130 results on '"Slavotinek AM"'
Search Results
2. Pregnancy and Birth Outcomes among Women with Idiopathic Thrombocytopenic Purpura.
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Slavotinek, Anne, Wyszynski, DF, Carman, WJ, Cantor, AB, Graham, JM, Kunz, LH, Slavotinek, AM, Kirby, RS, and Seeger, J
- Abstract
To examine pregnancy and birth outcomes among women with idiopathic thrombocytopenic purpura (ITP) or chronic ITP (cITP) diagnosed before or during pregnancy.A linkage of mothers and babies within a large U.S. health insurance database that combines enroll
- Published
- 2016
3. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects
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Slavotinek, AM, Garcia, ST, Chandratillake, G, Bardakjian, T, Ullah, E, Wu, D, Umeda, K, Lao, R, Tang, P L‐F, Wan, E, Madireddy, L, Lyalina, S, Mendelsohn, BA, Dugan, S, Tirch, J, Tischler, R, Harris, J, Clark, MJ, Chervitz, S, Patwardhan, A, West, JM, Ursell, P, de Alba Campomanes, A, Schneider, A, Kwok, P‐y, Baranzini, S, and Chen, RO
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Biological Sciences ,Bioinformatics and Computational Biology ,Biomedical and Clinical Sciences ,Genetics ,Ophthalmology and Optometry ,Pediatric ,Human Genome ,Brain Disorders ,Congenital Structural Anomalies ,Eye Disease and Disorders of Vision ,Clinical Research ,Rare Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Eye ,Anophthalmos ,Collagen Type IV ,DNA Mutational Analysis ,Exome ,Exoribonucleases ,Eye Abnormalities ,Female ,Humans ,Infant ,Male ,Membrane Proteins ,Microphthalmos ,Mutation ,Otx Transcription Factors ,Receptors ,Retinoic Acid ,anophthalmia ,microphthalmia ,COL4A1 ,exome sequencing ,FBLN1 ,PNPT1 ,anophthalmia/microphthalmia ,Clinical Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
Anophthalmia/microphthalmia (A/M) is a genetically heterogeneous birth defect for which the etiology is unknown in more than 50% of patients. We used exome sequencing with the ACE Exome(TM) (Personalis, Inc; 18 cases) and UCSF Genomics Core (21 cases) to sequence 28 patients with A/M and four patients with varied developmental eye defects. In the 28 patients with A/M, we identified de novo mutations in three patients (OTX2, p.(Gln91His), RARB, p.Arg387Cys and GDF6, p.Ala249Glu) and inherited mutations in STRA6 in two patients. In patients with developmental eye defects, a female with cataracts and cardiomyopathy had a de novo COL4A1 mutation, p.(Gly773Arg), expanding the phenotype associated with COL4A1 to include cardiomyopathy. A male with a chorioretinal defect, microcephaly, seizures and sensorineural deafness had two PNPT1 mutations, p.(Ala507Ser) and c.401-1G>A, and we describe eye defects associated with this gene for the first time. Exome sequencing was efficient for identifying mutations in pathogenic genes for which there is no clinical testing available and for identifying cases that expand phenotypic spectra, such as the PNPT1 and COL4A1-associated disorders described here.
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- 2015
4. Characterization of a variant of gap junction protein alpha 8 identified in a family with hereditary cataract
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Kuo, DS, Sokol, JT, Minogue, PJ, Berthoud, VM, Slavotinek, AM, Beyer, EC, and Gould, DB
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- 2017
5. The FgfrL1 receptor is required for development of slow muscle fibers
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Amann R Wyder S Slavotinek AM and Trueb B
- Abstract
FgfrL1 which interacts with Fgf ligands and heparin is a member of the fibroblast growth factor receptor (Fgfr) family. FgfrL1 deficient mice show two significant alterations when compared to wildtype mice: They die at birth due to a malformed diaphragm and they lack metanephric kidneys. Utilizing gene arrays qPCR and in situ hybridization we show here that the diaphragm of FgfrL1 knockout animals lacks any slow muscle fibers at E18.5 as indicated by the absence of slow fiber markers Myh7 Myl2 and Myl3. Similar lesions are also found in other skeletal muscles that contain a high proportion of slow fibers at birth such as the extraocular muscles. In contrast to the slow fibers fast fibers do not appear to be affected as shown by expression of fast fiber markers Myh3 Myh8 Myl1 and MylPF. At early developmental stages (E10.5 E15.5) FgfrL1 deficient animals express slow fiber genes at normal levels. The loss of slow fibers cannot be attributed to the lack of kidneys since Wnt4 knockout mice which also lack metanephric kidneys show normal expression of Myh7 Myl2 and Myl3. Thus FgfrL1 is specifically required for embryonic development of slow muscle fibers.
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- 2014
6. Homozygosity for aFBN1missense mutation causes a severe Marfan syndrome phenotype
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Hogue, J, primary, Lee, C, additional, Jelin, A, additional, Strecker, MN, additional, Cox, VA, additional, and Slavotinek, AM, additional
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- 2012
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7. Sequence variants in theHLXgene at chromosome 1q41-1q42 in patients with diaphragmatic hernia
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Slavotinek, AM, primary, Moshrefi, A, additional, Lopez Jiminez, N, additional, Chao, R, additional, Mendell, A, additional, Shaw, GM, additional, Pennacchio, LA, additional, and Bates, MD, additional
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- 2009
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8. Sudden death caused by pulmonary thromboembolism in Proteus syndrome
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Slavotinek, AM, primary, Vacha, SJ, additional, Peters, KF, additional, and Biesecker, LG, additional
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- 2000
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9. Genomic microarray analysis identifies candidate loci in patients with corpus callosum anomalies.
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Sherr EH, Owen R, Albertson DG, Pinkel D, Cotter PD, Slavotinek AM, Hetts SW, Jeremy RJ, Schilmoeller G, Schilmoeller K, Wakahiro M, and Barkovich AJ
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- 2005
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10. Homozygosity for a FBN1 missense mutation causes a severe Marfan syndrome phenotype.
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Hogue, J, Lee, C, Jelin, A, Strecker, MN, Cox, VA, and Slavotinek, AM
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HOMOZYGOSITY ,MARFAN syndrome ,MEXICAN American women ,DISEASES - Abstract
A letter to the editor is presented which discusses the case of a Mexican-American woman with severe Marfan syndrome homozygous due to FBN1 missense mutation.
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- 2013
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11. Diagnostic yield after next-generation sequencing in pediatric cardiovascular disease.
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Slavotinek AM, Thompson ML, Martin LJ, and Gelb BD
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- Humans, Child, Male, Female, Infant, Child, Preschool, Heart Defects, Congenital genetics, Heart Defects, Congenital diagnosis, Adolescent, Phenotype, Exome Sequencing methods, Infant, Newborn, High-Throughput Nucleotide Sequencing methods, Genetic Testing methods, Cardiovascular Diseases genetics, Cardiovascular Diseases diagnosis
- Abstract
Genetic testing with exome sequencing and genome sequencing is increasingly offered to infants and children with cardiovascular diseases. However, the rates of positive diagnoses after genetic testing within the different categories of cardiac disease and phenotypic subtypes of congenital heart disease (CHD) have been little studied. We report the diagnostic yield after next-generation sequencing in 500 patients with CHD from diverse population subgroups that were enrolled at three different sites in the Clinical Sequencing Evidence-Generating Research consortium. Patients were ascertained due to a primary cardiovascular issue comprising arrhythmia, cardiomyopathy, and/or CHD, and corresponding human phenotype ontology terms were selected to describe the cardiac and extracardiac findings. We examined the diagnostic yield for patients with arrhythmia, cardiomyopathy, and/or CHD and phenotypic subtypes of CHD comprising conotruncal defects, heterotaxy, left ventricular outflow tract obstruction, septal defects, and "other" heart defects. We found a significant increase in the frequency of positive findings for patients who underwent genome sequencing compared to exome sequencing and for syndromic cardiac defects compared to isolated cardiac defects. We also found significantly higher diagnostic rates for patients who presented with isolated cardiomyopathy compared to isolated CHD. For patients with syndromic presentations who underwent genome sequencing, there were significant differences in the numbers of positive diagnoses for phenotypic subcategories of CHD, ranging from 31.7% for septal defects to 60% for "other". Despite variation in the diagnostic yield at each site, our results support genetic testing in pediatric patients with syndromic and isolated cardiovascular issues and in all subtypes of CHD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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12. Embracing the Science of Motherhood: Pregnancy's Transformative Effects on the Central Nervous System and the Radiance of Maternal Hormones and Immune Responses.
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Marsili L, Magnusen AF, Trivedi VS, Slavotinek AM, and Pandey MK
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- Pregnancy, Infant, Humans, Female, Immunity, Central Nervous System, Central Nervous System Diseases
- Abstract
Pregnancy is often thought of as a time of happiness and anticipation, however, for some women, it can bring about significant emotional distress and feelings of vulnerability. The physiological changes that occur during pregnancy, including hormonal fluctuations and alterations to the immune and physical systems, can affect various parts of the body, including the central nervous system (CNS). As a result, existing conditions may be intensified or new ones, such as neurologic or psychiatric disorders, may arise, exposing women to increased risk of life-threatening conditions or suicide, in the worst-case scenarios. Given the impact of pregnancy on CNS diseases, it is crucial for healthcare providers and patients alike to be aware of these potential effects. By understanding how pregnancy may affect the CNS, clinicians can take appropriate steps to ensure that women receive the care and support they need to minimize any negative outcomes for both the mother and the baby. This paper aims to review the available evidence on the impact of pregnancy on CNS diseases, including mental health conditions, from both the clinical and biomolecular perspectives. By illuminating this crucial subject, this study fosters a delicate understanding within both patients and healthcare providers, thereby paving the way for enhanced outcomes for women throughout their pregnancy journey and beyond.
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- 2023
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13. Return of non-ACMG recommended incidental genetic findings to pediatric patients: considerations and opportunities from experiences in genomic sequencing.
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Bowling KM, Thompson ML, Kelly MA, Scollon S, Slavotinek AM, Powell BC, Kirmse BM, Hendon LG, Brothers KB, Korf BR, Cooper GM, Greally JM, and Hurst ACE
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- Humans, United States, Chromosome Mapping, Base Sequence, Genomics, Genome, Human, Exome
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Background: The uptake of exome/genome sequencing has introduced unexpected testing results (incidental findings) that have become a major challenge for both testing laboratories and providers. While the American College of Medical Genetics and Genomics has outlined guidelines for laboratory management of clinically actionable secondary findings, debate remains as to whether incidental findings should be returned to patients, especially those representing pediatric populations., Methods: The Sequencing Analysis and Diagnostic Yield working group in the Clinical Sequencing Evidence-Generating Research Consortium has collected a cohort of pediatric patients found to harbor a genomic sequencing-identified non-ACMG-recommended incidental finding. The incidental variants were not thought to be associated with the indication for testing and were disclosed to patients and families., Results: In total, 23 "non-ACMG-recommended incidental findings were identified in 21 pediatric patients included in the study. These findings span four different research studies/laboratories and demonstrate differences in incidental finding return rate across study sites. We summarize specific cases to highlight core considerations that surround identification and return of incidental findings (uncertainty of disease onset, disease severity, age of onset, clinical actionability, and personal utility), and suggest that interpretation of incidental findings in pediatric patients can be difficult given evolving phenotypes. Furthermore, return of incidental findings can benefit patients and providers, but do present challenges., Conclusions: While there may be considerable benefit to return of incidental genetic findings, these findings can be burdensome to providers and present risk to patients. It is important that laboratories conducting genomic testing establish internal guidelines in anticipation of detection. Moreover, cross-laboratory guidelines may aid in reducing the potential for policy heterogeneity across laboratories as it relates to incidental finding detection and return. However, future discussion is required to determine whether cohesive guidelines or policy statements are warranted., (© 2022. The Author(s).)
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- 2022
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14. Targeting the Complement-Sphingolipid System in COVID-19 and Gaucher Diseases: Evidence for a New Treatment Strategy.
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Trivedi VS, Magnusen AF, Rani R, Marsili L, Slavotinek AM, Prows DR, Hopkin RJ, McKay MA, and Pandey MK
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- Humans, Sphingolipids, SARS-CoV-2, Complement System Proteins, Complement C5a metabolism, Inflammation, Glycosphingolipids, Gaucher Disease drug therapy, COVID-19 Drug Treatment
- Abstract
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)-induced disease (COVID-19) and Gaucher disease (GD) exhibit upregulation of complement 5a (C5a) and its C5aR1 receptor, and excess synthesis of glycosphingolipids that lead to increased infiltration and activation of innate and adaptive immune cells, resulting in massive generation of pro-inflammatory cytokines, chemokines and growth factors. This C5a-C5aR1-glycosphingolipid pathway- induced pro-inflammatory environment causes the tissue damage in COVID-19 and GD. Strikingly, pharmaceutically targeting the C5a-C5aR1 axis or the glycosphingolipid synthesis pathway led to a reduction in glycosphingolipid synthesis and innate and adaptive immune inflammation, and protection from the tissue destruction in both COVID-19 and GD. These results reveal a common involvement of the complement and glycosphingolipid systems driving immune inflammation and tissue damage in COVID-19 and GD, respectively. It is therefore expected that combined targeting of the complement and sphingolipid pathways could ameliorate the tissue destruction, organ failure, and death in patients at high-risk of developing severe cases of COVID-19.
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- 2022
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15. Suleiman-El-Hattab syndrome: a histone modification disorder caused by TASP1 deficiency.
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Riedhammer KM, Burgemeister AL, Cantagrel V, Amiel J, Siquier-Pernet K, Boddaert N, Hertecant J, Kannouche PL, Pouvelle C, Htun S, Slavotinek AM, Beetz C, Diego-Alvarez D, Kampe K, Fleischer N, Awamleh Z, Weksberg R, Kopajtich R, Meitinger T, Suleiman J, and El-Hattab AW
- Subjects
- Abnormalities, Multiple, Animals, Endopeptidases genetics, Face abnormalities, Hematologic Diseases, Histone Methyltransferases genetics, Phenotype, Transcription Factor TFIIA genetics, Vestibular Diseases, Histone Code, Zebrafish genetics
- Abstract
Background: TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach., Methods: Chromosomal microarray/exome sequencing in all individuals. Western blotting from fibroblasts in two individuals. RNA sequencing and proteomics from fibroblasts in one individual. Methylome analysis from blood in two individuals. Knock-out of tasp1 orthologue in zebrafish and phenotyping., Results: All individuals had biallelic TASP1 loss-of-function variants and a phenotype including developmental delay, multiple congenital anomalies (including cardiovascular and posterior fossa malformations), a distinct facial appearance and happy demeanor. Western blot revealed absence of TASP1. RNA sequencing/proteomics showed HOX gene downregulation (HOXA4, HOXA7, HOXA1 and HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knock-out revealed smaller head size and abnormal cranial cartilage formation in tasp1 crispants., Conclusion: This work further delineates Suleiman-El-Hattab syndrome, a recognizable neurodevelopmental syndrome. Possible downstream mechanisms of TASP1 deficiency include perturbed HOX gene expression and dysregulated TFIIA complex. Methylation pattern suggests that Suleiman-El-Hattab syndrome can be categorized into the group of histone modification disorders including Wiedemann-Steiner and Kabuki syndrome., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
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- 2022
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16. Late-onset Proteus syndrome with cerebriform connective tissue nevus and subsequent development of intraductal papilloma.
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Modlin EW, Slavotinek AM, Darling TN, Lipkowitz S, Barr FG, Munster PN, Biesecker LG, and Ours CA
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- Female, Humans, Infant, Newborn, Middle Aged, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt genetics, Breast Neoplasms genetics, Nevus diagnosis, Nevus genetics, Nevus pathology, Papilloma, Intraductal, Proteus Syndrome diagnosis, Proteus Syndrome genetics, Proteus Syndrome pathology
- Abstract
Proteus syndrome (PS) is a rare segmental overgrowth disorder caused by a mosaic activating variant in AKT1. The features of PS are often not present at birth but develop during the first few years of life. We describe a 55-year-old female, whose first symptom of overgrowth, a cerebriform connective tissue nevus, occurred at 19 years of age. We report the identification of the AKT1 c.49G > A p.(Glu17Lys) variant in this progressive lesion, the bony overgrowth, and recurrence after surgical intervention. In the sixth decade of life, this individual developed intraductal papillomas within her right breast which were confirmed to contain the same activating AKT1 variant as the connective tissue nevus. While similar neoplasms have been described in an individual with Proteus syndrome, none has been evaluated for the presence of the AKT1 variant. The tumor also contained two likely pathogenic variants in PIK3R1, c.1392_1403dupTAGATTATATGA p.(Asp464_Tyr467dup) and c.1728_1730delGAG p.(Arg577del). The finding of additional genetic variation putatively affecting the PI3K/AKT pathway in the neoplastic tissue may provide preliminary evidence of a molecular mechanism for tumorigenesis in PS. The late onset of symptoms and molecular characterization of the breast tumor expand the clinical spectrum of this rare disorder., (© 2022 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)
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- 2022
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17. De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations.
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Dias KR, Carlston CM, Blok LER, De Hayr L, Nawaz U, Evans CA, Bayrak-Toydemir P, Htun S, Zhu Y, Ma A, Lynch SA, Moorwood C, Stals K, Ellard S, Bainbridge MN, Friedman J, Pappas JG, Rabin R, Nowak CB, Douglas J, Wilson TE, Guillen Sacoto MJ, Mullegama SV, Palculict TB, Kirk EP, Pinner JR, Edwards M, Montanari F, Graziano C, Pippucci T, Dingmann B, Glass I, Mefford HC, Shimoji T, Suzuki T, Yamakawa K, Streff H, Schaaf CP, Slavotinek AM, Voineagu I, Carey JC, Buckley MF, Schenck A, Harvey RJ, and Roscioli T
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- Brain metabolism, Gene Expression Regulation, Humans, Protein Domains, Exome Sequencing, Intellectual Disability genetics, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders metabolism
- Abstract
Purpose: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene., Methods: An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants., Results: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function., Conclusion: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability., Competing Interests: Conflict of Interest S.V.M., T.B.P., and M.J.G.S. are employees of GeneDx, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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18. Perspectives and preferences regarding genomic secondary findings in underrepresented prenatal and pediatric populations: A mixed-methods approach.
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Rego S, Hoban H, Outram S, Zamora AN, Chen F, Sahin-Hodoglugil N, Anguiano B, Norstad M, Yip T, Lianoglou B, Sparks TN, Norton ME, Koenig BA, Slavotinek AM, and Ackerman SL
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- Child, Exome genetics, Female, Genome, Human, Humans, Pregnancy, Exome Sequencing methods, Family, Genomics
- Abstract
Purpose: Patients undergoing clinical exome sequencing (ES) are routinely offered the option to receive secondary findings (SF). However, little is known about the views of individuals from underrepresented minority pediatric or prenatal populations regarding SF., Methods: We explored the preferences for receiving hypothetical categories of SF (H-SF) and reasons for accepting or declining actual SF through surveying (n = 149) and/or interviewing (n = 47) 190 families undergoing pediatric or prenatal ES., Results: Underrepresented minorities made up 75% of the probands. In total, 150 families (79%) accepted SF as part of their child/fetus's ES. Most families (63%) wanted all categories of H-SF. Those who declined SF as part of ES were less likely to want H-SF across all categories. Interview findings indicate that some families did not recall their SF decision. Preparing for the future was a major motivator for accepting SF, and concerns about privacy, discrimination, and psychological effect drove decliners., Conclusion: A notable subset of families (37%) did not want at least 1 category of H-SF, suggesting more hesitancy about receiving all available results than previously reported. The lack of recollection of SF decisions suggests a need for alternative communication approaches. Results highlight the importance of the inclusion of diverse populations in genomic research., Competing Interests: Conflict of Interest The first author, S.R., completed most of the work on this manuscript while being an employee of the University of California San Francisco and has since moved to a role as a full-time employee and shareholder of AllStripes Research. She has no conflicts of interest to disclose in either role. The other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
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- 2022
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19. S1P defects cause a new entity of cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome.
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Chen F, Ni C, Wang X, Cheng R, Pan C, Wang Y, Liang J, Zhang J, Cheng J, Chin YE, Zhou Y, Wang Z, Guo Y, Chen S, Htun S, Mathes EF, de Alba Campomanes AG, Slavotinek AM, Zhang S, Li M, and Yao Z
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- Alopecia genetics, Electron-Transferring Flavoproteins genetics, Electron-Transferring Flavoproteins metabolism, Humans, Riboflavin metabolism, Cataract genetics, Psoriasis
- Abstract
In this report, we discovered a new entity named cataract, alopecia, oral mucosal disorder, and psoriasis-like (CAOP) syndrome in two unrelated and ethnically diverse patients. Furthermore, patient 1 failed to respond to regular treatment. We found that CAOP syndrome was caused by an autosomal recessive defect in the mitochondrial membrane-bound transcription factor peptidase/site-1 protease (MBTPS1, S1P). Mitochondrial abnormalities were observed in patient 1 with CAOP syndrome. Furthermore, we found that S1P is a novel mitochondrial protein that forms a trimeric complex with ETFA/ETFB. S1P enhances ETFA/ETFB flavination and maintains its stability. Patient S1P variants destabilize ETFA/ETFB, impair mitochondrial respiration, decrease fatty acid β-oxidation activity, and shift mitochondrial oxidative phosphorylation (OXPHOS) to glycolysis. Mitochondrial dysfunction and inflammatory lesions in patient 1 were significantly ameliorated by riboflavin supplementation, which restored the stability of ETFA/ETFB. Our study discovered that mutations in MBTPS1 resulted in a new entity of CAOP syndrome and elucidated the mechanism of the mutations in the new disease., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)
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- 2022
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20. Preference for secondary findings in prenatal and pediatric exome sequencing.
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Swanson K, Sparks TN, Lianoglou BR, Chen F, Downum S, Patel S, Rego S, Yip T, Van Ziffle J, Koenig BA, Slavotinek AM, and Norton ME
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- Child, Cohort Studies, Female, Humans, Parents, Pregnancy, Prenatal Diagnosis, Exome Sequencing, Exome, Family
- Abstract
Objective: We aimed to determine the frequency of accepting secondary findings in families undergoing exome sequencing in prenatal and pediatric settings., Methods: This was a secondary analysis of prospectively enrolled patients undergoing trio exome sequencing for congenital anomalies or developmental disorders in prenatal and pediatric settings, in which families were offered receiving secondary findings (initially assessed in the proband and, if identified, then in the parents). The primary outcome was frequency of accepting secondary findings. Secondary outcomes included frequency of acceptance in prenatal versus pediatric settings, and sociodemographic differences between those who accepted versus declined secondary findings., Results: There were 682 families included in the cohort (289 prenatal and 393 pediatric). Overall, 84% (576/682) of families accepted secondary findings: 86.2% (249/289) of families undergoing prenatal versus 83.2% (327/393) pediatric (p = 0.30) testing. Secondary findings were identified in 2.6% (15/576) of cases, with no difference between prenatal and pediatric settings. There were no differences in sociodemographics between families that accepted versus declined secondary findings., Conclusion: The majority of families undergoing exome sequencing accepted secondary findings; this did not differ in prenatal versus pediatric settings. This highlights the need for guidance surrounding the offer of secondary findings in the prenatal setting., (© 2021 John Wiley & Sons Ltd.)
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- 2022
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21. US private payers' perspectives on insurance coverage for genome sequencing versus exome sequencing: A study by the Clinical Sequencing Evidence-Generating Research Consortium (CSER).
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Phillips KA, Trosman JR, Douglas MP, Gelb BD, Ferket BS, Hindorff LA, Slavotinek AM, Berg JS, Russell HV, Devine B, Greve V, and Smith HS
- Subjects
- Base Sequence, Chromosome Mapping, Humans, Exome Sequencing, Exome genetics, Insurance Coverage
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Purpose: There is limited payer coverage for genome sequencing (GS) relative to exome sequencing (ES) in the U.S. Our objective was to assess payers' considerations for coverage of GS versus coverage of ES and requirements payers have for coverage of GS. The study was conducted by the NIH-funded Clinical Sequencing Evidence-Generating Research Consortium (CSER)., Methods: We conducted semi-structured interviews with representatives of private payer organizations (payers, N = 12) on considerations and evidentiary and other needs for coverage of GS and ES. Data were analyzed using thematic analysis., Results: We described four categories of findings and solutions: demonstrated merits of GS versus ES, enhanced methods for evidence generation, consistent laboratory processes/sequencing methods, and enhanced implementation/care delivery. Payers see advantages to GS vs. ES and are open to broader GS coverage but need more proof of these advantages to consider them in coverage decision-making. Next steps include establishing evidence of benefits in specific clinical scenarios, developing quality standards, ensuring transparency of laboratory methods, developing clinical centers of excellence, and incorporating the role of genetic professionals., Conclusion: By comparing coverage considerations for GS and ES, we identified a path forward for coverage of GS. Future research should explicitly address payers' conditions for coverage., Competing Interests: Conflict of Interest Dr. Phillips receives consulting income from Illumina, Inc, not related to this manuscript. Mr. Douglas receives consulting income from Illumina, Inc, not related to this manuscript. Dr. Slavotinek receives consulting income from UptoDate, Inc and income for editorial duties from John Wiley & Sons, Inc. All other authors: declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
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- 2022
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22. Response to Hamosh et al.
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Biesecker LG, Adam MP, Alkuraya FS, Amemiya AR, Bamshad MJ, Beck AE, Bennett JT, Bird LM, Carey JC, Chung B, Clark RD, Cox TC, Curry C, Dinulos MBP, Dobyns WB, Giampietro PF, Girisha KM, Glass IA, Graham JM Jr, Gripp KW, Haldeman-Englert CR, Hall BD, Innes AM, Kalish JM, Keppler-Noreuil KM, Kosaki K, Kozel BA, Mirzaa GM, Mulvihill JJ, Nowaczyk MJM, Pagon RA, Retterer K, Rope AF, Sanchez-Lara PA, Seaver LH, Shieh JT, Slavotinek AM, Sobering AK, Stevens CA, Stevenson DA, Tan TY, Tan WH, Tsai AC, Weaver DD, Williams MS, Zackai E, and Zarate YA
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- 2021
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23. Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases.
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Rossignol F, Duarte Moreno MS, Benoist JF, Boehm M, Bourrat E, Cano A, Chabrol B, Cosson C, Díaz JLD, D'Harlingue A, Dimmock D, Freeman AF, García MT, Garganta C, Goerge T, Halbach SS, de Laffolie J, Lam CT, Martin L, Martins E, Meinhardt A, Melki I, Ombrello AK, Pérez N, Quelhas D, Scott A, Slavotinek AM, Soares AR, Stein SL, Süßmuth K, Thies J, Ferreira CR, and Schiff M
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- Child, Child, Preschool, Delayed Diagnosis, Humans, Phenotype, Crohn Disease, Leg Ulcer, Prolidase Deficiency diagnosis, Prolidase Deficiency genetics
- Abstract
Purpose: Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. We aim to provide a quantitative description of the natural history of the condition by describing 19 affected individuals and reviewing the literature., Methods: Nineteen patients were phenotyped per local institutional procedures. A systematic review following PRISMA criteria identified 132 articles describing 161 patients. Main outcome analyses were performed for manifestation frequency, diagnostic delay, overall survival, symptom-free survival, and ulcer-free survival., Results: Our cohort presented a wide variability of severity. Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis. Another immune finding was hemophagocytic lymphohistiocytosis (HLH). Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years). Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old., Conclusion: Prolidase deficiency has a broad range of manifestations. Symptoms at onset may be nonspecific, likely contributing to the diagnostic delay. Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)
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- 2021
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24. Third case of Bardet-Biedl syndrome caused by a biallelic variant predicted to affect splicing of IFT74.
- Author
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Mardy AH, Hodoglugil U, Yip T, and Slavotinek AM
- Subjects
- Adult, Alleles, Child, Exome genetics, Fingers abnormalities, Humans, Male, Phenotype, Polydactyly genetics, Retina pathology, Retinal Dystrophies genetics, Toes abnormalities, Exome Sequencing methods, Bardet-Biedl Syndrome genetics, Cytoskeletal Proteins genetics, Genetic Variation genetics, RNA Splicing genetics
- Abstract
Bardet-Biedl syndrome (BBS) is a rare ciliopathy characterized by rod-cone dystrophy, postaxial polydactyly, truncal obesity and renal anomalies with autosomal recessive inheritance. We describe a 6-year-old male with early onset retinal dystrophy, postaxial polydactyly, truncal obesity and motor delays. Exome sequencing revealed a homozygous variant predicted to affect splicing of the IFT74 gene, c.1685-1G > T. This is the third patient with BBS due to variants predicting loss of function in IFT74. All three patients have had retinal dystrophy, polydactyly, obesity, developmental differences, and a notable lack of renal anomalies. We recommend that IFT74 is added to gene panels for the diagnosis of BBS., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2021
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25. Genetic Testing Leading to Early Identification of Childhood Ocular Manifestations of Usher Syndrome.
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Brodie KD, Moore AT, Slavotinek AM, Meyer AK, Nadaraja GS, Conrad DE, Weinstein JE, and Chan DK
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- Adolescent, Child, Child, Preschool, Early Diagnosis, Female, Genotype, Humans, Infant, Male, Phenotype, Eye Diseases genetics, Genetic Testing, Usher Syndromes genetics
- Abstract
Objectives: Hearing-loss gene panel testing (HLGPT) is increasingly accessible as a first-line test in determining the etiology of sensorineural hearing loss (SNHL) in children. A major advantage of HLGPT is early identification of syndromic forms of SNHL, especially Usher syndrome, prior to the development of overt syndromic phenotype, which may impact management and counseling. Here, we describe early ocular findings in children with clinically non-syndromic SNHL identified by HLGPT as having two variants associated with Usher Syndrome., Methods: A total of 184 children, ages 1 month - 15 years of age, evaluated at one tertiary pediatric children's hospital for clinically non-syndromic SNHL, underwent next-generation sequencing of 150 genes involved in hearing loss. Children with two variants in genes associated with Usher syndrome were referred for evaluation by pediatric ophthalmology., Results: A total of 18/184 tested children had two variants in Usher syndrome-associated genes, including MYO7A, GPR98 (ADGRV1), USH2A, and PDZD7. SNHL varied from moderate to profound. 29% of the children who underwent clinical ophthalmology evaluation were found to have previously unidentified retinal abnormalities on retinal imaging or electroretinography consistent with inherited retinal degeneration., Conclusion: Among this ethnically and racially diverse pediatric population with apparently non-syndromic SNHL, HLGPT yielded a high proportion (10%) of children with two variants in genes associated with Usher syndrome. Early genetic testing allows early identification of variants conferring a diagnosis of Usher syndrome at a stage prior to visual symptoms. This allows for more informed genetic counseling, reproductive planning, and sensory deficit interventions., Level of Evidence: 4 Laryngoscope, 131:E2053-E2059, 2021., (© 2021 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)
- Published
- 2021
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26. PHENOTYPIC HETEROGENEITY IN A FAMILY WITH X-LINKED FAMILIAL EXUDATIVE VITREORETINOPATHY WITH PREVENTION OF VISUAL LOSS IN AN AFFECTED MALE CHILD WITH LASER TREATMENT IN INFANCY.
- Author
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Flores Pimentel MA, De la Huerta I, Duncan JL, Slavotinek AM, Moore AT, and de Alba Campomanes AG
- Subjects
- Adult, Child, Familial Exudative Vitreoretinopathies diagnosis, Female, Fluorescein Angiography, Humans, Infant, Male, Mutation, Missense, Pedigree, Phenotype, Retinoscopy, Retrospective Studies, Visual Acuity physiology, Blindness prevention & control, Eye Proteins genetics, Familial Exudative Vitreoretinopathies genetics, Familial Exudative Vitreoretinopathies surgery, Laser Coagulation, Nerve Tissue Proteins genetics, Retinal Detachment surgery, Retinal Hemorrhage surgery
- Abstract
Purpose: To present the scope of prenatal diagnosis and early treatment of patients with clinically heterogeneous phenotypic retinal dysplasia associated with NDP gene variants., Methods: Retrospective. Review of electronic medical records., Results: Twenty-nine-year-old woman known to carry a NDP gene variant presented to the eye clinic for consultation and risk assessment at her second pregnancy. Her 11-year-old son had bilateral retinal detachment, despite surgical treatment. The family declined prenatal testing. The patient was born full term, was examined, and underwent genetic testing after birth. He was found to have bilateral retinal avascular periphery abnormalities and preretinal hemorrhages on the left eye. The patient received bilateral laser treatment at 2 months of age. He was found to be doing well at 16 months after treatment with adequate visual acuity and flat maculae. The asymptomatic mother and maternal grandfather of the proband were found to have retinal periphery abnormalities with unremarkable posterior pole and excellent visual acuity., Conclusion: NDP gene variants associated with X-linked familial exudative vitreoretinopathy phenotype benefit from early treatment. Providers who take care of these patients need to monitor closely the pregnancy and delivery of a male child born to a female carrier to offer appropriate and timely treatment.
- Published
- 2021
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27. A dyadic approach to the delineation of diagnostic entities in clinical genomics.
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Biesecker LG, Adam MP, Alkuraya FS, Amemiya AR, Bamshad MJ, Beck AE, Bennett JT, Bird LM, Carey JC, Chung B, Clark RD, Cox TC, Curry C, Dinulos MBP, Dobyns WB, Giampietro PF, Girisha KM, Glass IA, Graham JM Jr, Gripp KW, Haldeman-Englert CR, Hall BD, Innes AM, Kalish JM, Keppler-Noreuil KM, Kosaki K, Kozel BA, Mirzaa GM, Mulvihill JJ, Nowaczyk MJM, Pagon RA, Retterer K, Rope AF, Sanchez-Lara PA, Seaver LH, Shieh JT, Slavotinek AM, Sobering AK, Stevens CA, Stevenson DA, Tan TY, Tan WH, Tsai AC, Weaver DD, Williams MS, Zackai E, and Zarate YA
- Subjects
- Cystic Fibrosis diagnosis, Cystic Fibrosis genetics, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Genotype, Humans, Mutation genetics, Phenotype, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn genetics, Genomics methods
- Abstract
The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships., (Copyright © 2020 American Society of Human Genetics. All rights reserved.)
- Published
- 2021
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28. The expanding spectrum of NFIB-associated phenotypes in a diverse patient population-A report of two new patients.
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Barrus K, Rego S, Yip T, Martin PM, Glen OA, Van Ziffle J, and Slavotinek AM
- Subjects
- Child, Child, Preschool, Developmental Disabilities genetics, Female, Humans, Intellectual Disability genetics, Male, Muscle Hypotonia genetics, Phenotype, Chromosome Deletion, Developmental Disabilities pathology, Haploinsufficiency, Intellectual Disability pathology, Muscle Hypotonia pathology, NFI Transcription Factors genetics
- Abstract
NFIB (Nuclear Factor I B) haploinsufficiency has recently been identified as a cause of intellectual disability and macrocephaly. Here we describe two patients with pathogenic variants in NFIB. The first is a 6-year-old Latino male with developmental delays, mild hypotonia, facial anomalies, and brain magnetic resonance imaging findings comprising mild thinning of the corpus callosum, with more marked thinning of the splenium and blunting of the rostrum and cavum septum pellucidum. Exome sequencing identified a previously described de novo variant in NFIB, c.265C>T, predicting p.Arg89Ter. The second is a 5-year-old Latino male with developmental delays, hypotonia, dysmorphic features, a preauricular tag and pit, a small ventricular septal defect, and brain magnetic resonance imaging findings including a dysmorphic corpus callosum and a small posterior fossa. A single nucleotide polymorphism microarray identified a 92 kb interstitial deletion at 9p23 including several exons of NFIB and no other known genes. Our two patients add to the knowledge of this rare condition through our addition of new brain MRI findings and dysmorphic features. Additionally, these are the first known Latino patients to be described with NFIB haploinsufficiency, expanding our understanding of the associated facial features in diverse populations. Further data are needed to determine genotype-phenotype relationships for NFIB., (© 2020 Wiley Periodicals LLC.)
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- 2020
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29. Exome sequencing in patients with microphthalmia, anophthalmia, and coloboma (MAC) from a consanguineous population.
- Author
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Islam F, Htun S, Lai LW, Krall M, Poranki M, Martin PM, Sobreira N, Wohler ES, Yu J, Moore AT, and Slavotinek AM
- Subjects
- Anophthalmos pathology, Calcium-Binding Proteins genetics, Cation Transport Proteins genetics, Coloboma pathology, Consanguinity, Exome genetics, Female, High-Throughput Nucleotide Sequencing, Humans, Kinesins genetics, Male, Microphthalmos pathology, Mitochondrial Membrane Transport Proteins genetics, Mutation genetics, Polymorphism, Single Nucleotide genetics, Exome Sequencing, Anophthalmos genetics, Cell Adhesion Molecules genetics, Coloboma genetics, Membrane Proteins genetics, Microphthalmos genetics, Nerve Tissue Proteins genetics, Tumor Suppressor Proteins genetics
- Abstract
Next-generation sequencing strategies have resulted in mutation detection rates of 21% to 61% in small cohorts of patients with microphthalmia, anophthalmia and coloboma (MAC), but despite progress in identifying novel causative genes, many patients remain without a genetic diagnosis. We studied a cohort of 19 patients with MAC who were ascertained from a population with high rates of consanguinity. Using single nucleotide polymorphism (SNP) arrays and whole exome sequencing (WES), we identified one pathogenic variant in TENM3 in a patient with cataracts in addition to MAC. We also detected novel variants of unknown significance in genes that have previously been associated with MAC, including KIF26B, MICU1 and CDON, and identified variants in candidate genes for MAC from the Wnt signaling pathway, comprising LRP6, WNT2B and IQGAP1, but our findings do not prove causality. Plausible variants were not found for many of the cases, indicating that our current understanding of the pathogenesis of MAC, a highly heterogeneous group of ocular defects, remains incomplete., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2020
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30. Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis.
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Sparks TN, Lianoglou BR, Adami RR, Pluym ID, Holliman K, Duffy J, Downum SL, Patel S, Faubel A, Boe NM, Field NT, Murphy A, Laurent LC, Jolley J, Uy C, Slavotinek AM, Devine P, Hodoglugil U, Van Ziffle J, Sanders SJ, MacKenzie TC, and Norton ME
- Subjects
- Female, Humans, Pregnancy, Prognosis, Genetic Variation, Hydrops Fetalis diagnosis, Hydrops Fetalis genetics, Prenatal Diagnosis, Exome Sequencing
- Abstract
Background: The cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear., Methods: We evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited., Results: In 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases., Conclusions: In this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.)., (Copyright © 2020 Massachusetts Medical Society.)
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- 2020
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31. A missense variant, p.(Ile269Asn), in MC4R as a secondary finding in a child with BCL11A-related intellectual disability.
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Beleford DT, Van Ziffle J, Hodoglugil U, and Slavotinek AM
- Subjects
- Child, Preschool, Developmental Disabilities pathology, Female, Humans, Intellectual Disability pathology, Developmental Disabilities genetics, Intellectual Disability genetics, Mutation, Missense, Receptor, Melanocortin, Type 4 genetics, Repressor Proteins genetics
- Abstract
We describe a three year old female who underwent clinical exome sequencing and was diagnosed with BCL11A-related intellectual disability/Dias-Logan syndrome due to a de novo, heterozygous variant in the BCL11A gene, NM_018014.3:c.148C > T; p.(Gln50*). A missense variant in MC4R, NM_005912.3:c.806T > A; p.(Ile269Asn), was also reported as a secondary finding. In her family, her father, paternal aunt, and paternal uncle were all reported to have height and weight measurements suggestive of Class 3 obesity with BMI>40 kg/m
2 . The MC4R gene is not currently listed among those recommended for reporting of secondary findings by the American College of Medical Genetics and Genomics (ACMG). The identification of genetic risk factors for obesity is an emerging field without established guidelines for the care of patients who are found to have a predisposing genetic variant for obesity as a secondary finding. Management suggestions include interventions for weight-management, early screening for obesity-related co-morbidities, such as diabetes and dyslipidemia, and targeted therapies, such as MC4R agonists., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)- Published
- 2020
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32. Announcing a new manuscript category for the American Journal of Medical Genetics Part A: Dispatches from Biotech.
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Solomon BD and Slavotinek AM
- Subjects
- Biotechnology trends, Humans, United States, Genetics, Medical trends, Peer Review, Research trends
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- 2020
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33. Going forward in a new world.
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Slavotinek AM and Solomon BD
- Subjects
- Societies, Medical, Genetics, Medical, Serial Publications
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- 2020
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34. A novel truncating variant in ring finger protein 113A (RNF113A) confirms the association of this gene with X-linked trichothiodystrophy.
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Mendelsohn BA, Beleford DT, Abu-El-Haija A, Alsaleh NS, Rahbeeni Z, Martin PM, Rego S, Huang A, Capodanno G, Shieh JT, Van Ziffle J, Risch N, Alkuraya FS, and Slavotinek AM
- Subjects
- Child, Child, Preschool, Female, Genetic Association Studies, Genetic Diseases, X-Linked diagnosis, Genetic Diseases, X-Linked pathology, Humans, Male, Mutation genetics, Trichothiodystrophy Syndromes diagnosis, Trichothiodystrophy Syndromes pathology, X Chromosome Inactivation genetics, DNA-Binding Proteins genetics, Genetic Diseases, X-Linked genetics, Genetic Predisposition to Disease, Trichothiodystrophy Syndromes genetics
- Abstract
We describe an 11-year old boy with severe global developmental delays, failure to thrive and growth retardation, refractory seizures with recurrent status epilepticus, hypogammaglobulinemia, hypergonadotropic hypogonadism, and duodenal strictures. He had facial and skin findings compatible with trichothiodystrophy, including sparse and brittle hair, thin eyebrows, and dry skin. Exome sequencing showed a hemizygous, truncating variant in RNF113A, c.903_910delGCAGACCA, predicting p.(Gln302fs*12), that was inherited from his mother. Although his clinical features overlap closely with features described in the two previously reported male first cousins with RNF113A loss of function mutations, the duodenal strictures seen in this patient have not been reported. Interestingly, the patient's mother had short stature and 100% skewed X-inactivation as seen in other obligate female carriers. A second male with developmental delays, microcephaly, seizures, ambiguous genitalia, and facial anomalies that included sparse and brittle hair, thin eyebrows and dry skin was recently reported to have c.897_898delTG, predicting p.(Cys299*) in RNF113A and we provide additional clinical details for this patient. This report further supports deleterious variants in RNF113A as a cause of a novel trichothiodystrophy syndrome., (© 2019 Wiley Periodicals, Inc.)
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- 2020
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35. Case Report of Floating-Harbor Syndrome With Bilateral Cleft Lip.
- Author
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Ko J, Pomerantz JH, Perry H, Shieh JT, Slavotinek AM, Oberoi S, and Klein OD
- Subjects
- Adenosine Triphosphatases, Growth Disorders, Heart Septal Defects, Ventricular, Humans, Abnormalities, Multiple, Cleft Lip, Cleft Palate, Craniofacial Abnormalities
- Abstract
Floating-Harbor syndrome (FHS) is a rare genetic disorder caused by heterozygous mutations in the Snf2-related CREBBP activator protein ( SRCAP ) gene. The syndrome is characterized by proportional short stature, delayed bone maturation, delayed speech development, and facial dysmorphism. Submucous cleft palate and cleft lip have been reported in FHS, but to our knowledge orofacial clefting in this condition has not been assessed in detail. Here, we report on a case of bilateral cleft lip in a patient with FHS confirmed by exome sequencing.
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- 2020
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36. Developmental and epileptic encephalopathy in two siblings with a novel, homozygous missense variant in SCN1B.
- Author
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Darras N, Ha TK, Rego S, Martin PM, Barroso E, Slavotinek AM, and Cilio MR
- Subjects
- Alleles, Amino Acid Substitution, Child, Preschool, Electroencephalography, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Magnetic Resonance Imaging, Male, Phenotype, Exome Sequencing, Epilepsy diagnosis, Epilepsy genetics, Homozygote, Mutation, Missense, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders genetics, Voltage-Gated Sodium Channel beta-1 Subunit genetics
- Abstract
Developmental and epileptic encephalopathies are genetic disorders in which both the developmental disability and the frequent epileptic activity are the effect of a specific gene variant. While heterozygous variants in SCN1B have been described in families with generalized epilepsy with febrile seizures plus, Type 1, only three cases of homozygous, missense variants in SCN1B have been reported in association with autosomal recessive inheritance of a severe developmental and epileptic encephalopathy. We present two siblings who are homozygous for a novel, missense variant in SCN1B, c.265C>T, predicting p.Arg89Cys. The proband is an 11-year-old female with infantile-onset, fever-induced, intractable generalized tonic-clonic seizures, myoclonic seizures, and developmental slowing and autism spectrum disorder occurring later in the course of the disease. Her 4-year-old brother had a similar epilepsy phenotype, but still displays normal development. This variant has not been previously reported in the homozygous state in control databases. The variant was predicted to be damaging and occurred in the vicinity of other epileptic encephalopathy-associated missense variants that are biallelic and located in the extracellular immunoglobulin loop domain of the protein, which mediates interaction of the beta-1 subunit with cellular adhesion molecules. Our report is the first set of siblings with homozygosity for the p.Arg89Cys variant in SCN1B and further implicates biallelic mutations in this gene as a cause of epileptic encephalopathy mimicking Dravet syndrome. Interestingly, the phenotype we observed was milder compared to that previously described in patients with recessive SCN1B mutations., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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37. De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia.
- Author
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Kanca O, Andrews JC, Lee PT, Patel C, Braddock SR, Slavotinek AM, Cohen JS, Gubbels CS, Aldinger KA, Williams J, Indaram M, Fatemi A, Yu TW, Agrawal PB, Vezina G, Simons C, Crawford J, Lau CC, Chung WK, Markello TC, Dobyns WB, Adams DR, Gahl WA, Wangler MF, Yamamoto S, Bellen HJ, and Malicdan MCV
- Published
- 2019
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38. Introducing in AJMG Part A: Genetic Syndromes in Adults.
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Slavotinek AM and Muenke M
- Subjects
- Adult, Genetic Diseases, Inborn genetics, Genetic Diseases, Inborn pathology, Humans, Periodicals as Topic, Syndrome, Editorial Policies, Genetic Diseases, Inborn diagnosis, Genetics, Medical
- Published
- 2019
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39. NAA10 polyadenylation signal variants cause syndromic microphthalmia.
- Author
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Johnston JJ, Williamson KA, Chou CM, Sapp JC, Ansari M, Chapman HM, Cooper DN, Dabir T, Dudley JN, Holt RJ, Ragge NK, Schäffer AA, Sen SK, Slavotinek AM, FitzPatrick DR, Glaser TM, Stewart F, Black GC, and Biesecker LG
- Subjects
- Alleles, Anophthalmos, Female, Genes, X-Linked, Genotype, Humans, Lod Score, Male, Microphthalmos, Pedigree, Sequence Analysis, DNA, X Chromosome Inactivation, 3' Untranslated Regions, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, N-Terminal Acetyltransferase A genetics, N-Terminal Acetyltransferase E genetics, Poly A
- Abstract
Background: A single variant in NAA10 (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia., Methods: Three families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in NAA10 were evaluated using quantitative PCR and RNAseq., Results: Genetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included NAA10 . Exome sequencing identified a hemizygous NAA10 polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct NAA10 PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced NAA10 mRNA levels and abnormal 3' UTRs in affected individuals. Targeted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the PAS., Conclusion: These data show that PAS variants are the most common variant type in NAA10 -associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that NAA10 harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yields., Competing Interests: Competing interests: LGB receives royalties from Genentech Corp, is an advisor to the Illumina Corp, received honoraria from Wiley-Blackwell and receives honoraria from Cold Spring Harbor Press. DNC is in receipt of funding from Qiagen Inc through a License Agreement with Cardiff University. AMS receives honoraria from Wiley-Blackwell, Inc, Oxford University Press and UptoDate, Inc., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2019
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40. The Genomic Medicine Integrative Research Framework: A Conceptual Framework for Conducting Genomic Medicine Research.
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Horowitz CR, Orlando LA, Slavotinek AM, Peterson J, Angelo F, Biesecker B, Bonham VL, Cameron LD, Fullerton SM, Gelb BD, Goddard KAB, Hailu B, Hart R, Hindorff LA, Jarvik GP, Kaufman D, Kenny EE, Knight SJ, Koenig BA, Korf BR, Madden E, McGuire AL, Ou J, Wasserstein MP, Robinson M, Leventhal H, and Sanderson SC
- Subjects
- Humans, Models, Theoretical, Biomedical Research, Delivery of Health Care, Integrated, Genetics, Medical, Genomics methods, Precision Medicine methods, Rare Diseases genetics, Research Design
- Abstract
Conceptual frameworks are useful in research because they can highlight priority research domains, inform decisions about interventions, identify outcomes and factors to measure, and display how factors might relate to each other to generate and test hypotheses. Discovery, translational, and implementation research are all critical to the overall mission of genomic medicine and prevention, but they have yet to be organized into a unified conceptual framework. To fill this gap, our diverse team collaborated to develop the Genomic Medicine Integrative Research (GMIR) Framework, a simple but comprehensive tool to aid the genomics community in developing research questions, strategies, and measures and in integrating genomic medicine and prevention into clinical practice. Here we present the GMIR Framework and its development, along with examples of its use for research development, demonstrating how we applied it to select and harmonize measures for use across diverse genomic medicine implementation projects. Researchers can utilize the GMIR Framework for their own research, collaborative investigations, and clinical implementation efforts; clinicians can use it to establish and evaluate programs; and all stakeholders can use it to help allocate resources and make sure that the full complexity of etiology is included in research and program design, development, and evaluation., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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41. Biallelic sequence variants in INTS1 in patients with developmental delays, cataracts, and craniofacial anomalies.
- Author
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Krall M, Htun S, Schnur RE, Brooks AS, Baker L, de Alba Campomanes A, Lamont RE, Gripp KW, Schneidman-Duhovny D, Innes AM, Mancini GMS, and Slavotinek AM
- Subjects
- Adolescent, Adult, Animals, Cataract physiopathology, Child, Child, Preschool, Craniofacial Abnormalities physiopathology, Developmental Disabilities physiopathology, Female, Frameshift Mutation genetics, Gastrulation genetics, Humans, Infant, Lens, Crystalline growth & development, Lens, Crystalline pathology, Male, Mutation, Missense genetics, Pedigree, Protein Folding, Exome Sequencing, Wnt1 Protein chemistry, Young Adult, Zebrafish genetics, Cataract genetics, Craniofacial Abnormalities genetics, Developmental Disabilities genetics, Wnt1 Protein genetics
- Abstract
The Integrator complex subunit 1 (INTS1) is a component of the integrator complex that comprises 14 subunits and associates with RPB1 to catalyze endonucleolytic cleavage of nascent snRNAs and assist RNA polymerase II in promoter-proximal pause-release on protein-coding genes. We present five patients, including two sib pairs, with biallelic sequence variants in INTS1. The patients manifested absent or severely limited speech, an abnormal gait, hypotonia and cataracts. Exome sequencing revealed biallelic variants in INTS1 in all patients. One sib pair demonstrated a missense variant, p.(Arg77Cys), and a frameshift variant, p.(Arg1800Profs*20), another sib pair had a homozygous missense variant, p.(Pro1874Leu), and the fifth patient had a frameshift variant, p.(Leu1764Cysfs*16) and a missense variant, p.(Leu2164Pro). We also report additional clinical data on three previously described individuals with a homozygous, loss of function variant, p.(Ser1784*) in INTS1 that shared cognitive delays, cataracts and dysmorphic features with these patients. Several of the variants affected the protein C-terminus and preliminary modeling showed that the p.(Pro1874Leu) and p.(Leu2164Pro) variants may interfere with INTS1 helix folding. In view of the cataracts observed, we performed in-situ hybridization and demonstrated expression of ints1 in the zebrafish eye. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 to make larvae with biallelic insertion/deletion (indel) variants in ints1. The mutant larvae developed typically through gastrulation, but sections of the eye showed abnormal lens development. The distinctive phenotype associated with biallelic variants in INTS1 points to dysfunction of the integrator complex as a mechanism for intellectual disability, eye defects and craniofacial anomalies.
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- 2019
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42. Private payer coverage policies for exome sequencing (ES) in pediatric patients: trends over time and analysis of evidence cited.
- Author
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Douglas MP, Parker SL, Trosman JR, Slavotinek AM, and Phillips KA
- Subjects
- Child, Cost-Benefit Analysis economics, Humans, Insurance Coverage economics, Neurodevelopmental Disorders pathology, Exome genetics, Neurodevelopmental Disorders economics, Neurodevelopmental Disorders genetics, Exome Sequencing economics
- Abstract
Purpose: Exome sequencing (ES) is being adopted for neurodevelopmental disorders in pediatric patients. However, little is known about current coverage policies or the evidence cited supporting these policies. Our study is the first in-depth review of private payer ES coverage policies for pediatric patients with neurodevelopmental disorders., Methods: We reviewed private payer coverage policies and examined evidence cited in the policies of the 15 largest payers in 2017, and trends in coverage policies and evidence cited (2015-2017) for the five largest payers., Results: There were four relevant policies (N = 5 payers) in 2015 and 13 policies (N = 15 payers) in 2017. In 2015, no payer covered ES, but by 2017, three payers from the original registry payers did. In 2017, 8 of the 15 payers covered ES. We found variations in the number and types of evidence cited. Positive coverage policies tended to include a larger number and range of citations., Conclusion: We conclude that more systematic assessment of evidence cited in coverage policies can provide a greater understanding of coverage policies and how evidence is used. Such assessments could facilitate the ability of researchers to provide the needed evidence, and the ability of clinicians to provide the most appropriate testing for patients.
- Published
- 2019
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43. Two patients with FOXF1 mutations with alveolar capillary dysplasia with misalignment of pulmonary veins and other malformations: Two different presentations and outcomes.
- Author
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Abu-El-Haija A, Fineman J, Connolly AJ, Murali P, Judge LM, and Slavotinek AM
- Subjects
- Autopsy, Biomarkers, Biopsy, Comparative Genomic Hybridization, Cytogenetic Analysis, Echocardiography, Female, Genetic Association Studies, Humans, Infant, Male, Phenotype, Polymorphism, Single Nucleotide, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Forkhead Transcription Factors genetics, Mutation, Persistent Fetal Circulation Syndrome diagnosis, Persistent Fetal Circulation Syndrome genetics, Pulmonary Alveoli abnormalities, Pulmonary Veins abnormalities
- Abstract
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) describes a group of developmental disorders affecting the lungs with its pulmonary vasculature. Mutations in the FOXF1 gene have been reported in most cases, and extrapulmonary findings were described. We present two patients with ACDMPV and FOXF1 mutations that illustrate the variability in presentation and outcome of their disease. Patient 1 was a full-term infant with imperforate anus and pulmonary hypertension. He required Extracorporeal Membrane Oxygenation on day of life (DOL) 3, and passed away on DOL 13 after no clinical improvement. Postmortem findings were consistent with ACDMPV. FOXF1 testing revealed a heterozygous pathogenic frameshift de novo mutation, c.1057_1078dup, p.(Gly360Valfs*58). Patient 2 is a 6-month-old female, with a small omphalocele. She had intermittent retractions at 1 week of age. She was admitted with pulmonary hypertension at 7 weeks of age. Lung biopsy confirmed ACDMPV. FOXF1 testing revealed a de novo, heterozygous likely pathogenic missense mutation c.253T>C, p.(Phe85Leu]). Our two patients had different presentations, ages of onset, and progression of their disease. Our second patient had patchy lung involvement on biopsy, which may explain the relatively delayed onset and longer survival. ACDMPV is an important consideration for full-term infants with worsening pulmonary hypertension early in life., (© 2018 Wiley Periodicals, Inc.)
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- 2018
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44. Evidence-based assessments of clinical actionability in the context of secondary findings: Updates from ClinGen's Actionability Working Group.
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Webber EM, Hunter JE, Biesecker LG, Buchanan AH, Clarke EV, Currey E, Dagan-Rosenfeld O, Lee K, Lindor NM, Martin CL, Milosavljevic A, Mittendorf KF, Muessig KR, O'Daniel JM, Patel RY, Ramos EM, Rego S, Slavotinek AM, Sobriera NLM, Weaver MA, Williams MS, Evans JP, and Goddard KAB
- Subjects
- Databases, Genetic, Exome genetics, Genetic Testing, Genetic Variation genetics, High-Throughput Nucleotide Sequencing, Humans, Genome, Human genetics
- Abstract
The use of genome-scale sequencing allows for identification of genetic findings beyond the original indication for testing (secondary findings). The ClinGen Actionability Working Group's (AWG) protocol for evidence synthesis and semi-quantitative metric scoring evaluates four domains of clinical actionability for potential secondary findings: severity and likelihood of the outcome, and effectiveness and nature of the intervention. As of February 2018, the AWG has scored 127 genes associated with 78 disorders (up-to-date topics/scores are available at www.clinicalgenome.org). Scores across these disorders were assessed to compare genes/disorders recommended for return as secondary findings by the American College of Medical Genetics and Genomics (ACMG) with those not currently recommended. Disorders recommended by the ACMG scored higher on outcome-related domains (severity and likelihood), but not on intervention-related domains (effectiveness and nature of the intervention). Current practices indicate that return of secondary findings will expand beyond those currently recommended by the ACMG. The ClinGen AWG evidence reports and summary scores are not intended as classifications of actionability, rather they provide a resource to aid decision makers as they determine best practices regarding secondary findings. The ClinGen AWG is working with the ACMG Secondary Findings Committee to update future iterations of their secondary findings list., (© Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)
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- 2018
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45. The Clinical Sequencing Evidence-Generating Research Consortium: Integrating Genomic Sequencing in Diverse and Medically Underserved Populations.
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Amendola LM, Berg JS, Horowitz CR, Angelo F, Bensen JT, Biesecker BB, Biesecker LG, Cooper GM, East K, Filipski K, Fullerton SM, Gelb BD, Goddard KAB, Hailu B, Hart R, Hassmiller-Lich K, Joseph G, Kenny EE, Koenig BA, Knight S, Kwok PY, Lewis KL, McGuire AL, Norton ME, Ou J, Parsons DW, Powell BC, Risch N, Robinson M, Rini C, Scollon S, Slavotinek AM, Veenstra DL, Wasserstein MP, Wilfond BS, Hindorff LA, Plon SE, and Jarvik GP
- Subjects
- Adult, Cost-Benefit Analysis methods, Delivery of Health Care methods, Europe, Exome genetics, Genomics methods, Humans, National Human Genome Research Institute (U.S.), Phenotype, United States, Whole Genome Sequencing methods, Genome, Human genetics
- Abstract
The Clinical Sequencing Evidence-Generating Research (CSER) consortium, now in its second funding cycle, is investigating the effectiveness of integrating genomic (exome or genome) sequencing into the clinical care of diverse and medically underserved individuals in a variety of healthcare settings and disease states. The consortium comprises a coordinating center, six funded extramural clinical projects, and an ongoing National Human Genome Research Institute (NHGRI) intramural project. Collectively, these projects aim to enroll and sequence over 6,100 participants in four years. At least 60% of participants will be of non-European ancestry or from underserved settings, with the goal of diversifying the populations that are providing an evidence base for genomic medicine. Five of the six clinical projects are enrolling pediatric patients with various phenotypes. One of these five projects is also enrolling couples whose fetus has a structural anomaly, and the sixth project is enrolling adults at risk for hereditary cancer. The ongoing NHGRI intramural project has enrolled primarily healthy adults. Goals of the consortium include assessing the clinical utility of genomic sequencing, exploring medical follow up and cascade testing of relatives, and evaluating patient-provider-laboratory level interactions that influence the use of this technology. The findings from the CSER consortium will offer patients, healthcare systems, and policymakers a clearer understanding of the opportunities and challenges of providing genomic medicine in diverse populations and settings, and contribute evidence toward developing best practices for the delivery of clinically useful and cost-effective genomic sequencing in diverse healthcare settings., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)
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- 2018
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46. Correction to: A zebrafish model of foxe3 deficiency demonstrates lens and eye defects with dysregulation of key genes involved in cataract formation in humans.
- Author
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Krall M, Htun S, Anand D, Hart D, Lachke SA, and Slavotinek AM
- Abstract
The authors noticed that Fig. 5A and B aspect ratios appeared sub-optimal in the online published version. This has now been changed.
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- 2018
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47. Natural history and genotype-phenotype correlations in 72 individuals with SATB2-associated syndrome.
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Zarate YA, Smith-Hicks CL, Greene C, Abbott MA, Siu VM, Calhoun ARUL, Pandya A, Li C, Sellars EA, Kaylor J, Bosanko K, Kalsner L, Basinger A, Slavotinek AM, Perry H, Saenz M, Szybowska M, Wilson LC, Kumar A, Brain C, Balasubramanian M, Dubbs H, Ortiz-Gonzalez XR, Zackai E, Stein Q, Powell CM, Schrier Vergano S, Britt A, Sun A, Smith W, Bebin EM, Picker J, Kirby A, Pinz H, Bombei H, Mahida S, Cohen JS, Fatemi A, Vernon HJ, McClellan R, Fleming LR, Knyszek B, Steinraths M, Velasco Gonzalez C, Beck AE, Golden-Grant KL, Egense A, Parikh A, Raimondi C, Angle B, Allen W, Schott S, Algrabli A, Robin NH, Ray JW, Everman DB, Gambello MJ, and Chung WK
- Subjects
- Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Adolescent, Adult, Child, Child, Preschool, Facies, Female, Humans, Infant, Inheritance Patterns, Male, Polymorphism, Single Nucleotide, Syndrome, Young Adult, Genetic Association Studies methods, Genetic Predisposition to Disease, Genotype, Matrix Attachment Region Binding Proteins genetics, Phenotype, Transcription Factors genetics
- Abstract
SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance., (© 2018 Wiley Periodicals, Inc.)
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- 2018
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48. A zebrafish model of foxe3 deficiency demonstrates lens and eye defects with dysregulation of key genes involved in cataract formation in humans.
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Krall M, Htun S, Anand D, Hart D, Lachke SA, and Slavotinek AM
- Subjects
- Amino Acid Sequence genetics, Animals, Aphakia genetics, Aphakia physiopathology, Cataract physiopathology, Disease Models, Animal, Glutamate-Ammonia Ligase genetics, Homozygote, Humans, Lens, Crystalline physiopathology, Membrane Proteins genetics, Microphthalmos genetics, Microphthalmos physiopathology, Phenotype, Zebrafish genetics, Cataract genetics, Eye Proteins genetics, Forkhead Transcription Factors genetics, Zebrafish Proteins genetics
- Abstract
The Forkhead box E3 (FOXE3) gene encodes a transcription factor with a forkhead/winged helix domain that is critical for development of the lens and anterior segment of the eye. Monoallelic and biallelic deleterious sequence variants in FOXE3 cause aphakia, cataracts, sclerocornea and microphthalmia in humans. We used clustered regularly interspaced short palindromic repeats/Cas9 injections to target the foxe3 transcript in zebrafish in order to create an experimental model of loss of function for this gene. Larvae that were homozygous for an indel variant, c.296_300delTGCAG, predicting p.(Val99Alafs*2), demonstrated severe eye defects, including small or absent lenses and microphthalmia. The lenses of the homozygous foxe3 indel mutants showed more intense staining with zl-1 antibody compared to control lenses, consistent with increased lens fiber cell differentiation. Whole genome transcriptome analysis (RNA-Seq) on RNA isolated from wildtype larvae and larvae with eye defects that were putative homozygotes for the foxe3 indel variant found significant dysregulation of genes expressed in the lens and eye whose orthologues are associated with cataracts in human patients, including cryba2a, cryba1l1, mipa and hsf4. Comparative analysis of this RNA-seq data with iSyTE data identified several lens-enriched genes to be down-regulated in foxe3 indel mutants. We also noted upregulation of lgsn and crygmxl2 and downregulation of fmodb and cx43.4, genes that are expressed in the zebrafish lens, but that are not yet associated with an eye phenotype in humans. These findings demonstrate that this new zebrafish foxe3 mutant model is highly relevant to the study of the gene regulatory networks conserved in vertebrate lens and eye development.
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- 2018
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49. Inner retinal dystrophy in a patient with biallelic sequence variants in BRAT1.
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Oatts JT, Duncan JL, Hoyt CS, Slavotinek AM, and Moore AT
- Subjects
- Developmental Disabilities diagnosis, Developmental Disabilities genetics, Electroretinography, Esotropia diagnosis, Esotropia genetics, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Microcephaly diagnosis, Microcephaly genetics, Nystagmus, Pathologic diagnosis, Nystagmus, Pathologic genetics, Retinal Dystrophies diagnosis, Frameshift Mutation, Mutation, Missense, Nuclear Proteins genetics, Retinal Dystrophies genetics
- Abstract
Background: Mutations in the BRCA1-associated protein required for the ataxia telangiectasia mutated (ATM) activation-1 (BRAT1) gene cause lethal neonatal rigidity and multifocal seizure syndrome characterized by rigidity and intractable seizures and a milder phenotype with intellectual disability, seizures, nonprogressive cerebellar ataxia or dyspraxia, and cerebellar atrophy. To date, nystagmus, cortical visual impairment, impairment of central vision, optic nerve hypoplasia, and optic atrophy have been described in this condition. This article describes the retinal findings in a patient with biallelic deleterious sequence variants in BRAT1., Materials and Methods: Case report of a child with biallelic sequence variants in the BRAT1 gene., Results: This patient had developmental delay, microcephaly, nystagmus, and esotropia, and full-field electroretinography (ERG) revealed an inner retinal dystrophy. She was found on exome sequencing to have compound heterozygous sequence variants in the BRAT1 gene: one maternally inherited frameshift variant (c.294dupA, predicting p.Leu99Thrfs*92), which has previously been reported, and one paternally inherited novel missense variant (c.803G>A, p.Arg268His), which is likely to affect protein function., Conclusions: Biallelic sequence variants in BRAT1 have been reported to cause a variety of ocular and systemic manifestations, but to our knowledge, this is the first report of inner retinal dysfunction manifest as selective loss of full-field ERG scotopic and photopic b-wave amplitudes.
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- 2017
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50. Clinical Report: Warsaw Breakage Syndrome with small radii and fibulae.
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Eppley S, Hopkin RJ, Mendelsohn B, and Slavotinek AM
- Subjects
- Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Abnormalities, Multiple physiopathology, Adolescent, Child, Chromosome Breakage, Fanconi Anemia diagnosis, Fanconi Anemia genetics, Fanconi Anemia physiopathology, Female, Genetic Predisposition to Disease, Gonadal Dysgenesis diagnosis, Gonadal Dysgenesis physiopathology, Hearing Loss, Sensorineural diagnosis, Hearing Loss, Sensorineural physiopathology, Humans, Intellectual Disability diagnosis, Intellectual Disability physiopathology, Mutation, Phenotype, DEAD-box RNA Helicases genetics, DNA Helicases genetics, Gonadal Dysgenesis genetics, Hearing Loss, Sensorineural genetics, Intellectual Disability genetics
- Abstract
We present two new cases of Warsaw Breakage Syndrome (WABS), an autosomal recessive cohesinopathy, in sisters aged 13 and 11 years who both had compound heterozygous mutations in DDX11. After exclusion of Fanconi anemia, Bloom syndrome and Nijmegen breakage syndrome, whole exome sequencing revealed two novel variants-c.1523T>G, predicting (p.Leu508Arg) and c.1949-1G>A (IVS19-1G>A), that were confirmed with Sanger sequencing in both affected individuals. DDX11 encodes an iron-sulfur-containing DNA helicase, and mutations in this gene have been reported in the five WABS cases previously identified to date. The sisters reported here display the distinguishing clinical features of WABS: pre- and post-natal growth restriction, microcephaly, intellectual disability, sensorineural hearing loss with cochlear abnormalities, and facial dysmorphic features. In addition, our cases had early menarche at 8 and 10 years of age, bilateral small thumbs, and the younger, more severely affected sister had small fibulae. These findings broaden the WABS phenotype and the limb malformations demonstrate further clinical overlap with Fanconi anemia and other cohesinopathies, such as Roberts Syndrome., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
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