73 results on '"Lebel RR"'
Search Results
2. Single photon emission computerized tomography (SPECT) in detecting neurodegeneration in Huntington's disease
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Robert W. Prost, Ronald S. Tikofsky, Benezra Ee, Hamsher Ks, Lebel Rr, Sara J. Swanson, Leighton P. Mark, Elejalde Br, Robert S. Hellman, and Norman C. Reynolds
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Neuropathology ,Central nervous system disease ,Degenerative disease ,Huntington's disease ,medicine ,Dementia ,Humans ,Radiology, Nuclear Medicine and imaging ,Aged ,Dystonia ,Tomography, Emission-Computed, Single-Photon ,Clinical pathology ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Chorea ,General Medicine ,DNA ,Middle Aged ,medicine.disease ,Huntington Disease ,Nerve Degeneration ,Female ,medicine.symptom ,Radiopharmaceuticals ,business - Abstract
Single photon emission computerized tomography (SPECT) studies were performed on 34 manifest Huntington's disease (HD) patients at various stages of clinical pathology ranging from early chorea to late dystonia with or without signs of dementia and 12 pre-symptomatic patients with abnormal terminal CAG expansions. Thirty HD patients with obvious clinical signs and seven pre-symptomatic patients without signs or symptoms of HD displayed selective caudate hypoperfusion by direct visual inspection. Such qualitative, selective striatal hypoperfusion patterns can be indicative of early and persistent metabolic changes in striatal neuropathology. SPECT studies can be useful in documenting early pre-clinical changes in patients with abnormal terminal CAG expansions and in confirming the presence of caudate pathology in patients with clinical signs of HD.
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- 2001
3. Ethical issues in cancer genetics
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Lebel, RR, primary
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- 2011
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4. Setting limits in Luggnagg
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Kane Rs and Lebel Rr
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Text mining ,business.industry ,Health Services for the Aged ,Quality of Life ,Medicine ,Humans ,General Medicine ,business ,Data science ,Aged - Published
- 1988
5. Suggestions for medical vocabulary
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Lebel Rr
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Medical education ,Vocabulary ,business.industry ,media_common.quotation_subject ,Terminology as Topic ,Medicine ,General Medicine ,Artificial Organs ,Prostheses and Implants ,business ,Symbiosis ,media_common - Published
- 1973
6. Aberrant Nuclear Projections of Neutrophils in Trisomy 13.
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Salama ME, Shah V, Lebel RR, and Vandyke DL
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- 2004
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7. CASK pathogenic variant which expands the clinical spectrum for MICPCH syndrome in an adult patient.
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Tellerday J, Black J, Schuessler DC, Dosa NP, Alcaraz W, and Lebel RR
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- Young Adult, Developmental Disabilities, Intellectual Disability genetics, Intellectual Disability pathology, Female, Mutation genetics, Nervous System Malformations genetics, Nervous System Malformations diagnosis, Nervous System Malformations pathology, Humans, Cerebellum abnormalities, Cerebellum pathology, Cerebellum diagnostic imaging, Phenotype, Guanylate Kinases genetics, Microcephaly genetics, Microcephaly diagnosis, Microcephaly pathology
- Abstract
The CASK gene and its product protein kinase have been associated with microcephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome and various other neurodevelopmental disorders. Clinical presentation is highly variable and generally includes intellectual disability, neurological disorders, and dysmorphic features, at a minimum. We present the case of one of the oldest known currently living patients with MICPCH syndrome with additional features not previously described in the literature (midface retrusion, macroglossia, dental crowding, adolescent-onset contractures at large joints, laxity at finger joints, and prominent wrist dystonia). Progressive hypertonicity throughout the patient's life has been managed with serial botulinum toxin injections. A comprehensive multimodal care team including physiatry, physical therapy, exercise therapy, and audiology has been assisting her with hearing deficits, communication skills, and mobility. This potentially expands the phenotype of MICPCH syndrome and provides information about the management of this condition into adulthood., (© 2024 Wiley Periodicals LLC.)
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- 2024
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8. TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome.
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Werren EA, LaForce GR, Srivastava A, Perillo DR, Li S, Johnson K, Baris S, Berger B, Regan SL, Pfennig CD, de Munnik S, Pfundt R, Hebbar M, Jimenez-Heredia R, Karakoc-Aydiner E, Ozen A, Dmytrus J, Krolo A, Corning K, Prijoles EJ, Louie RJ, Lebel RR, Le TL, Amiel J, Gordon CT, Boztug K, Girisha KM, Shukla A, Bielas SL, and Schaffer AE
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- Humans, Animals, Mice, RNA, Messenger genetics, RNA, Messenger metabolism, RNA Processing, Post-Transcriptional, RNA Transport, Mammals genetics, Nuclear Proteins metabolism, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, RNA metabolism, Intellectual Disability genetics, Stilbenes, Sulfonic Acids
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THOC6 variants are the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants reduce the binding affinity of ALYREF to THOC5 without affecting the protein expression of TREX members, implicating impaired TREX tetramer formation. Defects in RNA nuclear export functions were not detected in biallelic THOC6 LOF human neural cells. Instead, mis-splicing was detected in human and mouse neural tissue, revealing novel THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for key signaling pathways known to regulate the transition from proliferative to neurogenic divisions during human corticogenesis. Together, these findings implicate altered RNA processing in the developmental biology of TIDS neuropathology., (© 2024. The Author(s).)
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- 2024
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9. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.
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Li D, Wang Q, Bayat A, Battig MR, Zhou Y, Bosch DG, van Haaften G, Granger L, Petersen AK, Pérez-Jurado LA, Aznar-Laín G, Aneja A, Hancarova M, Bendova S, Schwarz M, Kremlikova Pourova R, Sedlacek Z, Keena BA, March ME, Hou C, O'Connor N, Bhoj EJ, Harr MH, Lemire G, Boycott KM, Towne M, Li M, Tarnopolsky M, Brady L, Parker MJ, Faghfoury H, Parsley LK, Agolini E, Dentici ML, Novelli A, Wright M, Palmquist R, Lai K, Scala M, Striano P, Iacomino M, Zara F, Cooper A, Maarup TJ, Byler M, Lebel RR, Balci TB, Louie R, Lyons M, Douglas J, Nowak C, Afenjar A, Hoyer J, Keren B, Maas SM, Motazacker MM, Martinez-Agosto JA, Rabani AM, McCormick EM, Falk MJ, Ruggiero SM, Helbig I, Møller RS, Tessarollo L, Tomassoni Ardori F, Palko ME, Hsieh TC, Krawitz PM, Ganapathi M, Gelb BD, Jobanputra V, Wilson A, Greally J, Jacquemont S, Jizi K, Bruel AL, Quelin C, Misra VK, Chick E, Romano C, Greco D, Arena A, Morleo M, Nigro V, Seyama R, Uchiyama Y, Matsumoto N, Taira R, Tashiro K, Sakai Y, Yigit G, Wollnik B, Wagner M, Kutsche B, Hurst AC, Thompson ML, Schmidt R, Randolph L, Spillmann RC, Shashi V, Higginbotham EJ, Cordeiro D, Carnevale A, Costain G, Khan T, Funalot B, Tran Mau-Them F, Fernandez Garcia Moya L, García-Miñaúr S, Osmond M, Chad L, Quercia N, Carrasco D, Li C, Sanchez-Valle A, Kelley M, Nizon M, Jensson BO, Sulem P, Stefansson K, Gorokhova S, Busa T, Rio M, Hadj Habdallah H, Lesieur-Sebellin M, Amiel J, Pingault V, Mercier S, Vincent M, Philippe C, Fatus-Fauconnier C, Friend K, Halligan RK, Biswas S, Rosser J, Shoubridge C, Corbett M, Barnett C, Gecz J, Leppig K, Slavotinek A, Marcelis C, Pfundt R, de Vries BB, van Slegtenhorst MA, Brooks AS, Cogne B, Rambaud T, Tümer Z, Zackai EH, Akizu N, Song Y, and Hakonarson H
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- Humans, Gene Regulatory Networks, Mutation, Missense, RNA Splicing, RNA Splicing Factors genetics, Nuclear Proteins genetics, DNA Repair Enzymes genetics, Spliceosomes genetics, Neurodevelopmental Disorders genetics
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Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
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- 2024
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10. Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome.
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Cousin MA, Veale EL, Dsouza NR, Tripathi S, Holden RG, Arelin M, Beek G, Bekheirnia MR, Beygo J, Bhambhani V, Bialer M, Bigoni S, Boelman C, Carmichael J, Courtin T, Cogne B, Dabaj I, Doummar D, Fazilleau L, Ferlini A, Gavrilova RH, Graham JM Jr, Haack TB, Juusola J, Kant SG, Kayani S, Keren B, Ketteler P, Klöckner C, Koopmann TT, Kruisselbrink TM, Kuechler A, Lambert L, Latypova X, Lebel RR, Leduc MS, Leonardi E, Lewis AM, Liew W, Machol K, Mardini S, McWalter K, Mignot C, McLaughlin J, Murgia A, Narayanan V, Nava C, Neuser S, Nizon M, Ognibene D, Park J, Platzer K, Poirsier C, Radtke M, Ramsey K, Runke CK, Guillen Sacoto MJ, Scaglia F, Shinawi M, Spranger S, Tan ES, Taylor J, Trentesaux AS, Vairo F, Willaert R, Zadeh N, Urrutia R, Babovic-Vuksanovic D, Zimmermann MT, Mathie A, and Klee EW
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- Genotype, Humans, Muscle Hypotonia, Mutation, Phenotype, Intellectual Disability genetics, Potassium Channels, Tandem Pore Domain genetics, Potassium Channels, Tandem Pore Domain metabolism
- Abstract
Background: Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood., Methods: This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies., Results: We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation., Conclusions: This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation., (© 2022. The Author(s).)
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- 2022
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11. Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.
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Stolz JR, Foote KM, Veenstra-Knol HE, Pfundt R, Ten Broeke SW, de Leeuw N, Roht L, Pajusalu S, Part R, Rebane I, Õunap K, Stark Z, Kirk EP, Lawson JA, Lunke S, Christodoulou J, Louie RJ, Rogers RC, Davis JM, Innes AM, Wei XC, Keren B, Mignot C, Lebel RR, Sperber SM, Sakonju A, Dosa N, Barge-Schaapveld DQCM, Peeters-Scholte CMPCD, Ruivenkamp CAL, van Bon BW, Kennedy J, Low KJ, Ellard S, Pang L, Junewick JJ, Mark PR, Carvill GL, and Swanson GT
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- 2021
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12. Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.
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Faundes V, Goh S, Akilapa R, Bezuidenhout H, Bjornsson HT, Bradley L, Brady AF, Brischoux-Boucher E, Brunner H, Bulk S, Canham N, Cody D, Dentici ML, Digilio MC, Elmslie F, Fry AE, Gill H, Hurst J, Johnson D, Julia S, Lachlan K, Lebel RR, Byler M, Gershon E, Lemire E, Gnazzo M, Lepri FR, Marchese A, McEntagart M, McGaughran J, Mizuno S, Okamoto N, Rieubland C, Rodgers J, Sasaki E, Scalais E, Scurr I, Suri M, van der Burgt I, Matsumoto N, Miyake N, Benoit V, Lederer D, and Banka S
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- Abnormalities, Multiple, DNA-Binding Proteins genetics, Face abnormalities, Female, Genetic Association Studies, Hematologic Diseases, Humans, Infant, Newborn, Male, Neoplasm Proteins genetics, Phenotype, Vestibular Diseases, Histone Demethylases genetics, Intellectual Disability genetics, Sex Characteristics
- Abstract
Purpose: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood., Methods: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed., Results: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID., Conclusion: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.
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- 2021
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13. Opinion and Special Articles: Cerebellar Ataxia and Liver Failure Complicating IPEX Syndrome.
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Rim J, Byler M, Soldatos A, Notarangelo L, Leibovitch E, Jacobson S, Gorman M, Lebel RR, and Werner K
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- Adult, Cerebellar Ataxia etiology, Diabetes Mellitus etiology, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 1 diagnosis, Diabetes Mellitus, Type 1 genetics, Diarrhea complications, Diarrhea genetics, Forkhead Transcription Factors genetics, Genetic Diseases, X-Linked complications, Genetic Diseases, X-Linked genetics, Humans, Immune System Diseases complications, Immune System Diseases diagnosis, Immune System Diseases genetics, Liver Failure etiology, Magnetic Resonance Imaging, Male, Pedigree, Exome Sequencing, Young Adult, Cerebellar Ataxia diagnosis, Diabetes Mellitus, Type 1 congenital, Diarrhea diagnosis, Genetic Diseases, X-Linked diagnosis, Immune System Diseases congenital
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- 2021
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14. Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants.
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Jacobs EZ, Brown K, Byler MC, D'haenens E, Dheedene A, Henderson LB, Humberson JB, van Jaarsveld RH, Kanani F, Lebel RR, Millan F, Oegema R, Oostra A, Parker MJ, Rhodes L, Saenz M, Seaver LH, Si Y, Vanlander A, Vergult S, and Callewaert B
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- Adolescent, Child, Child, Preschool, Cognition Disorders genetics, DNA Mutational Analysis, Developmental Disabilities genetics, Female, Humans, Male, Phenotype, Calcium-Binding Proteins genetics, Nervous System Diseases genetics, Trans-Activators genetics
- Abstract
The CAMTA1-associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome-based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N- and C- terminal functional domains. Clinical heterogeneity is observed, but 3'-terminal variants seem to associate with less pronounced cerebellar dysfunction., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2021
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15. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.
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Bryant L, Li D, Cox SG, Marchione D, Joiner EF, Wilson K, Janssen K, Lee P, March ME, Nair D, Sherr E, Fregeau B, Wierenga KJ, Wadley A, Mancini GMS, Powell-Hamilton N, van de Kamp J, Grebe T, Dean J, Ross A, Crawford HP, Powis Z, Cho MT, Willing MC, Manwaring L, Schot R, Nava C, Afenjar A, Lessel D, Wagner M, Klopstock T, Winkelmann J, Catarino CB, Retterer K, Schuette JL, Innis JW, Pizzino A, Lüttgen S, Denecke J, Strom TM, Monaghan KG, Yuan ZF, Dubbs H, Bend R, Lee JA, Lyons MJ, Hoefele J, Günthner R, Reutter H, Keren B, Radtke K, Sherbini O, Mrokse C, Helbig KL, Odent S, Cogne B, Mercier S, Bezieau S, Besnard T, Kury S, Redon R, Reinson K, Wojcik MH, Õunap K, Ilves P, Innes AM, Kernohan KD, Costain G, Meyn MS, Chitayat D, Zackai E, Lehman A, Kitson H, Martin MG, Martinez-Agosto JA, Nelson SF, Palmer CGS, Papp JC, Parker NH, Sinsheimer JS, Vilain E, Wan J, Yoon AJ, Zheng A, Brimble E, Ferrero GB, Radio FC, Carli D, Barresi S, Brusco A, Tartaglia M, Thomas JM, Umana L, Weiss MM, Gotway G, Stuurman KE, Thompson ML, McWalter K, Stumpel CTRM, Stevens SJC, Stegmann APA, Tveten K, Vøllo A, Prescott T, Fagerberg C, Laulund LW, Larsen MJ, Byler M, Lebel RR, Hurst AC, Dean J, Schrier Vergano SA, Norman J, Mercimek-Andrews S, Neira J, Van Allen MI, Longo N, Sellars E, Louie RJ, Cathey SS, Brokamp E, Heron D, Snyder M, Vanderver A, Simon C, de la Cruz X, Padilla N, Crump JG, Chung W, Garcia B, Hakonarson HH, and Bhoj EJ
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- Animals, Forkhead Transcription Factors genetics, Germ-Line Mutation, Humans, Zebrafish genetics, Zebrafish metabolism, Zebrafish Proteins metabolism, Histones genetics, Histones metabolism, Neurodegenerative Diseases genetics
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Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A ( H3F3A ) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
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- 2020
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16. MAGEL2-related disorders: A study and case series.
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Patak J, Gilfert J, Byler M, Neerukonda V, Thiffault I, Cross L, Amudhavalli S, Pacio-Miguez M, Palomares-Bralo M, Garcia-Minaur S, Santos-Simarro F, Powis Z, Alcaraz W, Tang S, Jurgens J, Barry B, England E, Engle E, Hess J, and Lebel RR
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- Adult, Child, Preschool, Cluster Analysis, DNA Mutational Analysis, Female, Humans, Infant, Infant, Newborn, Male, Mutation genetics, Young Adult, Abnormalities, Multiple genetics, Proteins genetics
- Abstract
Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap between CHS, SYS and PWS, and analyze genotype-phenotype correlations among them. We conclude that there is neither a clinical nor etiological difference between CHS and SYS, and propose that the two syndromes simply be referred to as MAGEL2-related disorders., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2019
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17. Central and peripheral dysmyelination in a 3-year-old girl with ring chromosome 18.
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Lammert DB, Miedema D, Ochotorena J, Dosa N, Petropoulou K, Lebel RR, and Sakonju A
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Myelin basic protein (MBP) contributes to peripheral and central nervous system myelin. Developmental myelinopathies exist on a clinical spectrum, but MBP is not included on leukodystrophy or CMT gene panels. This ring chromosome 18 case presents serial MRI and EMG/NCS, shedding light on the early clinical course of the disorder., Competing Interests: The authors have no conflicts of interest to disclose., (© 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)
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- 2019
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18. 50 Years Ago in The Journal of Pediatrics: A Familial Syndrome of Renal, Genital, and Middle Ear Anomalies.
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Lebel RR
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- Child, Family Health, Female, Genes, Recessive, Genetic Predisposition to Disease, History, 20th Century, Humans, Male, Syndrome, Ear, Middle abnormalities, Genetics history, Kidney abnormalities, Pediatrics history, Urogenital Abnormalities history, Vagina abnormalities
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- 2018
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19. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
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Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, Nassif C, Diallo O, Monlong J, Cadieux-Dion M, Dobrzeniecka S, Meloche C, Retterer K, Cho MT, Rosenfeld JA, Bi W, Massicotte C, Miguet M, Brunga L, Regan BM, Mo K, Tam C, Schneider A, Hollingsworth G, FitzPatrick DR, Donaldson A, Canham N, Blair E, Kerr B, Fry AE, Thomas RH, Shelagh J, Hurst JA, Brittain H, Blyth M, Lebel RR, Gerkes EH, Davis-Keppen L, Stein Q, Chung WK, Dorison SJ, Benke PJ, Fassi E, Corsten-Janssen N, Kamsteeg EJ, Mau-Them FT, Bruel AL, Verloes A, Õunap K, Wojcik MH, Albert DVF, Venkateswaran S, Ware T, Jones D, Liu YC, Mohammad SS, Bizargity P, Bacino CA, Leuzzi V, Martinelli S, Dallapiccola B, Tartaglia M, Blumkin L, Wierenga KJ, Purcarin G, O'Byrne JJ, Stockler S, Lehman A, Keren B, Nougues MC, Mignot C, Auvin S, Nava C, Hiatt SM, Bebin M, Shao Y, Scaglia F, Lalani SR, Frye RE, Jarjour IT, Jacques S, Boucher RM, Riou E, Srour M, Carmant L, Lortie A, Major P, Diadori P, Dubeau F, D'Anjou G, Bourque G, Berkovic SF, Sadleir LG, Campeau PM, Kibar Z, Lafrenière RG, Girard SL, Mercimek-Mahmutoglu S, Boelman C, Rouleau GA, Scheffer IE, Mefford HC, Andrade DM, Rossignol E, Minassian BA, and Michaud JL
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- Child, Child, Preschool, Female, Genome, Human genetics, Genome-Wide Association Study methods, Humans, Intellectual Disability genetics, Male, Recurrence, Seizures genetics, Brain Diseases genetics, Epilepsy genetics, Mutation genetics
- Abstract
Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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20. A novel PTEN mutation associated with colonic ganglioneuromatous polyps.
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Masood U, Pavelock N, Sharma A, Lebel RR, Gupta A, and Murthy U
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- Adult, Colonic Neoplasms pathology, Colonic Polyps pathology, Colonoscopy, Ganglioneuroma pathology, Humans, Male, Mutation, Colonic Neoplasms genetics, Colonic Polyps genetics, Ganglioneuroma genetics, PTEN Phosphohydrolase genetics
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- 2017
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21. Two cases of Legg-Perthes and intellectual disability in Tricho-Rhino-Phalangeal syndrome type 1 associated with novel TRPS1 mutations.
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Gilman JL, Newman HA, Freeman R, Singh KE, Puckett RL, Morohashi DK, Stein C, Palomino K, Lebel RR, and Kimonis VE
- Subjects
- Adolescent, Adult, Dysostoses diagnostic imaging, Dysostoses physiopathology, Humans, Intellectual Disability diagnostic imaging, Intellectual Disability physiopathology, Legg-Calve-Perthes Disease diagnostic imaging, Legg-Calve-Perthes Disease physiopathology, Magnetic Resonance Imaging, Male, Osteochondrodysplasias diagnostic imaging, Osteochondrodysplasias physiopathology, Repressor Proteins, Sequence Deletion, Young Adult, DNA-Binding Proteins genetics, Dysostoses genetics, Intellectual Disability genetics, Legg-Calve-Perthes Disease genetics, Osteochondrodysplasias genetics, Transcription Factors genetics
- Abstract
Tricho-Rhino-Phalangeal syndrome is a rare autosomal dominant genetic disorder caused by mutations in the TRPS1 gene. This malformation syndrome is characterized by distinctive craniofacial features including sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. In this report, we describe two patients with the physical manifestations and genotype of TRPS type I but with learning/intellectual disability not typically described as part of the syndrome. The first patient has a novel heterozygous two-base-pair deletion of nucleotides at 3198-3199 (c.3198-3199delAT) in the TRPS1 gene causing a translational frameshift and subsequent alternate stop codon. The second patient has a 3.08 million base-pair interstitial deletion at 8q23.3 (113,735,487-116,818,578), which includes the TRPS1 gene and CSMD3. Our patients have characteristic craniofacial features, Legg-Perthes syndrome, various skeletal abnormalities including cone shaped epiphyses, anxiety (first patient), and intellectual disability, presenting unusual phenotypes that add to the clinical spectrum of the disease., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
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- View/download PDF
22. Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping.
- Author
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Amos JS, Huang L, Thevenon J, Kariminedjad A, Beaulieu CL, Masurel-Paulet A, Najmabadi H, Fattahi Z, Beheshtian M, Tonekaboni SH, Tang S, Helbig KL, Alcaraz W, Rivière JB, Faivre L, Innes AM, Lebel RR, and Boycott KM
- Subjects
- Adolescent, Child, Exome genetics, Female, Genes, Recessive, Genotype, Humans, Intellectual Disability pathology, Male, Models, Molecular, Phenotype, Protein Domains, RNA-Binding Proteins chemistry, Sequence Analysis, DNA methods, Severity of Illness Index, Syndrome, Genetic Predisposition to Disease genetics, Intellectual Disability genetics, Mutation, Missense, RNA-Binding Proteins genetics
- Abstract
THOC6 is a part of the THO complex, which is involved in coordinating mRNA processing with export. The THO complex interacts with additional components to form the larger TREX complex (transcription export complex). Previously, a homozygous missense mutation in THOC6 in the Hutterite population was reported in association with syndromic intellectual disability. Using exome sequencing, we identified three unrelated patients with bi-allelic mutations in THOC6 associated with intellectual disability and additional clinical features. Two of the patients were compound heterozygous for a stop and a missense mutation, and the third was homozygous for a missense mutation; the missense mutations were predicted to be pathogenic by in silico analysis and modeling. Clinical features of the three newly identified patients and those previously reported are reviewed; intellectual disability is moderate to severe, and malformations are variable including renal and heart defects, cleft palate, microcephaly, and corpus callosum dysgenesis. Facial features are variable and include tall forehead, short upslanting palpebral fissures +/- deep set eyes, and a long nose with overhanging columella. These subtle facial features render the diagnosis difficult to make in isolation with certainty. Our results expand the mutational and clinical spectrum of this rare disease, confirm that THOC6 is an intellectual disability causing gene, while providing insight into the importance of the THO complex in neurodevelopment., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
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23. The complex behavioral phenotype of 15q13.3 microdeletion syndrome.
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Ziats MN, Goin-Kochel RP, Berry LN, Ali M, Ge J, Guffey D, Rosenfeld JA, Bader P, Gambello MJ, Wolf V, Penney LS, Miller R, Lebel RR, Kane J, Bachman K, Troxell R, Clark G, Minard CG, Stankiewicz P, Beaudet A, and Schaaf CP
- Subjects
- Activities of Daily Living, Adolescent, Adult, Autism Spectrum Disorder physiopathology, Child, Chromosome Deletion, Chromosome Disorders physiopathology, Chromosomes, Human, Pair 15 genetics, Cognitive Dysfunction physiopathology, Female, Genetic Association Studies, Humans, Intellectual Disability physiopathology, Male, Pedigree, Seizures physiopathology, Autism Spectrum Disorder genetics, Chromosome Disorders genetics, Cognitive Dysfunction genetics, Intellectual Disability genetics, Seizures genetics
- Abstract
Background: Chromosome 15q13.3 represents a hotspot for genomic rearrangements due to repetitive sequences mediating nonallelic homologous recombination. Deletions of 15q13.3 have been identified in the context of multiple neurological and psychiatric disorders, but a prospective clinical and behavioral assessment of affected individuals has not yet been reported., Methods: Eighteen subjects with 15q13.3 microdeletion underwent a series of behavioral assessments, along with clinical history and physical examination, to comprehensively define their behavioral phenotypes., Results: Cognitive deficits are the most prevalent feature in 15q13.3 deletion syndrome, with an average nonverbal IQ of 60 among the patients studied. Autism spectrum disorder was highly penetrant, with 31% of patients meeting clinical criteria and exceeding cutoff scores on both ADOS-2 and ADI-R. Affected individuals exhibited a complex pattern of behavioral abnormalities, most notably hyperactivity, attention problems, withdrawal, and externalizing symptoms, as well as impairments in functional communication, leadership, adaptive skills, and activities of daily living., Conclusions: The 15q13.3 deletion syndrome encompasses a heterogeneous behavioral phenotype that poses a major challenge to parents, caregivers, and treating providers. Further work to more clearly delineate genotype-phenotype relationships in 15q13.3 deletions will be important for anticipatory guidance and development of targeted therapies.Genet Med 18 11, 1111-1118.
- Published
- 2016
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24. De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability.
- Author
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Isidor B, Küry S, Rosenfeld JA, Besnard T, Schmitt S, Joss S, Davies SJ, Lebel RR, Henderson A, Schaaf CP, Streff HE, Yang Y, Jain V, Chida N, Latypova X, Le Caignec C, Cogné B, Mercier S, Vincent M, Colin E, Bonneau D, Denommé AS, Parent P, Gilbert-Dussardier B, Odent S, Toutain A, Piton A, Dina C, Donnart A, Lindenbaum P, Charpentier E, Redon R, Iemura K, Ikeda M, Tanaka K, and Bézieau S
- Subjects
- Alleles, Child, Child, Preschool, Exome, Facies, Female, High-Throughput Nucleotide Sequencing, Humans, Intellectual Disability diagnosis, Male, Phenotype, Syndrome, Chromosomal Proteins, Non-Histone genetics, Intellectual Disability genetics, Phosphoproteins genetics, Sequence Deletion
- Abstract
A rare syndromic form of intellectual disability with impaired speech was recently found associated with mutations in CHAMP1 (chromosome alignment-maintaining phosphoprotein 1), the protein product of which is directly involved in microtubule-kinetochore attachment. Through whole-exome sequencing in six unrelated nonconsanguineous families having a sporadic case of intellectual disability, we identified six novel de novo truncating mutations in CHAMP1: c.1880C>G p.(Ser627*), c.1489C>T; p.(Arg497*), c.1876_1877delAG; p.(Ser626Leufs*4), c.1043G>A; p.(Trp348*), c.1002G>A; p.(Trp334*), and c.958_959delCC; p.(Pro320*). Our clinical observations confirm the phenotypic homogeneity of the syndrome, which represents therefore a distinct clinical entity. Besides, our functional studies show that CHAMP1 protein variants are delocalized from chromatin and are unable to bind to two of its direct partners, POGZ and HP1. These data suggest a pathogenic mechanism of the CHAMP1-associated intellectual disability syndrome mediated by direct interacting partners of CHAMP1, several of which are involved in chromo/kinetochore-related disorders., (© 2016 WILEY PERIODICALS, INC.)
- Published
- 2016
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25. CLTC as a clinically novel gene associated with multiple malformations and developmental delay.
- Author
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DeMari J, Mroske C, Tang S, Nimeh J, Miller R, and Lebel RR
- Subjects
- Child, Preschool, Chromosome Segregation, Computational Biology, Facies, Female, Gene Duplication, High-Throughput Nucleotide Sequencing, Humans, Inheritance Patterns, Male, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Clathrin Heavy Chains genetics, Developmental Disabilities diagnosis, Developmental Disabilities genetics, Genetic Association Studies
- Abstract
Diagnostic exome sequencing has recently emerged as an invaluable tool in determining the molecular etiology of cases involving dysmorphism and developmental delay that are otherwise unexplained by more traditional methods of genetic testing. Our patient was large for gestational age at 35 weeks, delivered to a 27-year-old primigravid Caucasian whose pregnancy was complicated by preeclampsia. Neonatal period was notable for hypoglycemia, apnea, bradycardia, hyperbilirubinemia, grade I intraventricular hemorrhage, subdural hematoma, laryngomalacia, hypotonia, and feeding difficulties. The patient had numerous minor dysmorphic features. At three and a half years of age, she has global developmental delays and nystagmus, and is being followed for a mediastinal neuroblastoma that is currently in remission. Karyotype and oligo-microarray were normal. Whole-exome, next generation sequencing (NGS) coupled to bioinformatic filtering and expert medical review at Ambry Genetics revealed 14 mutations in 9 genes, and these genes underwent medical review. A heterozygous de novo frameshift mutation, c.2737_2738dupGA p.D913Efs*59, in which two nucleotides are duplicated in exon 17 of the CLTC gene, results in substitution of glutamic acid for aspartic acid at position 913 of the protein, as well as a frame shift that results in a premature termination codon situated 58 amino acids downstream. Clathrin Heavy Chain 1 (CHC1) has been shown to play an important role in the brain for vesicle recycling and neurotransmitter release at pre-synaptic nerve terminals. There is also evidence implicating it in the proper development of the placenta during the early stages of pregnancy. The CLTC alteration identified herein is likely to provide an explanation for the patient's adverse phenotype. Ongoing functional studies will further define the impact of this alteration on CHC1 function and consequently, human disease., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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26. Gastrointestinal manifestations in diploid/triploid mixoploidy.
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Lalani FK, Elsner GL, Lebel RR, and Beg MB
- Subjects
- Abnormalities, Multiple physiopathology, Child, Diagnosis, Differential, Female, Gastrointestinal Diseases physiopathology, Humans, Intellectual Disability genetics, Phenotype, Abnormalities, Multiple diagnosis, Diploidy, Gastrointestinal Diseases genetics, Mosaicism, Triploidy
- Abstract
A girl infant was delivered by cesarean section at 32 weeks of gestation because of growth arrest and poor movement patterns. The infant had feeding problems, which were based on gastroesophageal reflux, laryngomalacia, and decreased gut motility. Hypotonia was notable from the outset, and the patient eventually displayed significant delays in both motor and cognitive milestones. Meanwhile, lymphocytes had yielded a normal karyotype (46,XX), but at 2 years of age the patient underwent a skin biopsy and mosaicism because a 68,XX cell line was discovered in fibroblasts. At the age 6.4 years, the patient is short of stature below the 3rd percentile but has a weight at the 42nd percentile and head circumference above the 97th percentile. Other phenotypic features include low-set ears, piebald irides and scalp hair, eyelid ptosis, strabismus, broad nasal bridge, anteverted nares, upswept eyebrows, hypoplastic teeth, pectus excavatum, hypoplastic labia, scoliosis, 3-4 finger syndactyly, and 2-3 toe syndactyly. We present this case with a review of the literature for mixoploidy (the rare event of mosaicism for diploid and triploid cell lines). We add to the existing data on the clinical features of diploid/triploid mixoploidy. The complexities of the gastrointestinal problems make this case unusual.
- Published
- 2015
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27. A human mitochondrial poly(A) polymerase mutation reveals the complexities of post-transcriptional mitochondrial gene expression.
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Wilson WC, Hornig-Do HT, Bruni F, Chang JH, Jourdain AA, Martinou JC, Falkenberg M, Spåhr H, Larsson NG, Lewis RJ, Hewitt L, Baslé A, Cross HE, Tong L, Lebel RR, Crosby AH, Chrzanowska-Lightowlers ZM, and Lightowlers RN
- Subjects
- Fibroblasts metabolism, Gene Expression, Humans, Mitochondrial Proteins genetics, Mutation, Neoplasm Proteins metabolism, Oxidative Phosphorylation, Polynucleotide Adenylyltransferase genetics, Primary Cell Culture, RNA Processing, Post-Transcriptional, RNA, Mitochondrial, RNA-Binding Proteins metabolism, Mitochondrial Proteins metabolism, Polynucleotide Adenylyltransferase metabolism, RNA, Messenger metabolism
- Abstract
The p.N478D missense mutation in human mitochondrial poly(A) polymerase (mtPAP) has previously been implicated in a form of spastic ataxia with optic atrophy. In this study, we have investigated fibroblast cell lines established from family members. The homozygous mutation resulted in the loss of polyadenylation of all mitochondrial transcripts assessed; however, oligoadenylation was retained. Interestingly, this had differential effects on transcript stability that were dependent on the particular species of transcript. These changes were accompanied by a severe loss of oxidative phosphorylation complexes I and IV, and perturbation of de novo mitochondrial protein synthesis. Decreases in transcript polyadenylation and in respiratory chain complexes were effectively rescued by overexpression of wild-type mtPAP. Both mutated and wild-type mtPAP localized to the mitochondrial RNA-processing granules thereby eliminating mislocalization as a cause of defective polyadenylation. In vitro polyadenylation assays revealed severely compromised activity by the mutated protein, which generated only short oligo(A) extensions on RNA substrates, irrespective of RNA secondary structure. The addition of LRPPRC/SLIRP, a mitochondrial RNA-binding complex, enhanced activity of the wild-type mtPAP resulting in increased overall tail length. The LRPPRC/SLIRP effect although present was less marked with mutated mtPAP, independent of RNA secondary structure. We conclude that (i) the polymerase activity of mtPAP can be modulated by the presence of LRPPRC/SLIRP, (ii) N478D mtPAP mutation decreases polymerase activity and (iii) the alteration in poly(A) length is sufficient to cause dysregulation of post-transcriptional expression and the pathogenic lack of respiratory chain complexes., (© The Author 2014. Published by Oxford University Press.)
- Published
- 2014
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28. A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain.
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Leroy JG, Sillence D, Wood T, Barnes J, Lebel RR, Friez MJ, Stevenson RE, Steet R, and Cathey SS
- Subjects
- Alleles, Cathepsin D metabolism, DNA Mutational Analysis, Enzyme Activation, Exons, Facies, Female, Genetic Association Studies, Genotype, Humans, Infant, Infant, Newborn, Male, Mucolipidoses diagnosis, Mucolipidoses mortality, Phenotype, Siblings, Transferases (Other Substituted Phosphate Groups) chemistry, Mucolipidoses genetics, Mutation, Protein Interaction Domains and Motifs genetics, Transferases (Other Substituted Phosphate Groups) genetics
- Abstract
Mucolipidosis (ML) II and ML IIIα/β are allelic autosomal recessive metabolic disorders due to mutations in GNPTAB. The gene encodes the enzyme UDP-GlcNAc-1-phosphotransferase (GNPT), which is critical to proper trafficking of lysosomal acid hydrolases. The ML phenotypic spectrum is dichotomous. Criteria set for defining ML II and ML IIIα/β are inclusive for all but the few patients with phenotypes that span the archetypes. Clinical and biochemical findings of the 'intermediate' ML in eight patients with the c.10A>C missense mutation in GNPTAB are presented to define this intermediate ML and provide a broader insight into ML pathogenesis. Extensive clinical information, including radiographic examinations at various ages, was obtained from a detailed study of all patients. GNPTAB was sequenced in probands and parents. GNPT activity was measured and cathepsin D sorting assays were performed in fibroblasts. Intermediate ML patients who share the c.10A>C/p.K4Q mutation in GNPTAB demonstrate a distinct, consistent phenotype similar to ML II in physical and radiographic features and to ML IIIα/β in psychomotor development and life expectancy. GNPT activity is reduced to 7-12% but the majority of newly synthesized cathepsin D remains intracellular. The GNPTAB c.10A>C/p.K4Q missense allele results in an intermediate ML II/III with distinct clinical and biochemical characteristics. This delineation strengthens the utility of the discontinuous genotype-phenotype correlation in ML II and ML IIIα/β and prompts additional studies on the tissue-specific pathogenesis in GNPT-deficient ML.
- Published
- 2014
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29. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1.
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Hamvas A, Deterding RR, Wert SE, White FV, Dishop MK, Alfano DN, Halbower AC, Planer B, Stephan MJ, Uchida DA, Williames LD, Rosenfeld JA, Lebel RR, Young LR, Cole FS, and Nogee LM
- Subjects
- Adolescent, Adult, Child, Child, Preschool, DNA Mutational Analysis, Female, Follow-Up Studies, Humans, Immunohistochemistry, Infant, Infant, Newborn, Lung metabolism, Lung ultrastructure, Lung Diseases metabolism, Lung Diseases pathology, Male, Microscopy, Electron, Nuclear Proteins metabolism, Phenotype, Retrospective Studies, Thyroid Nuclear Factor 1, Transcription Factors metabolism, Young Adult, DNA genetics, Genetic Predisposition to Disease, Lung Diseases genetics, Mutation, Nuclear Proteins genetics, Transcription Factors genetics
- Abstract
Background: Mutations in the gene encoding thyroid transcription factor, NKX2-1, result in neurologic abnormalities, hypothyroidism, and neonatal respiratory distress syndrome (RDS) that together are known as the brain-thyroid-lung syndrome. To characterize the spectrum of associated pulmonary phenotypes, we identified individuals with mutations in NKX2-1 whose primary manifestation was respiratory disease., Methods: Retrospective and prospective approaches identified infants and children with unexplained diffuse lung disease for NKX2-1 sequencing. Histopathologic results and electron micrographs were assessed, and immunohistochemical analysis for surfactant-associated proteins was performed in a subset of 10 children for whom lung tissue was available., Results: We identified 16 individuals with heterozygous missense, nonsense, and frameshift mutations and five individuals with heterozygous, whole-gene deletions of NKX2-1. Neonatal RDS was the presenting pulmonary phenotype in 16 individuals (76%), interstitial lung disease in four (19%), and pulmonary fibrosis in one adult family member. Altogether, 12 individuals (57%) had the full triad of neurologic, thyroid, and respiratory manifestations, but five (24%) had only pulmonary symptoms at the time of presentation. Recurrent respiratory infections were a prominent feature in nine subjects. Lung histopathology demonstrated evidence of disrupted surfactant homeostasis in the majority of cases, and at least five cases had evidence of disrupted lung growth., Conclusions: Patients with mutations in NKX2-1 may present with pulmonary manifestations in the newborn period or during childhood when thyroid or neurologic abnormalities are not apparent. Surfactant dysfunction and, in more severe cases, disrupted lung development are likely mechanisms for the respiratory disease.
- Published
- 2013
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30. Risks of reproducing with a genetic disorder.
- Author
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Byler MC and Lebel RR
- Subjects
- Androgen-Insensitivity Syndrome diagnosis, Androgen-Insensitivity Syndrome genetics, Androgen-Insensitivity Syndrome physiopathology, Androgen-Insensitivity Syndrome therapy, Cystic Fibrosis diagnosis, Cystic Fibrosis genetics, Cystic Fibrosis physiopathology, Cystic Fibrosis therapy, Family Characteristics, Female, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn genetics, Genetic Diseases, Inborn therapy, Humans, Infertility, Male prevention & control, Klinefelter Syndrome diagnosis, Klinefelter Syndrome genetics, Klinefelter Syndrome physiopathology, Klinefelter Syndrome therapy, Male, Mutation, Preimplantation Diagnosis, Receptors, Androgen genetics, Reproductive Techniques, Assisted, Severity of Illness Index, Translocation, Genetic, XYY Karyotype diagnosis, XYY Karyotype genetics, XYY Karyotype physiopathology, Genetic Diseases, Inborn physiopathology, Infertility, Male etiology
- Abstract
Male-factor infertility is the cause of reproductive issues in many couples. For approximately 15% of these men, the origin of the infertility is genetic. These causes include both chromosomal and single-gene disorders frequently impacting spermatogenesis. By identifying the genetic mechanism behind the infertility, we determine the ability of the couple to use assisted reproduction technologies. Use of these methods has ignited a new spectrum of concerns for the genetic competence of the offspring. By knowing what specific genetic risks exist for the offspring of men with these particular disorders, we are able to use preimplantation genetic diagnosis to detect these problems., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)
- Published
- 2013
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31. Phenotypic heterogeneity of genomic disorders and rare copy-number variants.
- Author
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Girirajan S, Rosenfeld JA, Coe BP, Parikh S, Friedman N, Goldstein A, Filipink RA, McConnell JS, Angle B, Meschino WS, Nezarati MM, Asamoah A, Jackson KE, Gowans GC, Martin JA, Carmany EP, Stockton DW, Schnur RE, Penney LS, Martin DM, Raskin S, Leppig K, Thiese H, Smith R, Aberg E, Niyazov DM, Escobar LF, El-Khechen D, Johnson KD, Lebel RR, Siefkas K, Ball S, Shur N, McGuire M, Brasington CK, Spence JE, Martin LS, Clericuzio C, Ballif BC, Shaffer LG, and Eichler EE
- Subjects
- Autistic Disorder genetics, Child, Comparative Genomic Hybridization, Female, Genome, Human, Humans, Male, Oligonucleotide Array Sequence Analysis, Sex Factors, Congenital Abnormalities genetics, DNA Copy Number Variations, Developmental Disabilities genetics, Genetic Heterogeneity, Intellectual Disability genetics, Phenotype
- Abstract
Background: Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management., Methods: We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization., Results: Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02)., Conclusions: Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).
- Published
- 2012
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32. Distinctive phenotype in 9 patients with deletion of chromosome 1q24-q25.
- Author
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Burkardt DD, Rosenfeld JA, Helgeson ML, Angle B, Banks V, Smith WE, Gripp KW, Moline J, Moran RT, Niyazov DM, Stevens CA, Zackai E, Lebel RR, Ashley DG, Kramer N, Lachman RS, and Graham JM Jr
- Subjects
- Abnormalities, Multiple genetics, Adolescent, Child, Child, Preschool, Chromosome Disorders genetics, Comparative Genomic Hybridization, Humans, In Situ Hybridization, Fluorescence, Infant, Intellectual Disability genetics, Microarray Analysis, Syndrome, Young Adult, Abnormalities, Multiple pathology, Chromosome Deletion, Chromosome Disorders pathology, Chromosomes, Human, Pair 1 genetics, Face abnormalities, Intellectual Disability pathology, Phenotype
- Abstract
Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170,135,865-172,099,327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome., (Copyright © 2011 Wiley-Liss, Inc.)
- Published
- 2011
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33. That personal touch.
- Author
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Lebel RR
- Subjects
- Genetic Predisposition to Disease, Genetic Testing ethics, Humans, Precision Medicine, Genetic Counseling, Genetic Testing methods, Genetic Testing psychology
- Published
- 2011
34. Prenatal diagnostic accuracy in South Carolina demonstrated by autopsy.
- Author
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Lebel RR, Avery JM, Broome PJ, and Collins JS
- Subjects
- Abnormalities, Multiple diagnostic imaging, Aneuploidy, Female, Geography, Humans, Infant, Newborn, Karyotyping, Male, Physical Examination, Predictive Value of Tests, Pregnancy, Sensitivity and Specificity, South Carolina, Ultrasonography, Prenatal methods, Autopsy methods, Prenatal Diagnosis methods
- Abstract
Fully 150 consecutive fetal/neonatal autopsies were reviewed to determine to what extent they confirmed or altered the impressions gained through prenatal ultrasonographic fetal examination. Distinctions were made between features that may or may not be assessable by prenatal ultrasound. Analyses of weights and measures were based on recently published regressions derived from a worldwide review of normative data. Our analysis indicated a high level of correspondence between prenatal ultrasound findings and later observations of independent persons at autopsy (85% positive predictive value and 44% sensitivity). We concluded that skills of maternal-fetal medicine specialists, located at several geographically divergent centers, are confirmed by a high level of correspondence between prenatal ultrasound and autopsy findings. The low sensitivity was due in large part to the relatively subtle nature of many autopsy findings that had not been predicted by prenatal examination.
- Published
- 2009
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35. Colorectal carcinomas from Middle East. Molecular and tissue microarray analysis of genomic instability pathways.
- Author
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Trujillo C and Lebel RR
- Subjects
- Humans, Microarray Analysis, Saudi Arabia, Colorectal Neoplasms genetics, Genomic Instability genetics
- Published
- 2008
36. Fetal peritonitis due to appendiceal rupture: a rare complication of hydrops.
- Author
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Lebel RR, Avery JM, Broome PJ, Gregg AR, Alan C, and Mostafa M
- Subjects
- Adolescent, Appendicitis diagnostic imaging, Appendicitis virology, Fatal Outcome, Female, Humans, Hydrops Fetalis diagnostic imaging, Meconium virology, Parvoviridae Infections complications, Parvoviridae Infections embryology, Parvovirus B19, Human pathogenicity, Peritonitis diagnostic imaging, Peritonitis virology, Pregnancy, Pregnancy Trimester, Second, Ultrasonography, Prenatal, Appendicitis complications, Hydrops Fetalis virology, Parvoviridae Infections diagnosis, Peritonitis complications, Pregnancy Complications, Infectious diagnosis
- Abstract
A rare complication (appendiceal perforation with meconium peritonitis) was observed in a second trimester fetus affected by nonimmune fetal hydrops due to parvovirus B-19 infection. The complication is not considered specific to this or any other etiology for hydrops, which is highly heterogeneous; rather it is an expression of the fragility and friability of edematous tissues.
- Published
- 2008
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37. Cancer epidemiology and outcomes for the State of South Carolina.
- Author
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Lebel RR and Saul RA
- Subjects
- Genetic Predisposition to Disease, Humans, Neoplasms genetics, South Carolina epidemiology, Neoplasms epidemiology, Outcome Assessment, Health Care
- Published
- 2007
38. Quantitative standards for fetal and neonatal autopsy.
- Author
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Archie JG, Collins JS, and Lebel RR
- Subjects
- Body Weight physiology, Gestational Age, Humans, Organ Size physiology, Reference Standards, Anthropometry methods, Autopsy standards, Fetal Development physiology, Fetus physiology, Infant, Newborn growth & development
- Abstract
Growth curves are essential for determining whether growth parameters lie within normal ranges. In the case of fetal and neonatal autopsy, relevant data are scattered across many publications, and few sources examine a large enough sample to be considered definitive. To ameliorate these inadequacies, regressions were created incorporating data from multiple sources both to increase accuracy and to condense available data into a single standard. When measurements were not well studied, the best available published standards are given. These regressions provide a valuable tool for clinicians who need to understand the significance of measurements obtained during autopsy.
- Published
- 2006
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39. Genetic drift: Unexpected resiliency.
- Author
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Lebel RR
- Subjects
- Breast Neoplasms complications, Fatal Outcome, Female, Heart Failure complications, Humans, Adaptation, Psychological, Persons with Disabilities psychology
- Published
- 2006
- Full Text
- View/download PDF
40. Regarding trisomy 18.
- Author
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Lebel RR, Roberson J, and Van Dyke DL
- Subjects
- Abnormalities, Multiple pathology, Abnormalities, Multiple psychology, Adult, Fatal Outcome, Female, Humans, Social Support, Abnormalities, Multiple genetics, Chromosomes, Human, Pair 18 genetics, Trisomy
- Published
- 2006
- Full Text
- View/download PDF
41. The duty to re-contact for newly appreciated risk factors: fragile X premutation.
- Author
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Guzauskas GF and Lebel RR
- Subjects
- Age of Onset, Beneficence, Genetics, Medical legislation & jurisprudence, Genetics, Medical organization & administration, Humans, Personal Autonomy, Risk Assessment, Risk Factors, Duty to Recontact, Fragile X Mental Retardation Protein genetics, Fragile X Syndrome genetics, Genetic Testing legislation & jurisprudence, Genetic Testing organization & administration, Heterozygote, Mutation
- Published
- 2006
42. Ritscher-Schinzel cranio-cerebello-cardiac (3C) syndrome: report of four new cases and review.
- Author
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Leonardi ML, Pai GS, Wilkes B, and Lebel RR
- Subjects
- Abnormalities, Multiple genetics, Abnormalities, Multiple pathology, Fatal Outcome, Female, Fetal Death, Humans, Infant, Infant, Newborn, Male, Syndrome, Cerebellum abnormalities, Craniofacial Abnormalities pathology, Heart Defects, Congenital pathology
- Abstract
Ritscher-Schinzel syndrome, also known as the 3C syndrome, is a rare, autosomal recessive syndrome characterized by craniofacial, cerebellar, and cardiac anomalies. Cardiac manifestations include ventricular septal defect, atrial septal defect, tetralogy of Fallot, double outlet right ventricle, hypoplastic left heart, aortic stenosis, pulmonic stenosis and other valvular anomalies. Central nervous system anomalies include Dandy-Walker malformation, cerebellar vermis hypoplasia and enlargement of the cisterna magna. Craniofacial abnormalities seen are cleft palate, ocular coloboma, prominent occiput, low-set ears, hypertelorism, down-slanting palpebral fissures, depressed nasal bridge and micrognathia. Dandy-Walker malformation, posterior fossa cyst, hydrocephalus and congenital heart defect are common malformations that may occur in isolation or as a part of many syndromes. Accurate genetic diagnosis and counseling require detailed analysis of the external as well as the internal anatomy and knowledge of the relative frequencies of various malformations in syndromes that may have overlapping clinical signs. We have had the opportunity recently to study four cases of the Ritscher-Schinzel syndrome. A review of all reported cases is presented and an attempt made to define the minimum diagnostic criteria for the Ritscher-Schinzel syndrome. Of the nine craniofacial anomalies commonly reported as a part of the Ritscher-Schinzel syndrome, we consider two i.e., cleft palate and ocular coloboma, to be readily and objectively ascertainable. The other seven craniofacial traits, however, are somewhat subjective, require expert interpretation and are sometimes difficult to ascertain in a newborn or stillborn fetus. These are prominent forehead, prominent occiput, hypertelorism, down-slanting palpebral fissures, low-set ears, depressed nasal bridge and micrognathia. At least four of these were present in all cases that had a secure diagnosis of the Ritscher-Schinzel syndrome. Thus, the criteria we propose to establish the diagnosis of the Ritscher-Schinzel syndrome in a chromosomally normal sporadic case are the presence of cardiac malformation other than isolated patent ductus arteriosus, cerebellar malformation, and cleft palate or ocular coloboma or four of the following seven findings: prominent forehead, prominent occiput, hypertelorism, down-slanting palpebral fissures, low-set ears, depressed nasal bridge, and micrognathia., (Copyright 2001 Wiley-Liss, Inc.)
- Published
- 2001
43. Incidence of abdominal wall defects.
- Author
-
Lebel RR
- Subjects
- Gastroschisis epidemiology, Hernia, Umbilical epidemiology, Humans, Infant, Newborn, Abdominal Muscles abnormalities
- Published
- 1999
44. Duty to re-contact.
- Author
-
Hirschhorn K, Fleisher LD, Godmilow L, Howell RR, Lebel RR, McCabe ER, McGinniss MJ, Milunsky A, Pelias MZ, Pyeritz RE, Sujansky E, Thompson BH, and Zinberg RE
- Subjects
- Genetics, Humans, Professional-Patient Relations, Disclosure, Duty to Recontact, Ethics, Medical, Genetic Testing
- Published
- 1999
- Full Text
- View/download PDF
45. Re-contact to advise of testing available to detect high risk for carcinoma: response to letters sent to persons initially ascertained for other genetic reasons.
- Author
-
Swiglo BA and Lebel RR
- Subjects
- Genetic Testing, Humans, Prenatal Diagnosis, Disclosure, Duty to Recontact, Family, Genetic Counseling, Genetic Predisposition to Disease, Incidental Findings, Neoplasms
- Published
- 1997
46. Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21.
- Author
-
Schell U, Wienberg J, Köhler A, Bray-Ward P, Ward DE, Wilson WG, Allen WP, Lebel RR, Sawyer JR, Campbell PL, Aughton DJ, Punnett HH, Lammer EJ, Kao FT, Ward DC, and Muenke M
- Subjects
- Base Sequence, Chromosome Mapping, Chromosomes, Artificial, Yeast, Cloning, Molecular, DNA Primers, DNA Probes, Female, Humans, Hybrid Cells, Male, Molecular Sequence Data, Polymerase Chain Reaction, Chromosomes, Human, Pair 2, Gene Deletion, Holoprosencephaly genetics, Translocation, Genetic
- Abstract
Holoprosencephaly (HPE) is a common developmental defect involving the brain and face in humans. Cytogenetic deletions in patients with HPE have localized one of the HPE genes (HPE2) to the chromosomal region 2p21. Here we report the molecular genetic characterization of nine HPE patients with cytogenetic deletions or translocations involving 2p21. We have determined the parental origin of the deleted chromosomes and defined the HPE2 critical region between D2S119 and D2S88/D2S391. As a first step towards cloning the HPE2 gene which is crucial for normal brain development we have constructed a YAC contig which spans the smallest region of deletion overlap. Several of these YACs could be identified which span three different 2p21 breakpoints in HPE patients. These YACs narrow the HPE2 critical region to less than 1 Mb and are now being further analyzed to identify the gene causing holoprosencephaly on chromosome 2.
- Published
- 1996
- Full Text
- View/download PDF
47. Genetic testing for children and adolescents.
- Author
-
Lebel RR
- Subjects
- Adolescent, Child, Humans, Genetic Testing legislation & jurisprudence, Informed Consent
- Published
- 1995
- Full Text
- View/download PDF
48. Linear facial skin defects associated with microphthalmia and other malformations, with chromosome deletion Xp22.1.
- Author
-
Eng A, Lebel RR, Elejalde BR, Anderson C, and Bennett L
- Subjects
- Abnormalities, Multiple pathology, Ear, External abnormalities, Facial Bones abnormalities, Facial Dermatoses pathology, Female, Humans, Infant, Infant, Newborn, Microphthalmos pathology, Syndrome, Chromosome Deletion, Facial Dermatoses complications, Microphthalmos complications, X Chromosome
- Published
- 1994
- Full Text
- View/download PDF
49. Routine childhood varicella vaccination.
- Author
-
Lebel RR
- Subjects
- Chickenpox Vaccine, Child, Humans, Chickenpox prevention & control, Viral Vaccines adverse effects, Viral Vaccines standards
- Published
- 1994
50. Gazali-Temple syndrome.
- Author
-
McLeod SD, Sugar J, Elejalde BR, Eng A, and Lebel RR
- Subjects
- Agenesis of Corpus Callosum, Corneal Opacity congenital, Corneal Opacity genetics, Female, Humans, Infant, Newborn, Syndrome, X Chromosome, Abnormalities, Multiple genetics, Microphthalmos genetics, Skin Abnormalities, Translocation, Genetic
- Published
- 1994
- Full Text
- View/download PDF
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