derived RNA from the proband, consistent with nonsense-mediated decay. The morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotrophic hypogonadism seen in this individual recapitulates phenotypes in the previously described fat/fat and Cpe knockout mouse models, evidencing the importance of this peptide/hormone-processing enzyme in regulating body weight, metabolism, and brain and reproductive function in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131417PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485893PMC
March 2016

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

De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability.

Am J Hum Genet 2014 Apr 27;94(4):618-24. Epub 2014 Mar 27.

Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address:

To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations-four nonsense (c.1195A>T [p.Lys399(∗)], c.1333C>T [p.Arg445(∗)], c.1866C>G [p.Tyr622(∗)], and c.3001C>T [p.Arg1001(∗)]) and three frameshift (c.2177_2178del [p.Thr726Asnfs(∗)39], c.3771dup [p.Ser1258Glufs(∗)65], and c.3856del [p.Ser1286Leufs(∗)84])-were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID.
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http://dx.doi.org/10.1016/j.ajhg.2014.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980521PMC
April 2014

Chitayat-Hall syndrome: extending the clinical phenotype.

Clin Dysmorphol 2013 Oct;22(4):156-60

Departments of aPaediatric Neurology bGeneral Paediatrics cPaediatric Neuroradiology dNeonatal Medicine, Chelsea and Westminster Hospital, London eNorth West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Middlesex, UK.

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http://dx.doi.org/10.1097/MCD.0000000000000006DOI Listing
October 2013

Four patients with Sillence type I osteogenesis imperfecta and mild bone fragility, complicated by left ventricular cardiac valvular disease and cardiac tissue fragility caused by type I collagen mutations.

Am J Med Genet A 2014 Feb 5;164A(2):386-91. Epub 2013 Dec 5.

Ehlers-Danlos Syndrome National Diagnostic Service, North West London Hospitals NHS Trust, Harrow, Middlesex, United Kingdom.

Osteogenesis imperfecta (OI) type I is a hereditary disorder of connective tissue (HDCT) characterized by blue or gray sclerae, variable short stature, dentinogenesis imperfecta, hearing loss, and recurrent fractures from infancy. We present four examples of OI type I complicated by valvular heart disease and associated with tissue fragility. The diagnosis of a type I collagen disorder was confirmed by abnormal COL1A1 or COL1A2 gene sequencing. One patient was investigated with electrophoresis of collagens from cultured skin fibroblasts, showing structurally abnormal collagen type I, skin biopsy showed unusual histology and abnormal collagen fibril ultra-structure at electron microscopy. The combined clinical, surgical, histological, ultra-structural, and molecular genetic data suggest the type I collagen defect as contributory to cardiac valvular disease. The degree of tissue fragility experienced at cardiac surgery in these individuals, also reported in a small number of similar case reports, suggests that patients with OI type I need careful pre-operative assessment and consideration of the risks and benefits of cardiac surgery.
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http://dx.doi.org/10.1002/ajmg.a.36285DOI Listing
February 2014

Interstitial 3p25 deletion in a patient with features of 3p deletion syndrome: further evidence for the role of SRGAP3 in mental retardation.

Clin Dysmorphol 2014 Jan;23(1):29-31

North West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Northwick Park & St Marks Hospital, Harrow, UK.

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http://dx.doi.org/10.1097/MCD.0000000000000017DOI Listing
January 2014

A late presentation of Loeys-Dietz syndrome: joint hypermobility is not always benign.

Rheumatology (Oxford) 2014 Mar 25;53(3):574-6. Epub 2013 Aug 25.

Kennedy Institute of Rheumatology, 65 Aspenlea Road, London W6 8LH, UK.

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http://dx.doi.org/10.1093/rheumatology/ket138DOI Listing
March 2014

Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation.

Am J Hum Genet 2012 Jul 7;91(1):146-51. Epub 2012 Jun 7.

Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, Berlin, Germany.

Hyperphosphatasia with mental retardation syndrome (HPMRS), an autosomal-recessive form of intellectual disability characterized by facial dysmorphism, seizures, brachytelephalangy, and persistent elevated serum alkaline phosphatase (hyperphosphatasia), was recently shown to be caused by mutations in PIGV, a member of the glycosylphosphatidylinositol (GPI)-anchor-synthesis pathway. However, not all individuals with HPMRS harbor mutations in this gene. By exome sequencing, we detected compound-heterozygous mutations in PIGO, a gene coding for a membrane protein of the same molecular pathway, in two siblings with HPMRS, and we then found by Sanger sequencing further mutations in another affected individual; these mutations cosegregated in the investigated families. The mutant transcripts are aberrantly spliced, decrease the membrane stability of the protein, or impair enzyme function such that GPI-anchor synthesis is affected and the level of GPI-anchored substrates localized at the cell surface is reduced. Our data identify PIGO as the second gene associated with HPMRS and suggest that a deficiency in GPI-anchor synthesis is the underlying molecular pathomechanism of HPMRS.
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http://dx.doi.org/10.1016/j.ajhg.2012.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397269PMC
July 2012

De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome.

Am J Hum Genet 2012 Feb 19;90(2):290-4. Epub 2012 Jan 19.

Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, UK.

Genitopatellar syndrome (GPS) is a rare disorder in which patellar aplasia or hypoplasia is associated with external genital anomalies and severe intellectual disability. Using an exome-sequencing approach, we identified de novo mutations of KAT6B in five individuals with GPS; a single nonsense variant and three frameshift indels, including a 4 bp deletion observed in two cases. All identified mutations are located within the terminal exon of the gene and are predicted to generate a truncated protein product lacking evolutionarily conserved domains. KAT6B encodes a member of the MYST family of histone acetyltranferases. We demonstrate a reduced level of both histone H3 and H4 acetylation in patient-derived cells suggesting that dysregulation of histone acetylation is a direct functional consequence of GPS alleles. These findings define the genetic basis of GPS and illustrate the complex role of the regulation of histone acetylation during development.
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http://dx.doi.org/10.1016/j.ajhg.2011.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276665PMC
February 2012

Vestibular schwannomas occur in schwannomatosis and should not be considered an exclusion criterion for clinical diagnosis.

Am J Med Genet A 2012 Jan 21;158A(1):215-9. Epub 2011 Nov 21.

Department of Genetic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, UK.

Schwannomatosis is a recently delineated inherited condition that has clinical overlap with neurofibromatosis type 2 (NF2). Diagnostic criteria have been developed to distinguish schwannomatosis from NF2, but the existence of mosaic NF2, which may closely mimic schwannomatosis, makes even these criteria problematic. In particular, it is not clear why there is a relative sparing of the cranial nerves from schwannomas in schwannomatosis. We have identified two individuals with schwannomatosis and a unilateral vestibular schwannoma (VS), where a diagnosis of NF2 has been excluded. A third case with an identified SMARCB1 mutation was reported by two radiologists to have a VS, but this was later confirmed as a jugular schwannoma. These cases question whether the current exclusion of a VS from the clinical diagnosis of schwannomatosis is justified.
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http://dx.doi.org/10.1002/ajmg.a.34376DOI Listing
January 2012

Digenic inheritance of mutations in FOXC1 and PITX2 : correlating transcription factor function and Axenfeld-Rieger disease severity.

Hum Mutat 2011 Oct 8;32(10):1144-52. Epub 2011 Sep 8.

Ulverscroft Vision Research Group, UCL Institute of Child Health, London, United Kingdom.

Disease-causing mutations affecting either one of the transcription factor genes, PITX2 or FOXC1, have been previously identified in patients with Axenfeld-Rieger syndrome (AR). We identified a family who segregate novel mutations in both PITX2 (p.Ser233Leu) and FOXC1 (c.609delC). The most severely affected individual, who presented with an atypical phenotype of corneal opacification, lens extrusion, persistent hyperplastic primary vitreous (PHPV), and subsequent bilateral retinal detachment, inherited mutations in both genes, whereas the single heterozygous mutations caused mild AR phenotypes. This is the first report of such digenic inheritance. By analyzing cognate targets of each gene, we showed that FOXC1 and PITX2 can independently regulate their own and each other's target gene promoters and do not show synergistic action in vitro. Mutation in either gene caused reduced transcriptional activation to different extents on the FOXO1 and PLOD1 promoters, whereas both mutations in combination showed the lowest level of activation. These data show how the compensatory activity of one factor, when the other is impaired, may lessen the phenotypic impact of developmental anomalies, yet reduced activity of both transcription factors increased disease severity. This suggests an under-reported mechanism for phenotypic variability whereby single mutations cause mild AR phenotypes, whereas digenic inheritance increases phenotypic severity.
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http://dx.doi.org/10.1002/humu.21550DOI Listing
October 2011

Chromosome 19p13.3 deletion in a patient with macrocephaly, obesity, mental retardation, and behavior problems.

Am J Med Genet A 2011 May 4;155A(5):1192-5. Epub 2011 Apr 4.

Department of Genomics of Common Disease, Imperial College London, Hammersmith Hospital Campus, UK.

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http://dx.doi.org/10.1002/ajmg.a.33986DOI Listing
May 2011

Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.

Hum Mutat 2010 Jun;31(6):722-33

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

The etiology of mental retardation remains elusive in the majority of cases. Microdeletions within chromosomal bands 5q14.3q15 were recently identified as a recurrent cause of severe mental retardation, epilepsy, muscular hypotonia, and variable minor anomalies. By molecular karyotyping we identified two novel 2.4- and 1.5-Mb microdeletions of this region in patients with a similar phenotype. Both deletions contained the MEF2C gene, which is located proximally to the previously defined smallest region of overlap. Nevertheless, due to its known role in neurogenesis, we considered MEF2C as a phenocritical candidate gene for the 5q14.3q15 microdeletion phenotype. We therefore performed mutational analysis in 362 patients with severe mental retardation and found two truncating and two missense de novo mutations in MEF2C, establishing defects in this transcription factor as a novel relatively frequent autosomal dominant cause of severe mental retardation accounting for as much as 1.1% of patients. In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5. We therefore conclude that the phenotypic overlap of patients with MEF2C mutations and atypical Rett syndrome is due to the involvement of a common pathway.
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http://dx.doi.org/10.1002/humu.21253DOI Listing
June 2010

A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism.

Hum Mol Genet 2009 Sep 4;18(17):3257-65. Epub 2009 Jun 4.

Section of Genomic Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.

Genetic studies in patients with severe early-onset obesity have provided insights into the molecular and physiological pathways that regulate body weight in humans. We report a 19-year-old male with hyperphagia and severe obesity, mild learning difficulties and hypogonadism, in whom diagnostic tests for Prader-Willi syndrome (PWS) had been negative. We carried out detailed clinical and metabolic phenotyping of this patient and investigated the genetic basis of this obesity syndrome using Agilent 185 k array comparative genomic hybridization (aCGH) and Affymetrix 6.0 genotyping arrays. The identified deletion was validated using multiplex ligation-dependent probe amplification and long-range PCR, followed by breakpoint sequencing which enabled precise localization of the deletion. We identified a approximately 187 kb microdeletion at chromosome 15q11-13 that encompasses non-coding small nucleolar RNAs (including HBII-85 snoRNAs) which were not expressed in peripheral lymphocytes from the patient. Characterization of the clinical phenotype revealed increased ad libitum food intake, normal basal metabolic rate when adjusted for fat-free mass, partial hypogonadotropic hypogonadism and growth failure. We have identified a novel deletion on chromosome 15q11-13 in an individual with hyperphagia, obesity, hypogonadism and other features associated with PWS, which is normally caused by deficiency of several paternally expressed imprinted transcripts within chromosome 15q11-13, a region that includes multiple protein-coding genes as well as several non-coding snoRNAs. These findings provide direct evidence for the role of a particular family of non-coding RNAs, the HBII-85 snoRNA cluster, in human energy homeostasis, growth and reproduction.
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http://dx.doi.org/10.1093/hmg/ddp263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722987PMC
September 2009

Macrocephaly-cutis marmorata telangiectatica congenita: a report on the natural history of a mild case.

Clin Dysmorphol 2008 Oct;17(4):279-81

Kennedy-Galton Centre, North West Thames Regional Genetics Service, The North West London Hospitals NHS Trust, Middlesex, UK.

Macrocephaly-cutis marmorata telangiectatica congenita was first identified as a distinct syndrome in 1997. Since then there have been more than 10 further reports of the condition, several also comprising reviews of the earlier literature. Virtually all reported patients, however, are young children, and there is very little information about the natural evolution of the condition in adolescence and later life. This report describes a patient with features of macrocephaly-cutis marmorata telangiectatica congenita, though mildly affected, and her progression into teenage life. Her mild problems, many of which have largely resolved, demonstrate a possible more optimistic view of the condition than is currently held. The difficulties in making the diagnosis in an adult patient are also discussed.
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http://dx.doi.org/10.1097/MCD.0b013e3283136948DOI Listing
October 2008

Adams-Oliver syndrome with widespread CMTC and fatal pulmonary vascular disease.

Pediatr Dermatol 2007 Nov-Dec;24(6):651-3

Dermatology, Hammersmith Hospital, London, UK.

We report a neonate with cutis marmorata telangiectatica congenita and clinical features of Adams-Oliver syndrome in association with severe pulmonary vascular disease. We provide an overview of cutis marmorata telangiectatica congenita, distinguishing it from cutis marmorata, a common and benign physiologic cutaneous disorder seen in neonates. We highlight the need for thorough medical evaluation in cutis marmorata telangiectatica congenita to exclude associated congenital anomalies.
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http://dx.doi.org/10.1111/j.1525-1470.2007.00556.xDOI Listing
January 2008

Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor.

Am J Hum Genet 2007 Feb 4;80(2):345-52. Epub 2007 Jan 4.

Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

We have identified three truncating, two splice-site, and three missense variants at conserved amino acids in the CUL4B gene on Xq24 in 8 of 250 families with X-linked mental retardation (XLMR). During affected subjects' adolescence, a syndrome emerged with delayed puberty, hypogonadism, relative macrocephaly, moderate short stature, central obesity, unprovoked aggressive outbursts, fine intention tremor, pes cavus, and abnormalities of the toes. This syndrome was first described by Cazebas et al., in a family that was included in our study and that carried a CUL4B missense variant. CUL4B is a ubiquitin E3 ligase subunit implicated in the regulation of several biological processes, and CUL4B is the first XLMR gene that encodes an E3 ubiquitin ligase. The relatively high frequency of CUL4B mutations in this series indicates that it is one of the most commonly mutated genes underlying XLMR and suggests that its introduction into clinical diagnostics should be a high priority.
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http://dx.doi.org/10.1086/511134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785336PMC
February 2007

BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus.

Nat Genet 2006 May 2;38(5):521-4. Epub 2006 Apr 2.

Laboratoire de Génétique Médicale EA 3949, Faculté de Médecine de Strasbourg, Université Louis Pasteur, 67085 Strasbourg, France.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous ciliopathy. Although nine BBS genes have been cloned, they explain only 40-50% of the total mutational load. Here we report a major new BBS locus, BBS10, that encodes a previously unknown, rapidly evolving vertebrate-specific chaperonin-like protein. We found BBS10 to be mutated in about 20% of an unselected cohort of families of various ethnic origins, including some families with mutations in other BBS genes, consistent with oligogenic inheritance. In zebrafish, mild suppression of bbs10 exacerbated the phenotypes of other bbs morphants.
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http://dx.doi.org/10.1038/ng1771DOI Listing
May 2006

De novo t(7;10)(q33;q23) translocation and closely juxtaposed microdeletion in a patient with macrocephaly and developmental delay.

Hum Genet 2005 Jun 15;117(1):1-8. Epub 2005 Apr 15.

Institute for Human Genetics, Johannes Gutenberg University Mainz, Germany.

We have applied FISH with fully integrated BACs and BAC subfragments assessed in the human genome sequence to a de novo t(7;10)(q33;q23) translocation in a patient with developmental delay and macrocephaly. The translocation breakpoints disrupt the SEC8L1 gene on chromosome 7 and the PTEN gene on chromosome 10. RT-PCR demonstrated chimeric transcripts containing the first 11 exons of SEC8L1 fused to exon 3 of PTEN. In addition to the balanced translocation, we found a 7-Mb deletion in the translocated part of chromosome 7 at 4-Mb distance of the translocation breakpoint. This microdeletion, which disrupts the PTN and TPK1 genes and deletes 29 bonafide genes and the T-cell receptor beta locus, arose in the paternal germline. The patient's phenotype may be caused by a dominant-negative effect of the SEC8L1-PTEN fusion protein and/or haploinsufficiency of the disrupted or deleted genes. Our study demonstrates that de novo translocations can be associated with microdeletions outside the breakpoint region(s), rendering the study and risk estimation of such breakpoints more complicated than previously assumed.
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http://dx.doi.org/10.1007/s00439-005-1273-4DOI Listing
June 2005

Septo-optic dysplasia, subglottic stenosis and skeletal abnormalities: a case report.

Clin Dysmorphol 2003 Apr;12(2):105-7

North West Thames Regional Genetics Service, Kennedy-Galton Centre, Level 8 V, North West London Hospitals NHS Trust, Watford Road, Harrow, Middlesex HAl 3UJ, UK.

We report a girl with septo-optic dysplasia in association with subglottic stenosis, sagittal craniosynostosis, osteoporosis and dental anomalies. It is uncommon for patients with septo-optic dysplasia to have multiple, extra-cranial malformations. A number of differential diagnoses were considered in this case, including Cole-Carpenter syndrome, Pfeiffer syndrome and osteoglophonic dwarfism. However, none can account for all the abnormalities seen. We therefore believe that this is a previously unreported, but highly distinctive, phenotype.
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http://dx.doi.org/10.1097/00019605-200304000-00006DOI Listing
April 2003
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