40 results on '"Keppler-Noreuil K"'
Search Results
2. Myocardial fat overgrowth in Proteus syndrome
- Author
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Hannoush, H., Sachdev, V., Brofferio, A., Arai, A. E., LaRocca, G., Sapp, J., Sidenko, S., Brenneman, C., Biesecker, L. G., and Keppler-Noreuil, K. M.
- Published
- 2015
- Full Text
- View/download PDF
3. Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange
- Author
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Yan, J, Zhang, F, Brundage, E, Scheuerle, A, Lanpher, B, Erickson, R P, Powis, Z, Robinson, H B, Trapane, P L, Stachiw-Hietpas, D, Keppler-Noreuil, K M, Lalani, S R, Sahoo, T, Chinault, A C, Patel, A, Cheung, S W, and Lupski, J R
- Published
- 2009
- Full Text
- View/download PDF
4. Molecular study of three cases of odontohypophosphatasia resulting from heterozygosity for mutations in the tissue non-specific alkaline phosphatase gene
- Author
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Herasse, M, Spentchian, M, Taillandier, A, Keppler-Noreuil, K, Fliorito, A N M, Bergoffen, J, Wallerstein, R, Muti, C, Simon-Bouy, B, and Mornet, E
- Published
- 2003
5. Congenital laryngotracheal webs and early onset colorectal carcinoma in a family with three-genration transmission of del(22q11.2)
- Author
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Larsen-Haidle, J., Keppler-Noreuil, K., Kanis, A.B., Muilenburg, A., Welch, J., Qian, Q., Yang, L., and Patil, S.
- Subjects
Genetic disorders -- Research ,Chromosome deletion -- Physiological aspects ,Colorectal cancer -- Genetic aspects ,Human genetics -- Research ,Biological sciences - Published
- 2001
6. 266 Growth of the cerebriform connective tissue nevus in individuals with Proteus syndrome
- Author
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Nathan, N., primary, Patel, R., additional, Crenshaw, M., additional, Lindhurst, M., additional, Olsen, C., additional, Biesecker, L., additional, Keppler-Noreuil, K., additional, and Darling, T., additional
- Published
- 2016
- Full Text
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7. Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a down syndrome-like facies
- Author
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Niceta, M., Stellacci, E., Gripp, K. W., Zampino, Giuseppe, Kousi, M., Anselmi, M., Traversa, A., Ciolfi, Alessandro, Stabley, D., Bruselles, A., Caputo, V., Cecchetti, S., Prudente, S., Fiorenza, M. T., Boitani, C., Philip, N., Niyazov, D., Leoni, Chiara, Nakane, T., Keppler-Noreuil, K., Braddock, S. R., Gillessen-Kaesbach, G., Palleschi, A., Campeau, P. M., Lee, B. H. L., Pouponnot, C., Stella, L., Bocchinfuso, G., Katsanis, N., Sol-Church, K., Tartaglia, M., Zampino G. (ORCID:0000-0003-3865-3253), Ciolfi A., Leoni C., Niceta, M., Stellacci, E., Gripp, K. W., Zampino, Giuseppe, Kousi, M., Anselmi, M., Traversa, A., Ciolfi, Alessandro, Stabley, D., Bruselles, A., Caputo, V., Cecchetti, S., Prudente, S., Fiorenza, M. T., Boitani, C., Philip, N., Niyazov, D., Leoni, Chiara, Nakane, T., Keppler-Noreuil, K., Braddock, S. R., Gillessen-Kaesbach, G., Palleschi, A., Campeau, P. M., Lee, B. H. L., Pouponnot, C., Stella, L., Bocchinfuso, G., Katsanis, N., Sol-Church, K., Tartaglia, M., Zampino G. (ORCID:0000-0003-3865-3253), Ciolfi A., and Leoni C.
- Abstract
Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a leucine zipper-containing transcription factor of the AP1 superfamily, profoundly affect development. Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals. The distinctive clinical phenotype, for which we propose the eponym Aymé-Gripp syndrome, is not limited to lens and eye defects as previously reported for MAF/Maf loss of function but includes sensorineural deafness, intellectual disability, seizures, brachycephaly, distinctive flat facial appearance, skeletal anomalies, mammary gland hypoplasia, and reduced growth. Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts, and induced neurodevelopmental defects in an in vivo model. Our findings nosologically and clinically delineate a previously poorly understood recognizable multisystem disorder, provide evidence for MAF governing a wider range of developmental programs than previously appreciated, and describe a novel instance of protein dosage effect severely perturbing development.
- Published
- 2015
8. Sensenbrenner syndrome (Cranioectodermal dysplasie): Clinical and molecular analysis of 39 patients including two new patients
- Author
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Lin, A.E., Traum, A.Z., Sahai, I., Keppler-Noreuil, K., Kukolich, M.K., Adam, M.P., Westra, S.W., Arts, H.H., Lin, A.E., Traum, A.Z., Sahai, I., Keppler-Noreuil, K., Kukolich, M.K., Adam, M.P., Westra, S.W., and Arts, H.H.
- Abstract
Item does not contain fulltext
- Published
- 2013
9. Comprehensive genetic analysis of OEIS complex reveals no evidence for a recurrent microdeletion or duplication
- Author
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Vlangos, C.N., Siuniak, A., Ackley, T., Bokhoven, H. van, Veltman, J.A., Iyer, R., Park, J.M., Keppler-Noreuil, K., Keegan, C.E., Vlangos, C.N., Siuniak, A., Ackley, T., Bokhoven, H. van, Veltman, J.A., Iyer, R., Park, J.M., Keppler-Noreuil, K., and Keegan, C.E.
- Abstract
Item does not contain fulltext, Omphalocele-exstrophy of the bladder-imperforate anus-spinal defects (OEIS) complex, or cloacal exstrophy (EC), is a rare constellation of malformations in humans involving the urogenital, gastrointestinal, and skeletal systems, and less commonly the central nervous system. Although OEIS complex is well-recognized in the clinical setting, there remains a significant lack of understanding of this condition at both the developmental and the genetic level. While most cases are sporadic, familial cases have been reported, suggesting that one or more specific genes may play a significant role in this condition. Several developmental mechanisms have been proposed to explain the etiology of OEIS complex, and it is generally considered to be a defect early in caudal mesoderm development and ventral body wall closure. The goal of this study was to identify genetic aberrations in 13 patients with OEIS/EC using a combination of candidate gene analysis and microarray studies. Analysis of 14 candidate genes in combination with either high resolution SNP or oligonucleotide microarray did not reveal any disease-causing mutations, although novel variants were identified in five patients. To our knowledge, this is the most comprehensive genetic analysis of patients with OEIS complex to date. We conclude that OEIS is a complex disorder from an etiological perspective, likely involving a combination of genetic and environmental predispositions. Based on our data, OEIS complex is unlikely to be caused by a recurrent chromosomal aberration.
- Published
- 2011
10. A case of Williams syndrome with a large, visible cytogenetic deletion
- Author
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WU, Y., NICKERSON, E., SHAFFER, L., KEPPLER-NOREUIL, K., and MUILENBURG, A.
- Subjects
Letters to the Editor - Published
- 1999
11. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.
- Author
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Gong, Y., Slee, R.B., Fukai, N., Rawadi, G., Roman-Roman, S., Reginato, A.M., Wang, H., Cundy, T., Glorieux, F.H., Lev, D., Zacharin, M., Oexle, K., Marcelino, J., Suwairi, W., Heeger, S., Sabatakos, G., Apte, S., Adkins, W., Allgrove, J., Arslan-Kirchner, M., Batch, J.A., Beighton, P., Black, G.C.M., Boles, R.G., Boon, L., Borrone, C., Brunner, H.G., Carle, G.F., Dallapicola, B., Paepe, A. de, Floege, B., Halfhide, M.L., Hall, B.D., Hennekam, R.C.M., Hirose, T., Jans, A., Juppner, H., Kim, C., Keppler-Noreuil, K., Kohlschuetter, A., Lacombe, D., Lambert, M., Lemyre, E., Letteboer, T., Peltonen, L., Ramesar, R.S., Romanengo, M., Somer, H., Steichen-Gersdorf, E., Steinmann, B., Sullivan, B., Superti-Furga, A., Swoboda, W., Boogaard, M.J. van den, Hul, W. van, Vikkula, M., Votruba, M., Zabel, B., Garcia, T., Baron, R., Olsen, B.R., Warman, M.L., Gong, Y., Slee, R.B., Fukai, N., Rawadi, G., Roman-Roman, S., Reginato, A.M., Wang, H., Cundy, T., Glorieux, F.H., Lev, D., Zacharin, M., Oexle, K., Marcelino, J., Suwairi, W., Heeger, S., Sabatakos, G., Apte, S., Adkins, W., Allgrove, J., Arslan-Kirchner, M., Batch, J.A., Beighton, P., Black, G.C.M., Boles, R.G., Boon, L., Borrone, C., Brunner, H.G., Carle, G.F., Dallapicola, B., Paepe, A. de, Floege, B., Halfhide, M.L., Hall, B.D., Hennekam, R.C.M., Hirose, T., Jans, A., Juppner, H., Kim, C., Keppler-Noreuil, K., Kohlschuetter, A., Lacombe, D., Lambert, M., Lemyre, E., Letteboer, T., Peltonen, L., Ramesar, R.S., Romanengo, M., Somer, H., Steichen-Gersdorf, E., Steinmann, B., Sullivan, B., Superti-Furga, A., Swoboda, W., Boogaard, M.J. van den, Hul, W. van, Vikkula, M., Votruba, M., Zabel, B., Garcia, T., Baron, R., Olsen, B.R., and Warman, M.L.
- Abstract
Item does not contain fulltext, In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass. Gong, Y
- Published
- 2001
12. Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange
- Author
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Yan, J, primary, Zhang, F, additional, Brundage, E, additional, Scheuerle, A, additional, Lanpher, B, additional, Erickson, R P, additional, Powis, Z, additional, Robinson, H B, additional, Trapane, P L, additional, Stachiw-Hietpas, D, additional, Keppler-Noreuil, K M, additional, Lalani, S R, additional, Sahoo, T, additional, Chinault, A C, additional, Patel, A, additional, Cheung, S W, additional, and Lupski, J R, additional
- Published
- 2008
- Full Text
- View/download PDF
13. Kabuki syndrome – Report of six cases and review of the literature with emphasis on ocular features
- Author
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Kluijt, I., primary, van Dorp, D.B., additional, Kwee, M.L., additional, Toutain, A., additional, Keppler-Noreuil, K., additional, Warburg, M., additional, and Bitoun, P., additional
- Published
- 2000
- Full Text
- View/download PDF
14. Chromosome 1p terminal deletion: report of new findings and confirmation of two characteristic phenotypes.
- Author
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Keppler-Noreuil, K M, primary, Carroll, A J, additional, Finley, W H, additional, and Rutledge, S L, additional
- Published
- 1995
- Full Text
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15. Developmental delay and multiple congenital anomalies in a child with a unique combination of partial monosomy 18 and partial trisomy 16.
- Author
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Schmidt N, Van Dyke DC, Keppler-Noreuil K, Muilenburg A, Patil S, Kanis AB, Schmidt, N, Van Dyke, D C, Keppler-Noreuil, K, Muilenburg, A, Patil, S, and Kanis, A B
- Published
- 2001
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16. A case of Williams syndrome with a large, visible cytogenetic deletion
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Wu, Y-Q., Nickerson, E., Shaffer, L.G., Keppler-Noreuil, K., and Muilenburg, A.
- Published
- 1999
17. Brain tissue- and region-specific abnormalities on volumetric MRI scans in 21 patients with Bardet-Biedl syndrome (BBS)
- Author
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Johnston Jennifer, Brinckman Danielle, Sapp Julie C, Blumhorst Catherine, Keppler-Noreuil Kim M, Nopoulos Peggy C, and Biesecker Leslie G
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Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Bardet-Biedl syndrome (BBS) is a heterogeneous human disorder inherited in an autosomal recessive pattern, and characterized by the primary findings of obesity, polydactyly, hypogonadism, and learning and behavioural problems. BBS mouse models have a neuroanatomical phenotype consisting of third and lateral ventriculomegaly, thinning of the cerebral cortex, and reduction in the size of the corpus striatum and hippocampus. These abnormalities raise the question of whether humans with BBS have a characteristic morphologic brain phenotype. Further, although behavioral, developmental, neurological and motor defects have been noted in patients with BBS, to date, there are limited reports of brain findings in BBS. The present study represents the largest systematic evaluation for the presence of structural brain malformations and/or progressive changes, which may contribute to these functional problems. Methods A case-control study of 21 patients, most aged 13-35 years, except for 2 patients aged 4 and 8 years, who were diagnosed with BBS by clinical criteria and genetic analysis of known BBS genes, and were evaluated by qualitative and volumetric brain MRI scans. Healthy controls were matched 3:1 by age, sex and race. Statistical analysis was performed using SAS language with SAS STAT procedures. Results All 21 patients with BBS were found to have statistically significant region- and tissue-specific patterns of brain abnormalities. There was 1) normal intracranial volume; 2) reduced white matter in all regions of the brain, but most in the occipital region; 3) preserved gray matter volume, with increased cerebral cortex volume in only the occipital lobe; 4) reduced gray matter in the subcortical regions of the brain, including the caudate, putamen and thalamus, but not in the cerebellum; and 5) increased cerebrospinal fluid volume. Conclusions There are distinct and characteristic abnormalities in tissue- and region- specific volumes of the brain in patients with BBS, which parallel the findings, described in BBS mutant mouse models. Some of these brain abnormalities may be progressive and associated with the reported neurological and behavioral problems. Further future correlation of these MRI scan findings with detailed neurologic and neuropsychological exams together with genotype data will provide better understanding of the pathophysiology of BBS.
- Published
- 2011
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18. Diagnosis and clinical delineation of mosaic tetrasomy 5p.
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Blakey-Cheung S, Parker P, Schlaff W, Monseur B, Keppler-Noreuil K, and Al-Kouatly HB
- Subjects
- Abnormalities, Multiple genetics, Abnormalities, Multiple pathology, Adult, Amniocentesis methods, Child, Chromosome Disorders diagnosis, Chromosome Disorders genetics, Chromosomes, Human, Pair 5 genetics, Developmental Disabilities genetics, Developmental Disabilities pathology, Female, Genetic Testing, Humans, In Situ Hybridization, Fluorescence, Isochromosomes genetics, Karyotyping, Male, Pregnancy, Prenatal Diagnosis, Tetrasomy genetics, Tetrasomy pathology, Abnormalities, Multiple diagnosis, Developmental Disabilities diagnosis, Mosaicism, Tetrasomy diagnosis
- Abstract
Objective: Our objective was to review the phenotypic and genetic characteristics of tetrasomy 5p from the fetal period until adulthood including prenatal diagnostic evaluations., Background: Tetrasomy 5p is a rare chromosomal abnormality. Of the 14 reports, most document mosaic tetrasomy 5p resulting from a supernumerary marker chromosome or isochromosome. There is a wide range of phenotypic manifestations with severity related to more proximal breakpoints and the degree of mosaicism., Design: We conducted a systematic review using Scopus, PubMed Central® and Ovid MEDLINE® from inception through July 1, 2018 for all articles describing tetrasomy 5p. All articles describing the syndrome of tetrasomy 5p were included., Results: Of the 15 included cases, 13 exhibited mosaic tetrasomy and two had complete tetrasomy identified by amniocentesis. The most common features include seizures (8/11 live births, 73%), hypotonia (7/11 live births, 64%), developmental delay (7/9 cases that reached childhood, 78%), abnormal external ears (6/11 live births, 55%), short stature (6/11 live births, 55%), ventriculomegaly (5/11 live births, 45.5%) and congenital heart defect (6/15 cases, 40%). The clinical phenotype ranged in severity from mild with no defining characteristics to severe with seizures, developmental delay, and multiple congenital anomalies, resulting in early death. Of these 15 cases, only 6 were diagnosed prenatally by prenatal genetic testing (40%) with prenatal ultrasound identifying abnormalities in 4/6 (67%). Confined placental mosaicism (CPM) was diagnosed in six additional cases due to discordance between CVS and amniocentesis results. Four of the five live births returned for evaluation and each showed normal development., Conclusions: Fourteen out of 15 (93%) cases of tetrasomy 5p were associated with an abnormal phenotype. Once a diagnosis is made prenatally, a detailed anatomy ultrasound and fetal echocardiogram must be performed to further characterize any structural abnormalities of the fetus and potentially estimate the clinical severity. Caution should be exercised when prenatal diagnosis of mosaic tetrasomy 5p is found by chorionic villus sampling. CVS alone is insufficient to diagnose tetrasomy 5p and needs to be confirmed with amniocentesis. Our review seeks to inform clinicians on the current literature regarding tetrasomy 5p so that they may better counsel patients when this syndrome is diagnosed., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
19. Exome sequencing of family trios from the National Birth Defects Prevention Study: Tapping into a rich resource of genetic and environmental data.
- Author
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Jenkins MM, Almli LM, Pangilinan F, Chong JX, Blue EE, Shapira SK, White J, McGoldrick D, Smith JD, Mullikin JC, Bean CJ, Nembhard WN, Lou XY, Shaw GM, Romitti PA, Keppler-Noreuil K, Yazdy MM, Kay DM, Carter TC, Olshan AF, Moore KJ, Nascone-Yoder N, Finnell RH, Lupo PJ, Feldkamp ML, Nickerson DA, Bamshad MJ, Brody LC, and Reefhuis J
- Subjects
- Family, Humans, Congenital Abnormalities genetics, Congenital Abnormalities prevention & control, Gene-Environment Interaction, Exome Sequencing
- Abstract
Background: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens., Methods: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA., Results: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol., Conclusions: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
- Full Text
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20. Genetics of Bladder-Exstrophy-Epispadias Complex (BEEC): Systematic Elucidation of Mendelian and Multifactorial Phenotypes.
- Author
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Reutter H, Keppler-Noreuil K, E Keegan C, Thiele H, Yamada G, and Ludwig M
- Abstract
The Bladder-Exstrophy-Epispadias Complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and has a profound impact on continence, and on sexual and renal function. While previous reports of familial occurrence, in-creased recurrence among first-degree relatives, high concordance rates among monozygotic twins, and chromosomal aberra-tions were suggestive of causative genetic factors, the recent identification of copy number variations (CNVs), susceptibility regions and genes through the systematic application of array based analysis, candidate gene and genome-wide association studies (GWAS) provide strong evidence. These findings in human BEEC cohorts are underscored by the recent description of BEEC(-like) murine knock-out models. Here, we discuss the current knowledge of the potential molecular mechanisms, mediating abnormal uro-rectal development leading to the BEEC, demonstrating the importance of ISL1-pathway in human and mouse and propose SLC20A1 and CELSR3 as the first BEEC candidate genes, identified through systematic whole-exome sequencing (WES) in BEEC patients.
- Published
- 2016
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21. Exome sequencing identifies novel mutations in C5orf42 in patients with Joubert syndrome with oral-facial-digital anomalies.
- Author
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Wentzensen IM, Johnston JJ, Keppler-Noreuil K, Acrich K, David K, Johnson KD, Graham JM Jr, Sapp JC, and Biesecker LG
- Abstract
Oral-facial-digital syndrome VI (OFD6 OMIM #277170), also called Varadi-Papp syndrome, is a ciliopathy inherited in an autosomal recessive pattern. Recently, mutations in C5orf42 (OMIM #614571) have been associated with OFD6. OFD6 overlaps with Joubert syndrome and mutations in C5orf42 were described in Joubert syndrome 17 (JBTS17, OMIM #614571). Using exome sequencing we report three novel variants and one previously reported variant in the C5orf42 gene in patients with OFD6.
- Published
- 2015
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22. Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies.
- Author
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Niceta M, Stellacci E, Gripp KW, Zampino G, Kousi M, Anselmi M, Traversa A, Ciolfi A, Stabley D, Bruselles A, Caputo V, Cecchetti S, Prudente S, Fiorenza MT, Boitani C, Philip N, Niyazov D, Leoni C, Nakane T, Keppler-Noreuil K, Braddock SR, Gillessen-Kaesbach G, Palleschi A, Campeau PM, Lee BH, Pouponnot C, Stella L, Bocchinfuso G, Katsanis N, Sol-Church K, and Tartaglia M
- Subjects
- Cataract pathology, Down Syndrome genetics, Down Syndrome pathology, Humans, Intellectual Disability pathology, Mutation, Phenotype, Phosphorylation, Seizures genetics, Seizures pathology, Cataract genetics, Deafness genetics, Glycogen Synthase Kinase 3 genetics, Intellectual Disability genetics, Proto-Oncogene Proteins c-maf genetics
- Abstract
Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a leucine zipper-containing transcription factor of the AP1 superfamily, profoundly affect development. Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals. The distinctive clinical phenotype, for which we propose the eponym Aymé-Gripp syndrome, is not limited to lens and eye defects as previously reported for MAF/Maf loss of function but includes sensorineural deafness, intellectual disability, seizures, brachycephaly, distinctive flat facial appearance, skeletal anomalies, mammary gland hypoplasia, and reduced growth. Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts, and induced neurodevelopmental defects in an in vivo model. Our findings nosologically and clinically delineate a previously poorly understood recognizable multisystem disorder, provide evidence for MAF governing a wider range of developmental programs than previously appreciated, and describe a novel instance of protein dosage effect severely perturbing development., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
23. Sensenbrenner syndrome (Cranioectodermal dysplasia): clinical and molecular analyses of 39 patients including two new patients.
- Author
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Lin AE, Traum AZ, Sahai I, Keppler-Noreuil K, Kukolich MK, Adam MP, Westra SJ, and Arts HH
- Subjects
- Comparative Genomic Hybridization, DNA Mutational Analysis, Humans, Infant, Infant, Newborn, Karyotyping, Male, Phenotype, Bone and Bones abnormalities, Craniosynostoses diagnosis, Craniosynostoses genetics, Ectodermal Dysplasia diagnosis, Ectodermal Dysplasia genetics
- Abstract
Sensenbrenner syndrome, also known as cranioectodermal dysplasia, is a rare multiple anomaly syndrome with distinctive craniofacial appearance, skeletal, ectodermal, connective tissue, renal, and liver anomalies. Dramatic advances with next-generation sequencing have expanded its phenotypic variability and molecular heterogeneity. We review 39 patients including two new patients, one with compound heterozygous novel mutations in WDR35 and a previously unreported multisutural craniosynostosis that may be a part of Sensenbrenner syndrome. In 14 of 25 (56.0%) patients pathogenic mutations have been identified in 4 different genes that regulate (intraflagellar) cilia transport. We compared Sensenbrenner syndrome to asphyxiating thoracic dystrophy-Jeune syndrome (ATD-JS) and other ciliopathies. Our analyses showed that the high anterior hairline, forehead bossing and dolichocephaly (accompanied by sagittal craniosynostosis in more than half of the patients) occur in almost all patients with Sensenbrenner syndrome. Metaphyseal dysplasia with narrow thorax, proximal limb shortness, and short fingers are typical of Sensenbrenner syndrome and ATD-JS. Respiratory complications have been reported in both syndromes, usually less severe with Sensenbrenner syndrome. Proposed diagnostic criteria for Sensenbrenner syndrome include the distinctive craniofacial appearance, ubiquitous brachydactyly and ectodermal anomalies, and sagittal craniosynostosis. Mild heart defects have been noted, but there have been no atrioventricular canal or heterotaxy defects that are common in Ellis-Van Creveld syndrome. We anticipate that the steady identification of molecularly defined patients may allow correlation of phenotype and genotype. Additional natural history data will improve genetic counseling and current guidelines., (© 2013 Wiley Periodicals, Inc.)
- Published
- 2013
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24. Functional analysis of a de novo ACTB mutation in a patient with atypical Baraitser-Winter syndrome.
- Author
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Johnston JJ, Wen KK, Keppler-Noreuil K, McKane M, Maiers JL, Greiner A, Sapp JC, Demali KA, Rubenstein PA, and Biesecker LG
- Subjects
- Actins genetics, Cell Adhesion, Child, Developmental Disabilities genetics, Exome, Female, Humans, Intellectual Disability genetics, Microcephaly genetics, Mutation, Missense, Sequence Analysis, DNA, Syndrome, Abnormalities, Multiple genetics, Actins metabolism
- Abstract
Exome sequence analysis can be instrumental in identifying the genetic etiology behind atypical disease. We report a patient presenting with microcephaly, dysmorphic features, and intellectual disability with a tentative diagnosis of Dubowitz syndrome. Exome analysis was performed on the patient and both parents. A de novo missense variant was identified in ACTB, c.349G>A, p.E117K. Recent work in Baraitser-Winter syndrome has identified ACTB and ACTG1 mutations in a cohort of individuals, and we rediagnosed the patient with atypical Baraitser-Winter syndrome. We performed functional characterization of the variant actin and show that it alters cell adhesion and polymer formation supporting its role in disease. We present the clinical findings in the patient, comparison of this patient to other patients with ACTB/ACTG1 mutations, and results from actin functional studies that demonstrate novel functional attributes of this mutant protein., (© 2013 WILEY PERIODICALS, INC.)
- Published
- 2013
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25. Deletion 16p13.11 uncovers NDE1 mutations on the non-deleted homolog and extends the spectrum of severe microcephaly to include fetal brain disruption.
- Author
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Paciorkowski AR, Keppler-Noreuil K, Robinson L, Sullivan C, Sajan S, Christian SL, Bukshpun P, Gabriel SB, Gleeson JG, Sherr EH, and Dobyns WB
- Subjects
- Adolescent, Brain Diseases etiology, Corpus Callosum pathology, Frameshift Mutation, Humans, Infant, Phenotype, Segmental Duplications, Genomic, Chromosome Deletion, Chromosomes, Human, Pair 16, Fetal Diseases genetics, Microcephaly genetics, Microtubule-Associated Proteins genetics, Mutation
- Abstract
Deletions of 16p13.11 have been associated with a variety of phenotypes, and have also been found in normal individuals. We report on two unrelated patients with severe microcephaly, agenesis of the corpus callosum, scalp rugae, and a fetal brain disruption (FBD)-like phenotype with inherited deletions of 16p13.11. The first patient was subsequently found on whole exome sequencing to have a nonsense mutation (p.R44X) in NDE1 on the non-deleted chromosome 16 homolog. We then undertook copy number studies of 16p13.11 and sequencing of NDE1 in nine additional patients with a similar severe microcephaly, agenesis of the corpus callosum, and FBD-like phenotype. The second patient was found to have an inherited deletion of the entire NDE1 gene combined with a frameshift mutation (c.1020-1021het_delGA) in the non-deleted NDE1. These observations broaden the phenotype seen in NDE1-related microcephaly to include FBD. These data also represent the second described syndrome, after Bernard-Soulier syndrome, where an autosomal recessive condition combines an inherited segmental duplication mediated deletion with a mutation in a gene within the non-deleted homolog. Finally, we performed informatics analysis of the 16p13.11 gene content, and found that there are many genes within the region with evidence for role(s) in brain development. Sequencing of other candidate genes in this region in patients with deletion 16p13.11 and more severe neurophenotypes may be warranted., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2013
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26. Apparent germline mosaicism for a novel 19p13.13 deletion disrupting NFIX and CACNA1A.
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Nimmakayalu M, Horton VK, Darbro B, Patil SR, Alsayouf H, Keppler-Noreuil K, and Shchelochkov OA
- Subjects
- Adolescent, Comparative Genomic Hybridization, Female, Humans, Infant, Newborn, Mosaicism, Syndrome, Calcium Channels genetics, Chromosome Disorders genetics, Chromosomes, Human, Pair 19 genetics, Germ-Line Mutation, Intellectual Disability genetics, Sequence Deletion genetics
- Abstract
We report on a case of apparent germline mosaicism in a family of two sisters carrying a novel 19p13.13 deletion. The 11-year-old proposita was referred for evaluation of macrocephaly, moderate intellectual disability (ID), and episodic ataxia. Array comparative genomic hybridization (CGH) detected a 399 kb microdeletion with breakpoints within genes NFIX and CACNA1A. A similar deletion was also seen in the elder sibling who presented with macrocephaly, ID, and strabismus. The deletions were confirmed to be de novo after the parental aCGH analysis suggesting that this is an example of germinal mosaicism. This study contributes additional information for the newly identified 19p13 deletion syndrome and clarifies the clinical roles of genes in the involved region. This case of apparent germline mosaicism represents the only known family in the cohort of 1,800 patients analyzed by our group., (Copyright © 2013 Wiley Periodicals, Inc.)
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- 2013
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27. Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams-Oliver syndrome.
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Shaheen R, Aglan M, Keppler-Noreuil K, Faqeih E, Ansari S, Horton K, Ashour A, Zaki MS, Al-Zahrani F, Cueto-González AM, Abdel-Salam G, Temtamy S, and Alkuraya FS
- Subjects
- Child, Child, Preschool, Female, Homozygote, Humans, In Situ Hybridization, Infant, Male, Pedigree, Scalp Dermatoses etiology, Consanguinity, Ectodermal Dysplasia etiology, Exome genetics, Genes, Recessive, Genetic Heterogeneity, Guanine Nucleotide Exchange Factors genetics, Limb Deformities, Congenital etiology, Mutation genetics, N-Acetylglucosaminyltransferases genetics, Scalp Dermatoses congenital
- Abstract
Adams-Oliver syndrome (AOS) is a rare, autosomal-dominant or -recessive disorder characterized primarily by aplasia cutis congenita and terminal transverse limb defects. Recently, we demonstrated that homozygous mutations in DOCK6 cause an autosomal-recessive form of AOS. In this study, we sought to determine the contribution of DOCK6 mutations to the etiology of AOS in several consanguineous families. In two of the five families studied, we identified two homozygous truncating mutations (a splice-site mutation and a frameshift duplication). DOCK6 sequencing revealed no mutation in the remaining three families, consistent with their autozygosity mapping and linkage-analysis results, which revealed a single candidate locus in 3p14.1 on three different haplotype backgrounds in the three families. Indeed, exome sequencing in one family revealed one missense mutation in EOGT (C3orf64), and subsequent targeted sequencing of this gene revealed a homozygous missense mutation and a homozygous frameshift deletion mutation in the other two families. EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine (O-GlcNAc) transferase, which is involved in the O-GlcNAcylation (attachment of O-GlcNAc to serine and threonine residues) of a subset of extracellular EGF-domain-containing proteins. It has a documented role in epithelial-cell-matrix interactions in Drosophila, in which deficiency of its ortholog causes wing blistering. Our findings highlight a developmental role of O-GlcNAcylation in humans and expand the genetic heterogeneity of autosomal-recessive AOS., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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28. Comprehensive genetic analysis of OEIS complex reveals no evidence for a recurrent microdeletion or duplication.
- Author
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Vlangos CN, Siuniak A, Ackley T, van Bokhoven H, Veltman J, Iyer R, Park JM, Keppler-Noreuil K, and Keegan CE
- Subjects
- Genetic Association Studies, Humans, Microarray Analysis, Polymerase Chain Reaction, Polymorphism, Single Nucleotide genetics, Sequence Analysis, DNA, Anus, Imperforate genetics, Hernia, Umbilical genetics, Scoliosis genetics, Urogenital Abnormalities genetics
- Abstract
Omphalocele-exstrophy of the bladder-imperforate anus-spinal defects (OEIS) complex, or cloacal exstrophy (EC), is a rare constellation of malformations in humans involving the urogenital, gastrointestinal, and skeletal systems, and less commonly the central nervous system. Although OEIS complex is well-recognized in the clinical setting, there remains a significant lack of understanding of this condition at both the developmental and the genetic level. While most cases are sporadic, familial cases have been reported, suggesting that one or more specific genes may play a significant role in this condition. Several developmental mechanisms have been proposed to explain the etiology of OEIS complex, and it is generally considered to be a defect early in caudal mesoderm development and ventral body wall closure. The goal of this study was to identify genetic aberrations in 13 patients with OEIS/EC using a combination of candidate gene analysis and microarray studies. Analysis of 14 candidate genes in combination with either high resolution SNP or oligonucleotide microarray did not reveal any disease-causing mutations, although novel variants were identified in five patients. To our knowledge, this is the most comprehensive genetic analysis of patients with OEIS complex to date. We conclude that OEIS is a complex disorder from an etiological perspective, likely involving a combination of genetic and environmental predispositions. Based on our data, OEIS complex is unlikely to be caused by a recurrent chromosomal aberration., (Copyright © 2010 Wiley-Liss, Inc.)
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- 2011
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29. Mutations in the cyclin family member FAM58A cause an X-linked dominant disorder characterized by syndactyly, telecanthus and anogenital and renal malformations.
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Unger S, Böhm D, Kaiser FJ, Kaulfuss S, Borozdin W, Buiting K, Burfeind P, Böhm J, Barrionuevo F, Craig A, Borowski K, Keppler-Noreuil K, Schmitt-Mechelke T, Steiner B, Bartholdi D, Lemke J, Mortier G, Sandford R, Zabel B, Superti-Furga A, and Kohlhase J
- Subjects
- Cells, Cultured, DNA Mutational Analysis, Facial Asymmetry complications, Female, Humans, Infant, Point Mutation, Syndactyly complications, Urogenital Abnormalities complications, Anal Canal abnormalities, Cyclins genetics, Facial Asymmetry genetics, Genes, Dominant, Genes, X-Linked, Kidney abnormalities, Syndactyly genetics, Urogenital Abnormalities genetics
- Abstract
We identified four girls with a consistent constellation of facial dysmorphism and malformations previously reported in a single mother-daughter pair. Toe syndactyly, telecanthus and anogenital and renal malformations were present in all affected individuals; thus, we propose the name 'STAR syndrome' for this disorder. Using array CGH, qPCR and sequence analysis, we found causative mutations in FAM58A on Xq28 in all affected individuals, suggesting an X-linked dominant inheritance pattern for this recognizable syndrome.
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- 2008
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30. Syndrome of congenital cataracts, sensorineural deafness, Down syndrome-like facial appearance, short stature, and mental retardation: two additional cases.
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Keppler-Noreuil K, Welch J, and Baker-Lange K
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- Adolescent, Adult, Child, Down Syndrome complications, Female, Humans, Infant, Infant, Newborn, Syndrome, Abnormalities, Multiple, Cataract congenital, Dwarfism, Face abnormalities, Hearing Loss, Sensorineural congenital, Intellectual Disability
- Abstract
An apparently new syndrome of congenital cataracts, sensorineural deafness, Down syndrome-like facial appearance, short stature, and mental retardation was described by Gripp et al. 1996. The authors reported on two unrelated patients with congenital cataracts, sensorineural deafness, distinctive facial appearance, mental retardation, postnatal short stature, and skeletal changes. We report on two additional patients with findings most similar to the reported patients by Gripp et al. 1996, including bilateral congenital cataracts, hearing loss, craniofacial abnormalities, short stature, skeletal abnormalities, and developmental delay. Both of the patients reported herein had chromosome microarray analysis, which showed normal results in Patient 2 but abnormal results in Patient 1 and his mother who both had a chromosome 11q25 subtelomere deletion. Patient 1 and his mother's findings are atypical for the common findings reported in Jacobsen syndrome (11q terminal deletion syndrome), and consistent with the patients reported by Gripp et al. 1996. The etiology for these cases has been unknown. The microarray results on Patient 1 suggest that the other patients with findings of developmental delay, short stature, congenital cataracts, sensorineural hearing loss, and similar craniofacial features may have either a microdeletion of chromosome 11q terminal region or haploinsufficiency of a gene localized to this region., (Copyright 2007 Wiley-Liss, Inc.)
- Published
- 2007
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31. Prenatal ascertainment of OEIS complex/cloacal exstrophy - 15 new cases and literature review.
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Keppler-Noreuil K, Gorton S, Foo F, Yankowitz J, and Keegan C
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- Humans, Bladder Exstrophy diagnosis, Cloaca abnormalities, Ultrasonography, Prenatal
- Abstract
Omphalocele-exstrophy of the bladder-imperforate anus-spinal defects (OEIS) complex or cloacal exstrophy (EC), describes a rare grouping of more commonly occurring component malformations [Carey et al., 1978]. The etiology is unknown, but likely heterogeneous. While postnatal identification of its associated gastrointestinal, spinal, and genitourinary systems delineates the extent and natural history of OEIS complex, prenatal findings may provide additional information regarding early detection, possible causative factors, and outcome. The purposes of this study were to: (1) present the prenatal ascertainment of OEIS complex in this series of 15 cases identified through several different sources compared to the literature, and (2) discuss the relationship of these prenatal findings to possible abnormal developmental mechanisms causing OEIS complex. These 15 cases indicate that OEIS complex may be difficult to diagnose prenatally, and that the full extent of abnormalities may not be clear until postnatal exam. Confusion with limb-body wall complex (two of our cases) and pentalogy of Cantrell (one of our cases) can occur. Anal/gastrointestinal malformations and genital ambiguity are under-ascertained. Conversely, prenatal defects may resolve postnatally, yet may provide clues for pathogenetic mechanisms. For instance, the finding of nuchal thickening in our three cases (one reported) suggests vascular/hemodynamic compromise early in embryologic development, or intrathoracic compression leading to jugular lymphatic obstruction may play a role. The association of twinning and OEIS complex suggests they may occur as early as blastogenesis. Our three sets of discordant twins also suggest a non-genetic etiology for OEIS complex of uteroplacental insufficiency. This study also indicates that OEIS complex may be more common than previously thought., ((c) 2007 Wiley-Liss, Inc.)
- Published
- 2007
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32. Clinical features and management issues in Mowat-Wilson syndrome.
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Adam MP, Schelley S, Gallagher R, Brady AN, Barr K, Blumberg B, Shieh JT, Graham J, Slavotinek A, Martin M, Keppler-Noreuil K, Storm AL, and Hudgins L
- Subjects
- Abnormalities, Multiple diagnosis, Abnormalities, Multiple therapy, Adolescent, Adult, Agenesis of Corpus Callosum, Child, Child, Preschool, Craniofacial Abnormalities genetics, Female, Hirschsprung Disease genetics, Homeodomain Proteins genetics, Humans, Infant, Infant, Newborn, Language Development Disorders genetics, Male, Pulmonary Artery abnormalities, Repressor Proteins genetics, Seizures genetics, Syndrome, Zinc Finger E-box Binding Homeobox 2, Abnormalities, Multiple genetics, Intellectual Disability genetics
- Abstract
Mowat-Wilson syndrome (MWS) is a relatively newly described multiple congenital anomaly/mental retardation syndrome. Haploinsufficiency of a gene termed ZFHX1B (also known as SIP1) on chromosome 2 is responsible for this condition, and clinical genetic testing for MWS recently became available. The majority of reports in the literature originate from Northern Europe and Australia. Here we report our clinical experience with 12 patients diagnosed with MWS within a 2-year period of time in the United States, with particular emphasis on clinical characteristics and management strategies. Individuals with this condition have characteristic facial features, including microcephaly, hypertelorism, medially flared and broad eyebrows, prominent columella, pointed chin, and uplifted earlobes, which typically prompt the clinician to consider the diagnosis. Medical issues in our cohort of patients included seizures (75%) with no predeliction for any particular seizure type; agenesis of the corpus callosum (60% of our patients studied); congenital heart defects (75%), particularly involving the pulmonary arteries and/or valves; hypospadias (55% of males); severely impaired or absent speech (100% of individuals over 1 year of age) with relatively spared receptive language; and Hirschsprung disease (50%) or chronic constipation (25%). The incidence of MWS is unknown, but based on the number of patients identified in a short period of time within the US, it is likely greatly under recognized. MWS should be considered in any individual with severely impaired or absent speech, especially in the presence of seizures and anomalies involving the pulmonary arteries (particularly pulmonary artery sling) or pulmonary valves., ((c) 2006 Wiley-Liss, Inc.)
- Published
- 2006
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33. Behavioral management of a long-term survivor with tetrasomy 18p.
- Author
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Swingle HM, Ringdahl J, Mraz R, Patil S, and Keppler-Noreuil K
- Subjects
- Adolescent, Adult, Child, Chromosome Painting, Follow-Up Studies, Humans, Karyotyping, Male, Mental Disorders genetics, Chromosome Aberrations, Chromosomes, Human, Pair 18 genetics, Mental Disorders nursing, Survivors
- Abstract
We report on a 41-year-old male with dysmorphic features, marked obesity, profound mental retardation, and aggressive behavior who was recently diagnosed with tetrasomy of the short arm of chromosome 18, [47, XY, i(18)(p10)]. His initial diagnosis, based upon chromosomal analysis at 6 years of age in 1969, was "trisomy F syndrome." Approximately 60 cases of tetrasomy 18p are reported in the literature, with little information regarding their long-term behavioral profiles or outcomes from therapy. We describe the behavioral management as well as the medical and genetic evaluation for this older patient with tetrasomy. With improved preventive care and intervention, patients with rare chromosomal abnormalities are living longer and, therefore, provide insight into the natural history of their disorders. Efforts need to be directed toward behavior management, social skills training, and augmentation of communication if the quality of life of these individuals is to continue to improve., (2006 Wiley-Liss, Inc.)
- Published
- 2006
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34. Further delineation of Kabuki syndrome in 48 well-defined new individuals.
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Armstrong L, Abd El Moneim A, Aleck K, Aughton DJ, Baumann C, Braddock SR, Gillessen-Kaesbach G, Graham JM Jr, Grebe TA, Gripp KW, Hall BD, Hennekam R, Hunter A, Keppler-Noreuil K, Lacombe D, Lin AE, Ming JE, Kokitsu-Nakata NM, Nikkel SM, Philip N, Raas-Rothschild A, Sommer A, Verloes A, Walter C, Wieczorek D, Williams MS, Zackai E, and Allanson JE
- Subjects
- Abnormalities, Multiple genetics, Adolescent, Adult, Child, Child, Preschool, Chromosome Aberrations, Chromosomes, Human, Pair 8 genetics, Craniofacial Abnormalities pathology, DNA-Binding Proteins genetics, Developmental Disabilities pathology, Female, Growth Disorders pathology, Humans, Intellectual Disability pathology, Interferon Regulatory Factors, Karyotyping, Male, Maternal Age, Paternal Age, Review Literature as Topic, Syndrome, Transcription Factors genetics, Abnormalities, Multiple pathology, Cardiovascular Abnormalities, Gastrointestinal Tract abnormalities, Immune System abnormalities, Musculoskeletal Abnormalities, Urogenital Abnormalities
- Abstract
Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases-providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined., ((c) 2004 Wiley-Liss, Inc.)
- Published
- 2005
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35. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.
- Author
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Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Jüppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, and Warman ML
- Subjects
- Adaptor Proteins, Signal Transducing, Adult, Animals, Animals, Outbred Strains, Bone Morphogenetic Protein 2, Bone Morphogenetic Proteins pharmacology, COS Cells, Child, Child, Preschool, Chlorocebus aethiops, Chromosomes, Human, Pair 11 genetics, Culture Media, Conditioned pharmacology, DNA, Complementary genetics, Dishevelled Proteins, Female, Genes, Recessive, Heterozygote, Humans, LDL-Receptor Related Proteins, Low Density Lipoprotein Receptor-Related Protein-5, Male, Mesoderm cytology, Mice, Mice, Inbred C57BL, Organ Culture Techniques, Phosphoproteins genetics, Phosphoproteins physiology, Proteins genetics, Proteins physiology, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins physiology, Receptors, LDL deficiency, Receptors, LDL genetics, Recombinant Fusion Proteins physiology, Recombinant Proteins, Signal Transduction, Skull cytology, Species Specificity, Stromal Cells cytology, Stromal Cells drug effects, Syndrome, Transfection, Wnt Proteins, Wnt-5a Protein, Wnt2 Protein, Wnt3 Protein, Wnt4 Protein, Bone Density genetics, Eye embryology, Eye Abnormalities genetics, Osteoblasts metabolism, Osteoporosis genetics, Receptors, LDL physiology, Transforming Growth Factor beta, Zebrafish Proteins
- Abstract
In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.
- Published
- 2001
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36. OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): a review of 14 cases.
- Author
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Keppler-Noreuil KM
- Subjects
- Abnormalities, Multiple etiology, Abnormalities, Multiple pathology, Anus, Imperforate etiology, Anus, Imperforate pathology, Bladder Exstrophy etiology, Bladder Exstrophy pathology, Child, Child, Preschool, Cloaca pathology, Family Health, Female, Hernia, Umbilical etiology, Hernia, Umbilical pathology, Humans, Infant, Infant, Newborn, Male, Neural Tube Defects etiology, Neural Tube Defects pathology, Pedigree, Prenatal Diagnosis, Spinal Dysraphism etiology, Spinal Dysraphism pathology, Urogenital Abnormalities etiology, Urogenital Abnormalities pathology, Cloaca abnormalities
- Abstract
OEIS complex refers to a combination of defects consisting of omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects. Possible embryologic mechanisms proposed for these findings have included: a single defect of early blastogenesis or a defect of mesodermal migration during the primitive streak period. Fourteen cases with OEIS complex and related malformations were reviewed for demographic features, prenatal and family histories, and clinical, radiological and pathological findings including the frequency and types of associated anomalies. The pathogenetic mechanisms causing OEIS complex and related malformations, such as anorectal and spinal defects, are discussed. The findings in these cases illustrate the spectrum of defects that can occur in the embryologic development of the cloaca and the urorectal septum. Differences in the timing and extent of mesenchymal ingrowth as well as cloacal membrane rupture may account for these variable findings. A developmental field defect involving the intraembryonic mesoderm suggests a possible etiologic role for homeobox genes, such as HLXB9 with mutations, resulting in anorectal and spine abnormalities, or retinoic acid receptors. OEIS complex with its mostly sporadic occurrence suggests etiologic heterogeneity with a possible role for environmental and genetic causes., (Copyright 2001 Wiley-Liss, Inc.)
- Published
- 2001
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37. Chromosome 18q paracentric inversion in a family with mental retardation and hearing loss.
- Author
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Keppler-Noreuil KM, Carroll AJ, Finley SC, Descartes M, Cody JD, DuPont BR, Gay CT, and Leach RJ
- Subjects
- Adult, Female, Genotype, Hearing Loss, Bilateral diagnosis, Humans, In Situ Hybridization, Fluorescence, Infant, Intellectual Disability diagnosis, Leukocytes, Centromere genetics, Chromosome Inversion, Chromosomes, Human, Pair 18 genetics, Hearing Loss, Bilateral genetics, Intellectual Disability genetics
- Abstract
We report on a mother and child with a paracentric inversion of the long arm of chromosome 18: 46,XX,inv(18)(q21.1q23). The child had findings in common with those seen in 18q- syndrome including: microcephaly, epicanthal folds, midface hypoplasia, and abnormally modeled ears, dermatoglyphic whorls on fingertips, clubfeet, hearing loss, and developmental delay. The mother and several maternal relatives had mild mental retardation and hearing loss. Magnetic resonance imaging of the child's brain showed abnormal myelination. Molecular studies including PCR-based markers for the MBP locus and fluorescent in situ hybridization with a P1 genomic clone on mother and child demonstrated only one copy of the MBP locus (18q23) with the deletion extending beyond the MBP locus. Therefore, the deletion in the MBP region may account for the abnormal myelination seen in the patient. The other clinical findings, including mental retardation and hearing loss in this family, may reflect disruption of distal or proximal genes within the deleted MBP region or at the more proximal breakpoint 18q21.1, and may represent a contiguous gene syndrome. Further study of this family may help define those genes functioning in the MBP region that contribute to the phenotype of 18q- syndrome.
- Published
- 1998
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38. Terminal deletion of the long arm of chromosome 4 in a mother and two sons.
- Author
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Descartes M, Keppler-Noreuil K, Knops J, Longshore JW, Finley WH, and Carroll AJ
- Subjects
- Abnormalities, Multiple pathology, Adult, Child, Preschool, Chromosome Aberrations pathology, Chromosome Disorders, Chromosomes, Human, Pair 4 ultrastructure, Face abnormalities, Female, Humans, Infant, Karyotyping, Male, Phenotype, Abnormalities, Multiple genetics, Chromosome Aberrations genetics, Chromosome Deletion, Chromosomes, Human, Pair 4 genetics, Intellectual Disability genetics
- Abstract
Deletion of chromosome 4q31-->pter has been characterized as a distinctive malformation syndrome. We report a mother and two sons with deletion of the long arm (q) of chromosome 4 del(4)(q34.2).
- Published
- 1996
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39. Cranioectodermal Dysplasia
- Author
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Tan W, Lin A, Keppler-Noreuil K, Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, and Amemiya A
- Abstract
Clinical Characteristics: Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur., Diagnosis/testing: The diagnosis of CED is established in a proband with characteristic clinical and radiographic features (including two frequent features and two other abnormalities, with at least one ectodermal defect – i.e., involvement of the teeth, hair, or nails) and/or by identification of biallelic pathogenic variants in one of the six genes currently known to be associated with CED: IFT43 , IFT52 , IFT122 , IFT140 , WDR19 , or WDR35 ., Management: Treatment of manifestations: As needed, surgery to correct sagittal craniosynostosis usually before age one year. Surgical correction may be needed for polydactyly of the hands and feet. Orthopedic care for hip dysplasia. Human growth hormone therapy could be considered in those who meet standard treatment criteria. Standard treatment for dental anomalies, nephronophthisis, liver disease, cardiac anomalies, and/or inguinal and umbilical hernias. For those with progressive visual impairment: low vision aids and appropriate educational programs. Mechanical ventilation may be required in newborns with pulmonary hypoplasia. For those with developmental delay, speech and physical therapy and appropriate educational programs. Surveillance: In infancy and childhood: monitor tooth development; morning urine osmolarity testing, urine collection assay for polyuria, blood pressure, serum creatinine and blood urea assessment, and renal ultrasound as recommended by nephrologist; hepatic transaminases and measurement of synthetic liver function as recommended by hepatologist. Annual ophthalmologic examinations starting at age four years to detect early signs of retinal degeneration. Cardiac examinations, ECG, and echocardiography per cardiologist. Review of developmental progress at each primary care visit, and formal evaluation with neuropsychological testing if delays noted., Genetic Counseling: CED is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CED-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible once the CED-causing pathogenic variants have been identified in an affected family member. Second-trimester ultrasound examination may detect renal cysts, shortening of the limbs, and/or polydactyly., (Copyright © 1993-2021, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.)
- Published
- 1993
40. PIK3CA -Related Overgrowth Spectrum
- Author
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Mirzaa G, Graham JM Jr, Keppler-Noreuil K, Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, and Amemiya A
- Abstract
Clinical Characteristics: PIK3CA -related overgrowth spectrum (PROS) encompasses a range of clinical findings in which the core features are congenital or early-childhood onset of segmental/focal overgrowth with or without cellular dysplasia. Prior to the identification of PIK3CA as the causative gene, PROS was separated into distinct clinical syndromes based on the tissues and/or organs involved (e.g., MCAP [ m egalencephaly- cap illary malformation] syndrome and CLOVES [ c ongenital l ipomatous asymmetric o vergrowth of the trunk, lymphatic, capillary, venous, and combined-type v ascular malformations, e pidermal nevi, s keletal and s pinal anomalies] syndrome). The predominant areas of overgrowth include the brain, limbs (including fingers and toes), trunk (including abdomen and chest), and face, all usually in an asymmetric distribution. Generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures resulting in ventriculomegaly, a markedly thick corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa. Vascular malformations may include capillary, venous, and less frequently, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations. Lymphatic malformations may be in various locations (internal and/or external) and can cause various clinical issues, including swelling, pain, and occasionally localized bleeding secondary to trauma. Lipomatous overgrowth may occur ipsilateral or contralateral to a vascular malformation, if present. The degree of intellectual disability appears to be mostly related to the presence and severity of seizures, cortical dysplasia (e.g., polymicrogyria), and hydrocephalus. Many children have feeding difficulties that are often multifactorial in nature. Endocrine issues affect a small number of individuals and most commonly include hypoglycemia (largely hypoinsulinemic hypoketotic hypoglycemia), hypothyroidism, and growth hormone deficiency., Diagnosis/testing: The diagnosis of PROS is established in a proband with suggestive findings and a heterozygous mosaic (or rarely, constitutional) activating pathogenic variant in PIK3CA . Sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from freshly obtained dermal biopsy overlying an affected area, from surgical excision of the overgrown tissue, or from uncultured tissues (such as skin fibroblasts or other tissues) ‒ should be prioritized for genetic testing. Targeted capture of the entire PIK3CA coding region followed by next-generation sequencing at very deep coverage is recommended for somatic variant detection, as it allows for detection of very low levels of mosaicism throughout the gene., Management: Targeted treatment of manifestations : Alpelisib (VIJOICE
® ) 50 mg orally with food once a day (at about the same time every day) for those between age two years and <18 years with PROS. In those age six years or older, the dose may be increased to 125 mg once a day after 24 weeks. A starting dose of 250 mg orally with food once a day (at about the same time every day) has been approved for those age ≥18 years. Alpelisib has been approved specifically for the reduction of overgrowth, vascular lesions, and other functional complications. To date, it is unknown whether this drug has any efficacy in treating the neurologic manifestations of PROS (as, e.g., in MCAP syndrome). Supportive treatment of manifestations: Significant or lipomatous segmental overgrowth may require debulking; scoliosis and leg-length discrepancy may require orthopedic care and surgical intervention. Neurologic complications (e.g., obstructive hydrocephalus, increased intracranial pressure, progressive and/or symptomatic cerebellar tonsillar ectopia or Chiari malformation, and epilepsy in those with brain overgrowth/malformations) may warrant neurosurgical intervention. Depending on the type of vascular malformations, sclerotherapy, laser therapy, or oral medications such as sirolimus may be used. Similarly, lymphatic malformations may be treated through oral medications or careful surgical debulking, preferably by a vascular anomalies team. For those with pain, evaluation for the source of pain and treatment of the underlying cause is recommended. For those with growth hormone deficiency, a trial of growth hormone therapy may be considered with careful monitoring of linear growth and overgrowth. Routine treatment of the following, when present, is indicated: cardiac and renal abnormalities; intellectual disabilities and behavior problems; polydactyly and foot deformities; coagulopathy or thrombosis; Wilms tumor; hypothyroidism; and hypoglycemia. Surveillance : At each visit: measurement of growth parameters including head circumference, length of arms, hands, legs, and feet; assess for new neurologic manifestations (seizures, changes in tone, and other signs/symptoms of Chiari malformation); monitor developmental progress and behavior; assess motor skills; clinical assessment for scoliosis and abdominal examination for organomegaly and/or abdominal masses. Serial head MRI imagining is recommended, with frequency based on the severity of findings on initial assessment and the degree of brain maturation. For those with CNS overgrowth or dysplasia, brain MRI every six months until age two years and then annually until age eight years to monitor specifically for progressive hydrocephalus and Chiari malformation. As clinically indicated: clinical assessment and monitoring of any vascular and/or lymphatic malformations; radiographs of the limbs in those with overgrowth of a limb or portion of a limb; ultrasound or MRI follow up in those with truncal overgrowth; spinal MRI in those with scoliosis or deformities that affect the spine. Hematology consultation with recommendations for assessment for thrombosis and coagulopathy risk after any surgical intervention, particularly in those with the CLOVES phenotype and/or those with vascular malformations. Consideration of renal ultrasound every three months until age eight years (tumor screening for Wilms tumor is controversial)., Genetic Counseling: PROS disorders are not known to be inherited, as most identified pathogenic variants are somatic (mosaic). No confirmed vertical transmission or sib recurrence has been reported to date. The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in PIK3CA would be expected to be the same as in the general population. All but a few affected individuals with PROS have had somatic mosaicism for a PIK3CA pathogenic variant, suggesting that mutation occurred post fertilization in one cell of the multicellular embryo. Therefore, the risk for transmission to offspring is expected to be less than 50%., (Copyright © 1993-2022, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.)- Published
- 1993
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