279 results on '"Phillips JA 3rd"'
Search Results
2. Telomerase mutations in families with idiopathic pulmonary fibrosis.
- Author
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Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA 3rd, Lansdorp PM, Greider CW, Loyd JE, Armanios, Mary Y, Chen, Julian J-L, Cogan, Joy D, Alder, Jonathan K, Ingersoll, Roxann G, Markin, Cheryl, and Lawson, William E
- Abstract
Background: Idiopathic pulmonary fibrosis is progressive and often fatal; causes of familial clustering of the disease are unknown. Germ-line mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase and telomerase RNA, respectively, cause autosomal dominant dyskeratosis congenita, a rare hereditary disorder associated with premature death from aplastic anemia and pulmonary fibrosis.Methods: To test the hypothesis that familial idiopathic pulmonary fibrosis may be caused by short telomeres, we screened 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for mutations in hTERT and hTR.Results: Six probands (8%) had heterozygous mutations in hTERT or hTR; mutant telomerase resulted in short telomeres. Asymptomatic subjects with mutant telomerase also had short telomeres, suggesting that they may be at risk for the disease. We did not identify any of the classic features of dyskeratosis congenita in five of the six families.Conclusions: Mutations in the genes encoding telomerase components can appear as familial idiopathic pulmonary fibrosis. Our findings support the idea that pathways leading to telomere shortening are involved in the pathogenesis of this disease. [ABSTRACT FROM AUTHOR]- Published
- 2007
3. An improved polymerase chain reaction (PCR) protocol for unambigous detection of growth hormone gene deletions
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Vincenzo Nigro, A.M. Sinisi, Gherardo Mazziotti, C. M. Mone, John A. Phillips, Mario Rotondi, A. Del Buono, Carlo Carella, M. Riondino, L. Ghizzoni, Antonio Bellastella, Mone, Cm, Nigro, Vincenzo, Rotondi, M, DEL BUONO, A, Mazziotti, G, Riondino, M, Sinisi, Am, Ghizzoni, L, PHILLIPS JA, 3rd, Bellastella, A, and Carella, C.
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Endocrinology, Diabetes and Metabolism ,Genetic Carrier Screening ,Polymerase Chain Reaction ,DNA sequencing ,SmaI ,law.invention ,Endonuclease ,Endocrinology ,law ,Ethidium ,Homologous chromosome ,Medicine ,Humans ,Gene ,Polymerase chain reaction ,Fluorescent Dyes ,Genetics ,biology ,business.industry ,Human Growth Hormone ,Homozygote ,Molecular biology ,Pediatrics, Perinatology and Child Health ,biology.protein ,business ,Nested polymerase chain reaction ,Gene Deletion - Abstract
hGH-1 gene deletions are detected by simultaneous PCR amplification along the two homologous DNA sequences flanking the hGH-1 gene on both sides and are differentiated by SmaI restriction enzyme digestion. We have observed that among the SmaI digested PCR products from normal homozygous subjects, from those heterozygous for the 7.6 kb deletion and from those heterozygous for a 6.7 kb deletion, along with the expected fragments there is an unexpected 1470 bp fragment. This fragment arises from the co-amplification of a third homologous sequence located downstream from the hGH-1 gene and it confuses differentiation between normal homozygous and heterozygous for 7.6 kb subjects from the 6.7 kb heterozygous subjects. To overcome this problem we have improved PCR conditions using a different reverse primer. These changes avoid the interaction of the primers with the third homologous sequence located downstream from the hGH-1 gene and prevent the appearance of this additional band that complicates the interpretation of the results. We conclude that the new reverse primer sequence avoids the amplification of the downstream hGH-1 gene sequence and the production of the 1474 bp band after SmaI endonuclease enzyme digestion and makes it possible to differentiate homozygous normal subjects and those who are heterozygous for a 7.6 kb deletion from those who are heterozygous for a 6.7 kb deletion.
- Published
- 1998
4. A review of multiple diagnostic approaches in the undiagnosed diseases network to identify inherited metabolic diseases.
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Furuta Y, Tinker RJ, Hamid R, Cogan JD, Ezell KM, Oglesbee D, DeBerardinis RJ, and Phillips JA 3rd
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- Humans, Retrospective Studies, High-Throughput Nucleotide Sequencing methods, Metabolism, Inborn Errors diagnosis, Metabolism, Inborn Errors genetics, Metabolic Diseases diagnosis, Metabolic Diseases genetics, Undiagnosed Diseases diagnosis
- Abstract
Background: The number of known inherited metabolic diseases (IMDs) has been expanding, and the rate of diagnosis is improving with the development of innovative approaches including next generation sequencing (NGS). However, a substantial proportion of IMDs remain undetected by traditional diagnostic approaches. We aim to highlight the spectrum of IMDs diagnosed by the Undiagnosed Diseases Network (UDN) and to learn from the UDN diagnostic processes that were able to detect IMDs., Methods: We conducted a retrospective analysis of 757 UDN participants diagnosed from 2015 until 2023 using the cohort database, which were divided into a cohort with IMDs (n = 194; 27%) and a cohort whose phenotypes were not explained by an IMD (n = 563; 73%), based on the International Classification of Inherited Metabolic Disorders (ICIMD). Then, we divided the causes of the metabolic 194 diagnoses into seven groups that included all the ICIMD categories. We inspected which clinical and laboratory approaches contributed to a final UDN diagnosis. We also present a UDN case example from each group to highlight the diagnostic yields that resulted from combining newer diagnostic approaches in the UDN and illustrate potential pitfalls of current NGS methods., Results: These 194 cases of IMDs included examples from 21/25 (84%) of the ICIMD categories. Of the UDN subjects 164/194 (85%) were diagnosed with IMDs through NGS., Conclusion: The spectrum of IMDs detected in the UDN cohort is large and growing and appropriate use of newer multiple diagnostic approaches should further increase diagnosis of IMDs that are presently missed by the traditional laboratory screening methods., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests There are no conflicts of interest to declare., (© 2024. The Author(s).)
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- 2024
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5. Advancing Equity in Rare Disease Research: Insights From the Undiagnosed Disease Network.
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Borja NA, Tinker RJ, Bivona SA, Smith CA, Locker TK, Fernandes S, Phillips JA 3rd, Stoler J, Taylor H, Zuchner S, and Tekin M
- Abstract
Rare diseases affect 6%-8% of the population and present diagnostic challenges, particularly for historically marginalized ethnic and racial groups. The Undiagnosed Diseases Network (UDN) aims to enhance diagnosis rates and research participation among such minoritized groups. A retrospective review was conducted from 2015 to 2023, analyzing 2235 UDN participants to evaluate its progress toward this objective. Data on demographics, disease phenotypes, diagnostic outcomes, and socioeconomic factors were collected and statistical analyses assessed differences among ethnic and racial groups. This demonstrated that Hispanic and Black non-Hispanic groups were underrepresented, while White non-Hispanic participants were overrepresented in the UDN compared to the US population. Individuals whose primary language was not English were also significantly underrepresented. Diagnosis rates varied, with the highest rates among Asian non-Hispanic (39.5%) and Hispanic (35.3%) groups and the lowest rate in the White non-Hispanic group (26.8%) (p < 0.001). Binomial logistic regression found, however, that only participant age and disease phenotype predicted the likelihood of receiving a diagnosis (p < 0.001). Persistent ethnic and racial disparities in UDN participation appear to be associated with major differences in application rates. Under-enrollment of historically marginalized ethnic and racial groups may be due to economic hardships and language barriers. No differences in the diagnostic yield among ethnic and racial groups were observed after controlling for other factors. This work highlights the value of comprehensive genetic evaluations for addressing healthcare disparities and suggests priorities for advancing inclusion in rare disease research., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
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- 2024
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6. Review and metabolomic profiling of unsolved case reveals newly reported autosomal dominant congenital disorder of glycosylation, type Iw formerly thought to only be an autosomal recessive condition.
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Ezell KM, Furuta Y, Oglesbee D, Pivnick EK, Rinker D, Sheehan JH, Tinker RJ, Hamid R, Cogan JD, Rives L, Neumann S, Corner B, Koziura M, and Phillips JA 3rd
- Abstract
Autosomal dominant congenital disorder of glycosylation (CDG) type Iw (OMIM# 619714) is caused by a heterozygous mutation in the STT3A gene. Most CDGs have an autosomal recessive (AR) mode of inheritance, but several cases with an autosomal dominant (AD) form of an AR CDG have been recently identified. This report describes a 17-year-old male who was referred to the Undiagnosed Diseases Network (UDN) with a history of macrocephaly, failure to thrive, short stature, epilepsy, autism, attention-deficit/hyperactivity disorder, mild developmental delay, intermittent hypotonia, dysmorphic features, and mildly enlarged aortic root. Trio exome sequencing was negative. His biochemical workup included normal plasma amino acids, ammonia, acylcarnitine profile and urine organic and amino acids. His UDN genome sequencing (GS) identified a previously unreported de novo STT3A variant (c.1631A > G: p.Asn544Ser). This variant removes a glycosylation site and was predicted to be destabilizing by structural biology modeling. The patient was formally diagnosed by the UDN Metabolomics Core as having an abnormal transferrin profile indicative of CDG type Iw through metabolomic profiling. We report here an affected male with phenotypic, molecular, and metabolic findings consistent with CDG type Iw due to a heterozygous STT3A variant. This case highlights the importance of further testing of individuals with the phenotypic and metabolic findings of an AR disorder who are heterozygous for a single disease-causing allele and can be shown to have a new AD form of the disorder that represents clinical heterogeneity., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)
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- 2024
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7. Prevalence of Individuals With Multiple Diagnosed Genetic Diseases in the Undiagnosed Diseases Network.
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Gimeno AF, Tinker RJ, Furuta Y, and Phillips JA 3rd
- Abstract
Report the prevalence of multiple genetic diseases in the Undiagnosed Diseases Network (UDN) cohort in the post-exome-sequencing era. UDN subjects underwent genome sequencing before inclusion in the cohort. Records of all UDN subjects until January 2024 were analyzed. The number of diagnoses, proportion of molecular versus nonmolecular (i.e., not attributable to a discretely identifiable genetic change) diagnoses, and the inheritance patterns of the genetic diagnoses were determined. Of 2799 subjects, 766 (27.4%) had diagnoses. Of these 766, 95.4% had one diagnosis, 4.0% had two diagnoses, and 0.5% had three diagnoses. Of the diagnosed subjects, 93.4% had a genetic disease, and 6.5% had a nonmolecular disease. Of subjects with two diagnoses, both diagnoses were molecular in 90.3%, while 9.7% had one molecular and one nonmolecular diagnosis. All four subjects with three diagnoses had three molecular diagnoses. 4.2% of diagnosed subjects in the UDN had more than one molecular diagnosis, with four individuals having three concurrent Mendelian diagnoses. Additionally, three subjects had concurrent molecular and nonmolecular diagnoses. Given that numerous UDN subjects had a negative genome sequence prior to UDN enrollment, multiple molecular diagnoses may contribute to diagnostic uncertainty even with genome sequencing, as may concurrent nonmolecular disease., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
- Published
- 2024
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8. Recurrent Myalgia, Dark Urine, and Exercise Intolerance: Glycogen Storage Disease Type X Diagnosed Through Gene Sequencing Panel.
- Author
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Furuta Y and Phillips JA 3rd
- Abstract
Evaluation of a single episode of exercise-induced myalgia, dark urine, and elevated creatine phosphokinase (CPK) levels relies primarily on clinical history and physical examinations. However, recurrent episodes necessitate further investigations for potential genetic conditions. This is a case of an 11-year-old male who presents with recurrent myalgia, dark discolored urine, and exercise intolerance for the past year. The initial examination revealed hematuria and a mild elevation of transaminases. Referral to nephrology showed elevated CPK level, prompting further evaluation by neurology. A DNA sequencing-based neuromuscular genetic panel identified a heterozygous pathogenic variant and two variants of uncertain significance in his PGAM2 genes, leading to a diagnosis of glycogen storage disease X. Metabolic myopathies should be considered in children with recurrent exercise-induced myalgia and dark discoloration of urine. Screening for myoglobinuria, elevated plasma CPK levels, and characteristic acylcarnitine profiles should be considered when clinically indicated. DNA sequencing-based gene panel testing can serve as a non-invasive alternative to muscle biopsy for diagnosing metabolic myopathies when suspicion is high., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Furuta et al.)
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- 2024
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9. The Clinical Spectrum of Mosaic Genetic Disease.
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Geiger H, Furuta Y, van Wyk S, Phillips JA 3rd, and Tinker RJ
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- Humans, Genetic Diseases, Inborn genetics, Phenotype, Mosaicism
- Abstract
Genetic mosaicism is defined as the presence of two or more cell lineages with different genotypes arising from a single zygote. Mosaicism has been implicated in hundreds of genetic diseases with diverse genetic etiologies affecting every organ system. Mosaic genetic disease (MDG) is a spectrum that, on the extreme ends, enables survival from genetic severe disorders that would be lethal in a non-mosaic form. On the milder end of the spectrum, mosaicism can result in little if any phenotypic effects but increases the risk of transmitting a pathogenic genotype. In the middle of the spectrum, mosaicism has been implicated in reducing the phenotypic severity of genetic disease. In this review will describe the spectrum of mosaic genetic disease whilst discussing the status of the detection and prevalence of mosaic genetic disease.
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- 2024
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10. Heterozygous ZNHIT3 variants within the 17q12 recurrent deletion region are associated with Mayer-Rokitansky-Kuster Hauser (MRKH) syndrome.
- Author
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Brakta S, Du Q, Chorich LP, Hawkins ZA, Sullivan ME, Ko EK, Kim HG, Knight J, Taylor HS, Friez M, Phillips JA 3rd, and Layman LC
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- Adolescent, Adult, Female, Humans, Pedigree, 46, XX Disorders of Sex Development genetics, Chromosomes, Human, Pair 17 genetics, Congenital Abnormalities genetics, Heterozygote, Mullerian Ducts abnormalities
- Abstract
The molecular basis of mullerian aplasia, also known as Mayer-Rokitansky-Kuster Hauser (MRKH) or congenital absence of the uterus and vagina, is largely unknown. We applied a multifaceted genetic approach to studying the pathogenesis of MRKH including exome sequencing of trios and duos, genome sequencing of families, qPCR, RT-PCR, and Sanger sequencing to detect intragenic deletions, insertions, splice variants, single nucleotide variants, and rearrangements in 132 persons with MRKH. We identified two heterozygous variants in ZNHIT3 localized to a commonly involved CNV region at chromosome 17q12 in two different families with MRKH. One is a frameshift, truncating variant that is predicted to interfere with steroid hormone binding of the LxxLL sequence of the C-terminal region. The second variant is a double missense/stopgain variant. Both variants impair protein expression in vitro. In addition, four more probands with MRKH harbored the stopgain variant without the nearby missense variant. In total, 6/132 (4.5%) of patients studied, including five with associated anomalies (type 2 MRKH), had ZNHIT3 variants that impair function in vitro. Our findings implicate ZNHIT3 as an important gene associated with MRKH within the 17q12 CNV region., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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11. Undiagnosed Disease Network collaborative approach in diagnosing rare disease in a patient with a mosaic CACNA1D variant.
- Author
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Ezell KM, Tinker RJ, Furuta Y, Gulsevin A, Bastarache L, Hamid R, Cogan JD, Rives L, Neumann S, Corner B, Kozuria M, and Phillips JA 3rd
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- Humans, Female, Child, Preschool, Undiagnosed Diseases genetics, Undiagnosed Diseases diagnosis, Phenotype, Mutation genetics, Seizures genetics, Seizures diagnosis, Calcium Channels, L-Type genetics, Mosaicism, Rare Diseases genetics, Rare Diseases diagnosis
- Abstract
The Undiagnosed Disease Network (UDN) is comprised of clinical and research experts collaborating to diagnose rare disease. The UDN is funded by the National Institutes of Health and includes 12 different clinical sites (About Us, 2022). Here we highlight the success of collaborative efforts within the UDN Clinical Site at Vanderbilt University Medical Center (VUMC) in utilizing a cohort of experts in bioinformatics, structural biology, and genetics specialists in diagnosing rare disease. Our UDN team identified a de novo mosaic CACNA1D variant c.2299T>C in a 5-year-old female with a history of global developmental delay, dystonia, dyskinesis, and seizures. Using a collaborative multidisciplinary approach, our VUMC UDN team diagnosed the participant with Primary Aldosteronism, Seizures, and Neurologic abnormalities (PASNA) OMIM: 615474 due to a rare mosaic CACNA1D variant (O'Neill, 2013). Interestingly, this patient was mosaic, a phenotypic trait previously unreported in PASNA cases. This report highlights the importance of a multidisciplinary approach in diagnosing rare disease., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
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- 2024
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12. Data from electronic healthcare records expand our understanding of X-linked genetic diseases.
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Tinker RJ, Bastarache L, Ezell K, Neumann SM, Furuta Y, Morgan KA, and Phillips JA 3rd
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- Humans, Male, Female, Penetrance, Biomarkers, Electronics, Electronic Health Records, Inheritance Patterns, Genetic Diseases, X-Linked genetics
- Abstract
Disease specific cohort studies have reported details on X linked (XL) disorders affecting females. We investigated the spectrum and penetrance of XL disorders seen in electronic health records (EHR). We generated a cohort of individuals diagnosed with XL disorders at Vanderbilt University Medical Center over 20 years. Our cohort included 477 males and 203 females diagnosed with 108 different XL genetic disorders. We found large differences between the female/male (F/M) ratios for various XL disorders regardless of their OMIM annotated mode of inheritance. We identified four XL recessive disorders affecting women previously only described in men. Biomarkers for XL disease had unique gender-specific patterns differing between modes of inheritance. EHRs provide large cohorts of XL genetic disorders that give new insights compared to the literature. Differences in the F/M ratios and biomarkers of XL disorders observed likely result from disease specific and sex dependent penetrance. We conclude that observed gender ratios associated with specific XL disorders may be more useful than those predicted by Mendelian genetics provided by OMIM. Our findings of a gender specific penetrance and severity for XL disorders show unexpected differences from Mendelian predictions. Further work is required to validate our findings in larger combined EHR cohorts., (© 2024 Wiley Periodicals LLC.)
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- 2024
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13. Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase.
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Jones AG, Aquilino M, Tinker RJ, Duncan L, Jenkins Z, Carvill GL, DeWard SJ, Grange DK, Hajianpour MJ, Halliday BJ, Holder-Espinasse M, Horvath J, Maitz S, Nigro V, Morleo M, Paul V, Spencer C, Esterhuizen AI, Polster T, Spano A, Gómez-Lozano I, Kumar A, Poke G, Phillips JA 3rd, Underhill HR, Gimenez G, Namba T, and Robertson SP
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- Animals, Humans, Mice, Brain metabolism, Glutamates metabolism, Epilepsy, Generalized genetics, Glutamate-Ammonia Ligase genetics, Glutamate-Ammonia Ligase metabolism, Glutamine genetics, Glutamine metabolism
- Abstract
Glutamine synthetase (GS), encoded by GLUL, catalyzes the conversion of glutamate to glutamine. GS is pivotal for the generation of the neurotransmitters glutamate and gamma-aminobutyric acid and is the primary mechanism of ammonia detoxification in the brain. GS levels are regulated post-translationally by an N-terminal degron that enables the ubiquitin-mediated degradation of GS in a glutamine-induced manner. GS deficiency in humans is known to lead to neurological defects and death in infancy, yet how dysregulation of the degron-mediated control of GS levels might affect neurodevelopment is unknown. We ascertained nine individuals with severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry with de novo variants in GLUL. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon. Using transfection-based expression systems and mass spectrometry, these variants were shown to lead to translation initiation of GS from methionine 18, downstream of the N-terminal degron motif, resulting in a protein that is stable and enzymatically competent but insensitive to negative feedback by glutamine. Analysis of human single-cell transcriptomes demonstrated that GLUL is widely expressed in neuro- and glial-progenitor cells and mature astrocytes but not in post-mitotic neurons. One individual with a start-loss GLUL variant demonstrated periventricular nodular heterotopia, a neuronal migration disorder, yet overexpression of stabilized GS in mice using in utero electroporation demonstrated no migratory deficits. These findings underline the importance of tight regulation of glutamine metabolism during neurodevelopment in humans., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)
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- 2024
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14. De novo variants in DENND5B cause a neurodevelopmental disorder.
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Scala M, Tomati V, Ferla M, Lena M, Cohen JS, Fatemi A, Brokamp E, Bican A, Phillips JA 3rd, Koziura ME, Nicouleau M, Rio M, Siquier K, Boddaert N, Musante I, Tamburro S, Baldassari S, Iacomino M, Scudieri P, Rosenfeld JA, Bellus G, Reed S, Al Saif H, Russo RS, Walsh MB, Cantagrel V, Crunk A, Gustincich S, Ruggiero SM, Fitzgerald MP, Helbig I, Striano P, Severino M, Salpietro V, Pedemonte N, and Zara F
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- Humans, Brain metabolism, Guanine Nucleotide Exchange Factors genetics, Guanine Nucleotide Exchange Factors metabolism, Lipids, rab GTP-Binding Proteins metabolism, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders metabolism, Epilepsy genetics, Epilepsy metabolism, Intellectual Disability genetics, Intellectual Disability metabolism
- Abstract
The Rab family of guanosine triphosphatases (GTPases) includes key regulators of intracellular transport and membrane trafficking targeting specific steps in exocytic, endocytic, and recycling pathways. DENND5B (Rab6-interacting Protein 1B-like protein, R6IP1B) is the longest isoform of DENND5, an evolutionarily conserved DENN domain-containing guanine nucleotide exchange factor (GEF) that is highly expressed in the brain. Through exome sequencing and international matchmaking platforms, we identified five de novo variants in DENND5B in a cohort of five unrelated individuals with neurodevelopmental phenotypes featuring cognitive impairment, dysmorphism, abnormal behavior, variable epilepsy, white matter abnormalities, and cortical gyration defects. We used biochemical assays and confocal microscopy to assess the impact of DENND5B variants on protein accumulation and distribution. Then, exploiting fluorescent lipid cargoes coupled to high-content imaging and analysis in living cells, we investigated whether DENND5B variants affected the dynamics of vesicle-mediated intracellular transport of specific cargoes. We further generated an in silico model to investigate the consequences of DENND5B variants on the DENND5B-RAB39A interaction. Biochemical analysis showed decreased protein levels of DENND5B mutants in various cell types. Functional investigation of DENND5B variants revealed defective intracellular vesicle trafficking, with significant impairment of lipid uptake and distribution. Although none of the variants affected the DENND5B-RAB39A interface, all were predicted to disrupt protein folding. Overall, our findings indicate that DENND5B variants perturb intracellular membrane trafficking pathways and cause a complex neurodevelopmental syndrome with variable epilepsy and white matter involvement., Competing Interests: Declaration of interests A.C. is an employee of GeneDx, LLC. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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15. Probable digenic inheritance of Diamond-Blackfan anemia.
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Furuta Y, Tinker RJ, Gulsevin A, Neumann SM, Hamid R, Cogan JD, Rives L, Liu Q, Chen HC, Joos KM, and Phillips JA 3rd
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- Humans, Female, Adult, Ribosomal Proteins genetics, Genotype, Alleles, Phenotype, Base Sequence, Mutation, Anemia, Diamond-Blackfan diagnosis, Anemia, Diamond-Blackfan genetics
- Abstract
A 26-year-old female proband with a clinical diagnosis and consistent phenotype of Diamond-Blackfan anemia (DBA, OMIM 105650) without an identified genotype was referred to the Undiagnosed Diseases Network. DBA is classically associated with monoallelic variants that have an autosomal-dominant or -recessive mode of inheritance. Intriguingly, her case was solved by a detection of a digenic interaction between non-allelic RPS19 and RPL27 variants. This was confirmed with a machine learning structural model, co-segregation analysis, and RNA sequencing. This is the first report of DBA caused by a digenic effect of two non-allelic variants demonstrated by machine learning structural model. This case suggests that atypical phenotypic presentations of DBA may be caused by digenic inheritance in some individuals. We also conclude that a machine learning structural model can be useful in detecting digenic models of possible interactions between products encoded by alleles of different genes inherited from non-affected carrier parents that can result in DBA with an unrealized 25% recurrence risk., (© 2023 Wiley Periodicals LLC.)
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- 2024
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16. A medical odyssey of a 72-year-old man with Charcot-Marie-Tooth disease type 2 newly diagnosed with biallelic variants in SORD gene causing sorbitol dehydrogenase deficiency.
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Furuta Y, Nelson ET, Neumann SM, Phillips JA 3rd, Hamid R, Tinker RJ, Cogan JD, Rives L, and Newman JH
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- Humans, Male, Aged, L-Iditol 2-Dehydrogenase genetics, Mutation, Charcot-Marie-Tooth Disease diagnosis, Charcot-Marie-Tooth Disease genetics
- Abstract
A 72-year-old man was referred to the Undiagnosed Diseases Network (UDN) because of gradual progressive weakness in both lower extremities for the past 45 years. He was initially diagnosed as having Charcot-Marie-Tooth disease type 2 (CMT2) without a defined molecular genetic cause. Exome sequencing (ES) failed to detect deleterious neuromuscular variants. Very recently, biallelic variants in sorbitol dehydrogenase (SORD) were discovered to be a novel cause of inherited neuropathies including CMT2 or distal hereditary motor neuropathy (dHMN) referred to as Sorbitol Dehydrogenase Deficiency with Peripheral Neuropathy (SORDD, OMIM 618912). The most common variant identified was c.757delG; p.A253Qfs*27. Through the Vanderbilt UDN clinical site, this patient was formally diagnosed with SORDD after the identification of homozygosity for the above SORD frameshift through UDN Genome Sequencing (GS). His medical odyssey was solved by GS and detection of extremely high levels of sorbitol. The diagnosis provided him the opportunity to receive potential treatment with an investigational drug in a clinical trial for SORDD. We suggest that similar studies be considered in other individuals thought to possibly have CMT2 or dHMN., (© 2023 Wiley Periodicals LLC.)
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- 2023
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17. Efficacy and safety of a synthetic biotic for treatment of phenylketonuria: a phase 2 clinical trial.
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Vockley J, Sondheimer N, Puurunen M, Diaz GA, Ginevic I, Grange DK, Harding C, Northrup H, Phillips JA 3rd, Searle S, Thomas JA, Zori R, Denney WS, Ernst SL, Humphreys K, McWhorter N, Kurtz C, and Brennan AM
- Subjects
- Adult, Humans, Male, Female, Phenylalanine Ammonia-Lyase therapeutic use, Administration, Oral, Escherichia coli, Phenylalanine therapeutic use, Phenylketonurias drug therapy
- Abstract
Despite available treatment options, many patients with phenylketonuria (PKU) cannot achieve target plasma phenylalanine (Phe) levels
1 . We previously modified Escherichia coli Nissle 1917 to metabolize Phe in the gut after oral administration (SYNB1618) and designed a second strain (SYNB1934) with enhanced activity of phenylalanine ammonia lyase2,3 . In a 14-day open-label dose-escalation study (Synpheny-1, NCT04534842 ), we test a primary endpoint of change from baseline in labeled Phe (D5-Phe AUC0-24 ; D5-Phe area under the curve (AUC) over 24 hours after D5-Phe administration) in plasma after D5-Phe challenge in adult participants with screening Phe of greater than 600 µM. Secondary endpoints were the change from baseline in fasting plasma Phe and the incidence of treatment-emergent adverse events. A total of 20 participants (ten male and ten female) were enrolled and 15 completed the study treatment. Here, we show that both strains lower Phe levels in participants with PKU: D5-Phe AUC0-24 was reduced by 43% from baseline with SYNB1934 and by 34% from baseline with SYNB1618. SYNB1934 led to a decrease in fasting plasma Phe of 40% (95% CI, -52, -24). There were no serious adverse events or infections. Four participants discontinued because of adverse events, and one withdrew during the baseline period. We show that synthetic biotics can metabolize Phe in the gut, lower post-prandial plasma Phe levels and lower fasting plasma Phe in patients with PKU., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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18. The contribution of mosaicism to genetic diseases and de novo pathogenic variants.
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Tinker RJ, Bastarache L, Ezell K, Kobren SN, Esteves C, Rosenfeld JA, Macnamara EF, Hamid R, Cogan JD, Rinker D, Mukharjee S, Glass I, Dipple K, and Phillips JA 3rd
- Subjects
- Humans, Genetic Testing, Exome, Parents, Mosaicism, Genetic Variation
- Abstract
The contribution of mosaicism to diagnosed genetic disease and presumed de novo variants (DNV) is under investigated. We determined the contribution of mosaic genetic disease (MGD) and diagnosed parental mosaicism (PM) in parents of offspring with reported DNV (in the same variant) in the (1) Undiagnosed Diseases Network (UDN) (N = 1946) and (2) in 12,472 individuals electronic health records (EHR) who underwent genetic testing at an academic medical center. In the UDN, we found 4.51% of diagnosed probands had MGD, and 2.86% of parents of those with DNV exhibited PM. In the EHR, we found 6.03% and 2.99% and (of diagnosed probands) had MGD detected on chromosomal microarray and exome/genome sequencing, respectively. We found 2.34% (of those with a presumed pathogenic DNV) had a parent with PM for the variant. We detected mosaicism (regardless of pathogenicity) in 4.49% of genetic tests performed. We found a broad phenotypic spectrum of MGD with previously unknown phenotypic phenomena. MGD is highly heterogeneous and provides a significant contribution to genetic diseases. Further work is required to improve the diagnosis of MGD and investigate how PM contributes to DNV risk., (© 2023 Wiley Periodicals LLC.)
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- 2023
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19. The Genetic Landscape of Familial Pulmonary Fibrosis.
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Liu Q, Zhou Y, Cogan JD, Mitchell DB, Sheng Q, Zhao S, Bai Y, Ciombor KK, Sabusap CM, Malabanan MM, Markin CR, Douglas K, Ding G, Banovich NE, Nickerson DA, Blue EE, Bamshad MJ, Brown KK, Schwartz DA, Phillips JA 3rd, Martinez-Barricarte R, Salisbury ML, Shyr Y, Loyd JE, Kropski JA, and Blackwell TS
- Subjects
- Humans, Endothelial Cells, Risk Factors, Telomere, Genetic Predisposition to Disease genetics, Receptors, Lysophosphatidic Acid genetics, Pulmonary Fibrosis genetics, Lung Diseases, Interstitial genetics
- Abstract
Rationale and Objectives: Up to 20% of idiopathic interstitial lung disease is familial, referred to as familial pulmonary fibrosis (FPF). An integrated analysis of FPF genetic risk was performed by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds. Methods: Whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds was performed, followed by cosegregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell-type enrichment analysis, and coexpression network construction. Measurements and Main Results: It was found that 14.9-23.4% of genetic risk in kindreds could be explained by RVs in genes previously linked to FPF, predominantly telomere-related genes. New candidate genes were identified in a small number of families-including SYDE1 , SERPINB8 , GPR87 , and NETO1 -and tools were developed for evaluation and prioritization of RV-containing genes across kindreds. Several pathways were enriched for RV-containing genes in FPF, including focal adhesion and mitochondrial complex I assembly. By combining single-cell transcriptomics with prioritized candidate genes, expression of RV-containing genes was discovered to be enriched in smooth muscle cells, type II alveolar epithelial cells, and endothelial cells. Conclusions: In the most comprehensive FPF genetic study to date, the prevalence of RVs in known FPF-related genes was defined, and new candidate genes and pathways relevant to FPF were identified. However, new RV-containing genes shared across multiple kindreds were not identified, thereby suggesting that heterogeneous genetic variants involving a variety of genes and pathways mediate genetic risk in most FPF kindreds.
- Published
- 2023
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20. Rare structural variants, aneuploidies, and mosaicism in individuals with Mullerian aplasia detected by optical genome mapping.
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Brakta S, Hawkins ZA, Sahajpal N, Seman N, Kira D, Chorich LP, Kim HG, Xu H, Phillips JA 3rd, Kolhe R, and Layman LC
- Subjects
- Humans, In Situ Hybridization, Fluorescence, Aneuploidy, Chromosome Mapping, Mosaicism, Congenital Abnormalities genetics
- Abstract
The molecular basis of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome remains largely unknown. Pathogenic variants in WNT4 and HNF1B have been confirmed in a small percent of individuals. A variety of copy number variants have been reported, but causal gene(s) remain to be identified. We hypothesized that rare structural variants (SVs) would be present in some individuals with MRKH, which could explain the genetic basis of the syndrome. Large molecular weight DNA was extracted from lymphoblastoid cells from 87 individuals with MRKH and available parents. Optical genome mapping (OGM) was performed to identify SVs, which were confirmed by another method (quantitative PCR, chromosomal microarray, karyotype, or fluorescent in situ hybridization) when possible. Thirty-four SVs that overlapped coding regions of genes with potential involvement in MRKH were identified, 14 of which were confirmed by a second method. These 14 SVs were present in 17/87 (19.5%) of probands with MRKH and included seven deletions, three duplications, one new translocation in 5/50 cells-t(7;14)(q32;q32), confirmation of a previously identified translocation-t(3;16)(p22.3;p13.3), and two aneuploidies. Of interest, three cases of mosaicism (3.4% of probands) were identified-25% mosaicism for trisomy 12, 45,X(75%)/46,XX (25%), and 10% mosaicism for a 7;14 translocation. Our study constitutes the first systematic investigation of SVs by OGM in individuals with MRKH. We propose that OGM is a promising method that enables a comprehensive investigation of a variety of SVs in a single assay including cryptic translocations and mosaic aneuploidies. These observations suggest that mosaicism could play a role in the genesis of MRKH., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2023
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21. A Case Study of Dysfunctional Nicotinamide Metabolism in a 20-Year-Old Male.
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DeBalsi KL, Newman JH, Sommerville LJ, Phillips JA 3rd, Hamid R, Cogan J, Fessel JP, Evans AM, Undiagnosed Diseases Network, and Kennedy AD
- Abstract
We present a case study of a 20-year-old male with an unknown neurodegenerative disease who was referred to the Undiagnosed Diseases Network Vanderbilt Medical Center site. A previous metabolic panel showed that the patient had a critical deficiency in nicotinamide intermediates that are generated during the biosynthesis of NAD(H). We followed up on these findings by evaluating the patient's ability to metabolize nicotinamide. We performed a global metabolic profiling analysis of plasma samples that were collected: (1) under normal fed conditions (baseline), (2) after the patient had fasted, and (3) after he was challenged with a 500 mg nasogastric tube bolus of nicotinamide following the fast. Our findings showed that the patient's nicotinamide N-methyltransferase (NNMT), a key enzyme in NAD(H) biosynthesis and methionine metabolism, was not functional under normal fed or fasting conditions but was restored in response to the nicotinamide challenge. Altered levels of metabolites situated downstream of NNMT and in neighboring biochemical pathways provided further evidence of a baseline defect in NNMT activity. To date, this is the only report of a critical defect in NNMT activity manifesting in adulthood and leading to neurodegenerative disease. Altogether, this study serves as an important reference in the rare disease literature and also demonstrates the utility of metabolomics as a diagnostic tool for uncharacterized metabolic diseases.
- Published
- 2023
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22. Publisher Correction: Safety and pharmacodynamics of an engineered E. coli Nissle for the treatment of phenylketonuria: a first-in-human phase 1/2a study.
- Author
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Puurunen MK, Vockley J, Searle SL, Sacharow SJ, Phillips JA 3rd, Denney WS, Goodlett BD, Wagner DA, Blankstein L, Castillo MJ, Charbonneau MR, Isabella VM, Sethuraman VV, Riese RJ, Kurtz CB, and Brennan AM
- Published
- 2022
- Full Text
- View/download PDF
23. Lessons learned: next-generation sequencing applied to undiagnosed genetic diseases.
- Author
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Schuler BA, Nelson ET, Koziura M, Cogan JD, Hamid R, and Phillips JA 3rd
- Subjects
- Genetic Testing methods, Genomics, High-Throughput Nucleotide Sequencing methods, Humans, Phenotype, Undiagnosed Diseases
- Abstract
Rare genetic disorders, when considered together, are relatively common. Despite advancements in genetics and genomics technologies as well as increased understanding of genomic function and dysfunction, many genetic diseases continue to be difficult to diagnose. The goal of this Review is to increase the familiarity of genetic testing strategies for non-genetics providers. As genetic testing is increasingly used in primary care, many subspecialty clinics, and various inpatient settings, it is important that non-genetics providers have a fundamental understanding of the strengths and weaknesses of various genetic testing strategies as well as develop an ability to interpret genetic testing results. We provide background on commonly used genetic testing approaches, give examples of phenotypes in which the various genetic testing approaches are used, describe types of genetic and genomic variations, cover challenges in variant identification, provide examples in which next-generation sequencing (NGS) failed to uncover the variant responsible for a disease, and discuss opportunities for continued improvement in the application of NGS clinically. As genetic testing becomes increasingly a part of all areas of medicine, familiarity with genetic testing approaches and result interpretation is vital to decrease the burden of undiagnosed disease.
- Published
- 2022
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24. Efficacy of virtual and asynchronous teaching of computer-assisted diagnosis of genetic diseases seen in clinics.
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Hash MG, Walker PD, Laferriere HE, Melton L, Heller LS, and Phillips JA 3rd
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- Decision Support Systems, Clinical, Education, Medical, Humans, Physicians, Surveys and Questionnaires, Diagnosis, Computer-Assisted methods, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn genetics, Teaching, User-Computer Interface
- Abstract
We studied if clinicians could gain sufficient working knowledge of a computer-assisted diagnostic decision support system (DDSS) (SimulConsult), to make differential diagnoses (DDx) of genetic disorders. We hypothesized that virtual training could be convenient, asynchronous, and effective in teaching clinicians how to use a DDSS. We determined the efficacy of virtual, asynchronous teaching for clinicians to gain working knowledge to make computer-assisted DDx. Our study consisted of three surveys (Baseline, Training, and After Use) and a series of case problems sent to clinicians at Vanderbilt University Medical Center. All participants were able to generate computer-assisted DDx that achieved passing scores of the case problems. Between 75% and 92% agreed/completely agreed the DDSS was useful to their work and for clinical decision support and was easy to use. Participants' use of the DDSS resulted in statistically significant time savings in key tasks and in total time spent on clinical tasks. Our results indicate that virtual, asynchronous teaching can be an effective format to gain a working knowledge of a DDSS, and its clinical use could result in significant time savings across multiple tasks as well as facilitate synergistic interaction between clinicians and lab specialists. This approach is especially pertinent and offers value amid the COVID-19 pandemic., (© 2021 Wiley Periodicals LLC.)
- Published
- 2022
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25. International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia.
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Savarirayan R, Ireland P, Irving M, Thompson D, Alves I, Baratela WAR, Betts J, Bober MB, Boero S, Briddell J, Campbell J, Campeau PM, Carl-Innig P, Cheung MS, Cobourne M, Cormier-Daire V, Deladure-Molla M, Del Pino M, Elphick H, Fano V, Fauroux B, Gibbins J, Groves ML, Hagenäs L, Hannon T, Hoover-Fong J, Kaisermann M, Leiva-Gea A, Llerena J, Mackenzie W, Martin K, Mazzoleni F, McDonnell S, Meazzini MC, Milerad J, Mohnike K, Mortier GR, Offiah A, Ozono K, Phillips JA 3rd, Powell S, Prasad Y, Raggio C, Rosselli P, Rossiter J, Selicorni A, Sessa M, Theroux M, Thomas M, Trespedi L, Tunkel D, Wallis C, Wright M, Yasui N, and Fredwall SO
- Subjects
- Consensus, Humans, Mutation, Osteogenesis, Receptor, Fibroblast Growth Factor, Type 3 genetics, Achondroplasia diagnosis, Achondroplasia genetics, Achondroplasia therapy, Quality of Life
- Abstract
Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition is caused by a common, recurring, gain-of-function mutation in FGFR3, the gene that encodes fibroblast growth factor receptor 3. This mutation leads to impaired endochondral ossification of the human skeleton. The clinical and radiographic hallmarks of achondroplasia make accurate diagnosis possible in most patients. However, marked variability exists in the clinical care pathways and protocols practised by clinicians who manage children and adults with this condition. A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process. The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide in order to optimize their clinical outcomes and quality of life., (© 2021. Springer Nature Limited.)
- Published
- 2022
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26. Evidence of feedback regulation of C-type natriuretic peptide during Vosoritide therapy in Achondroplasia.
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Prickett TCR, Espiner EA, Irving M, Bacino C, Phillips JA 3rd, Savarirayan R, Day JRS, Fisheleva E, Larimore K, Chan ML, and Jeha GS
- Subjects
- Adolescent, Bone Development drug effects, Bone and Bones drug effects, Child, Child, Preschool, Feedback, Female, Growth Disorders drug therapy, Humans, Male, Natriuretic Peptide, C-Type pharmacology, Time Factors, Treatment Outcome, Achondroplasia drug therapy, Natriuretic Peptide, C-Type analogs & derivatives, Natriuretic Peptide, C-Type metabolism
- Abstract
Evidence from genetic disorders of CNP signalling suggests that plasma concentrations of CNP are subject to feedback regulation. In subjects with Achondroplasia (Ach), CNP intracellular activity is suppressed and plasma concentrations are raised but the therapeutic impact of exogenous CNP agonists on endogenous CNP is unknown. In this exploratory dose finding and extension study of 28 Ach children receiving Vosoritide over a 5 year period of treatment, endogenous CNP production was assessed using measurements of plasma aminoterminal proCNP (NTproCNP) adjusted for age and sex and normalised as standard deviation score (SDS), and then related to skeletal growth. Before treatment NTproCNP SDS was raised. Within the first 3 months of accelerating growth, levels were significantly reduced. Across the 5 years of sustained growth, levels varied widely and were markedly increased in some subjects during adolescence. Plasma NTproCNP was suppressed at 4 h post-injection in proportion to the prevailing level of hormone resistance as reflected by SDS before injection. We conclude CNP remains subject to regulation during growth promoting doses of Vosoritide. Fall in CNP during accelerating growth is consistent with an indirect feedback whereas the fall at 4 h is likely to be a direct effect from removal of intra cellular CNP resistance., (© 2021. The Author(s).)
- Published
- 2021
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27. Identifying digenic disease genes via machine learning in the Undiagnosed Diseases Network.
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Mukherjee S, Cogan JD, Newman JH, Phillips JA 3rd, Hamid R, Meiler J, and Capra JA
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- Databases, Genetic, Humans, Rare Diseases genetics, Undiagnosed Diseases genetics, Disease genetics, Genomics methods, Machine Learning, Multifactorial Inheritance, Phenotype, Rare Diseases diagnosis, Undiagnosed Diseases diagnosis
- Abstract
Rare diseases affect millions of people worldwide, and discovering their genetic causes is challenging. More than half of the individuals analyzed by the Undiagnosed Diseases Network (UDN) remain undiagnosed. The central hypothesis of this work is that many of these rare genetic disorders are caused by multiple variants in more than one gene. However, given the large number of variants in each individual genome, experimentally evaluating combinations of variants for potential to cause disease is currently infeasible. To address this challenge, we developed the digenic predictor (DiGePred), a random forest classifier for identifying candidate digenic disease gene pairs by features derived from biological networks, genomics, evolutionary history, and functional annotations. We trained the DiGePred classifier by using DIDA, the largest available database of known digenic-disease-causing gene pairs, and several sets of non-digenic gene pairs, including variant pairs derived from unaffected relatives of UDN individuals. DiGePred achieved high precision and recall in cross-validation and on a held-out test set (PR area under the curve > 77%), and we further demonstrate its utility by using digenic pairs from the recent literature. In contrast to other approaches, DiGePred also appropriately controls the number of false positives when applied in realistic clinical settings. Finally, to enable the rapid screening of variant gene pairs for digenic disease potential, we freely provide the predictions of DiGePred on all human gene pairs. Our work enables the discovery of genetic causes for rare non-monogenic diseases by providing a means to rapidly evaluate variant gene pairs for the potential to cause digenic disease., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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28. One is the loneliest number: genotypic matchmaking using the electronic health record.
- Author
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Brokamp E, Koziura ME, Phillips JA 3rd, Tang LA, Cogan JD, Rives LC, Robertson AK, Duncan L, Bican A, Peterson JF, Newman JH, Hamid R, and Bastarache L
- Subjects
- Genotype, Humans, Electronic Health Records
- Published
- 2021
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29. Safety and pharmacodynamics of an engineered E. coli Nissle for the treatment of phenylketonuria: a first-in-human phase 1/2a study.
- Author
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Puurunen MK, Vockley J, Searle SL, Sacharow SJ, Phillips JA 3rd, Denney WS, Goodlett BD, Wagner DA, Blankstein L, Castillo MJ, Charbonneau MR, Isabella VM, Sethuraman VV, Riese RJ, Kurtz CB, and Brennan AM
- Subjects
- Amidohydrolases genetics, Amidohydrolases metabolism, Biological Therapy adverse effects, Genetic Engineering, Humans, Phenylalanine Ammonia-Lyase genetics, Phenylalanine Ammonia-Lyase metabolism, Phenylketonurias blood, Phenylketonurias genetics, Treatment Outcome, Biological Therapy methods, Escherichia coli enzymology, Escherichia coli genetics, Phenylketonurias therapy
- Abstract
Phenylketonuria (PKU) is a rare disease caused by biallelic mutations in the PAH gene that result in an inability to convert phenylalanine (Phe) to tyrosine, elevated blood Phe levels and severe neurological complications if untreated. Most patients are unable to adhere to the protein-restricted diet, and thus do not achieve target blood Phe levels. We engineered a strain of E. coli Nissle 1917, designated SYNB1618, through insertion of the genes encoding phenylalanine ammonia lyase and L-amino acid deaminase into the genome, which allow for bacterial consumption of Phe within the gastrointestinal tract. SYNB1618 was studied in a phase 1/2a randomized, placebo-controlled, double-blind, multi-centre, in-patient study ( NCT03516487 ) in adult healthy volunteers (n = 56) and patients with PKU and blood Phe level ≥600 mmol l
-1 (n = 14). Participants were randomized to receive a single dose of SYNB1618 or placebo (part 1) or up to three times per day for up to 7 days (part 2). The primary outcome of this study was safety and tolerability, and the secondary outcome was microbial kinetics. A D5-Phe tracer (15 mg kg-1 ) was used to study exploratory pharmacodynamic effects. SYNB1618 was safe and well tolerated with a maximum tolerated dose of 2 × 1011 colony-forming units. Adverse events were mostly gastrointestinal and of mild to moderate severity. All participants cleared the bacteria within 4 days of the last dose. Dose-responsive increases in strain-specific Phe metabolites in plasma (trans-cinnamic acid) and urine (hippuric acid) were observed, providing a proof of mechanism for the potential to use engineered bacteria in the treatment of rare metabolic disorders., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2021
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30. Familial Autonomic Ganglionopathy Caused by Rare CHRNA3 Genetic Variants.
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Shibao CA, Joos K, Phillips JA 3rd, Cogan J, Newman JH, Hamid R, Meiler J, Capra J, Sheehan J, Vetrini F, Yang Y, Black B, Diedrich A, Roberston D, and Biaggioni I
- Subjects
- Adolescent, Adult, Constipation genetics, Female, Genes, Recessive, Humans, Hypotension, Orthostatic genetics, Male, Miosis genetics, Pedigree, Exome Sequencing, Autonomic Nervous System Diseases genetics, Mutation, Receptors, Nicotinic genetics
- Abstract
Objective: To determine the molecular basis of a new monogenetic recessive disorder that results in familial autonomic ganglionopathy with diffuse autonomic failure., Methods: Two adult siblings from one family (I-4 and I-5) and another participant from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small nonreactive pupils, and constipation. All 3 affected members had low norepinephrine levels and diffuse panautonomic failure., Results: Whole exome sequencing of DNA from I-4 and I-5 showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115)/c.688 G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, α3 subunit gene ( CHRNA3 ). II-3 from the second family was homozygous for the same frameshift (fs) variant (p.L303Dfs*115//p.L303Dfs*115). CHRNA3 encodes a critical subunit of the nicotinic acetylcholine receptors (nAChRs) responsible for fast synaptic transmission in the autonomic ganglia. The fs variant is clearly pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). The p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits based on structural modeling and is predicted to destabilize the nAChR pentameric complex., Conclusions: We report a novel genetic disease that affected 3 individuals from 2 unrelated families who presented with severe nOH, miosis, and constipation. These patients had rare pathologic variants in the CHRNA3 gene that cosegregate with and are predicted to be the likely cause of their diffuse panautonomic failure., (© 2021 American Academy of Neurology.)
- Published
- 2021
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31. Clinical diagnosis of neurofibromatosis type I in multiple family members due to cosegregation of a unique balanced translocation with disruption of the NF1 locus: Testing considerations for accurate diagnosis.
- Author
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Smith RB, Solem EP, Metz EC, Wheeler FC, Phillips JA 3rd, and Yenamandra A
- Subjects
- Child, Preschool, Female, Genetic Testing methods, Humans, In Situ Hybridization, Fluorescence, Karyotype, Neurofibromatosis 1 genetics, Neurofibromatosis 1 pathology, Cytogenetic Analysis, Neurofibromatosis 1 diagnosis, Neurofibromin 1 genetics, Translocation, Genetic genetics
- Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that causes a predisposition to develop tumors along the peripheral nervous system. The NF1 gene, located at 17q11.2, has the highest mutation rate among known human genes and about half of NF1 patients have de novo pathogenic variants. We present a case of clinical NF1 diagnoses in multiple family members with phenotypes ranging from mild to severe. Chromosome analysis of the 3-year-old female proband with NF1 resulted in an abnormal karyotype that was inherited from her mother: 46,XX,t(4;17)(q21.3;q11.2) mat. However, no NF1 genetic variants were identified by either NGS analysis of NF1 DNA coding regions, deletion-duplication studies, or by cytogenomic microarray copy number analysis. Follow-up chromosome studies of the proband's two male siblings demonstrated cosegregation of the same balanced translocation and a clinical diagnosis of NF1. Based on the cosegregation of the translocation with the NF1 clinical presentation in this family, we hypothesized that the NF1 gene may have been disrupted by this unique rearrangement. Subsequent fluorescence in situ hybridization (FISH) analysis of the metaphase cells of an affected sibling revealed a disruption of the NF1 gene confirming the underlying basis of the clinical NF1 presentation in this family. The utilization of traditional cytogenetic as well as evolving molecular methods was not only pivotal in the diagnosis of NF1 and management for this family, but is also pertinent to other patients with a family history of NF1., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
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32. Mitochondrial NADP + is essential for proline biosynthesis during cell growth.
- Author
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Tran DH, Kesavan R, Rion H, Soflaee MH, Solmonson A, Bezwada D, Vu HS, Cai F, Phillips JA 3rd, DeBerardinis RJ, and Hoxhaj G
- Subjects
- Animals, Cell Cycle genetics, Humans, Mice, Mice, Knockout, Oxygen Consumption, Pancreas metabolism, Phosphotransferases (Alcohol Group Acceptor) genetics, Reactive Oxygen Species metabolism, Xenograft Model Antitumor Assays, Cell Proliferation, Mitochondria metabolism, NADP metabolism, Proline biosynthesis
- Abstract
Nicotinamide adenine dinucleotide phosphate (NADP
+ ) is vital to produce NADPH, a principal supplier of reducing power for biosynthesis of macromolecules and protection against oxidative stress. NADPH exists in separate pools, in both the cytosol and mitochondria; however, the cellular functions of mitochondrial NADPH are incompletely described. Here, we find that decreasing mitochondrial NADP(H) levels through depletion of NAD kinase 2 (NADK2), an enzyme responsible for production of mitochondrial NADP+ , renders cells uniquely proline auxotrophic. Cells with NADK2 deletion fail to synthesize proline, due to mitochondrial NADPH deficiency. We uncover the requirement of mitochondrial NADPH and NADK2 activity for the generation of the pyrroline-5-carboxylate metabolite intermediate as the bottleneck step in the proline biosynthesis pathway. Notably, after NADK2 deletion, proline is required to support nucleotide and protein synthesis, making proline essential for the growth and proliferation of NADK2-deficient cells. Thus, we highlight proline auxotrophy in mammalian cells and discover that mitochondrial NADPH is essential to enable proline biosynthesis.- Published
- 2021
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33. Genetics of agenesis/hypoplasia of the uterus and vagina: narrowing down the number of candidate genes for Mayer-Rokitansky-Küster-Hauser Syndrome.
- Author
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Mikhael S, Dugar S, Morton M, Chorich LP, Tam KB, Lossie AC, Kim HG, Knight J, Taylor HS, Mukherjee S, Capra JA, Phillips JA 3rd, Friez M, and Layman LC
- Subjects
- 46, XX Disorders of Sex Development pathology, Animals, Congenital Abnormalities pathology, Female, Genetic Variation, Humans, Mice, Mullerian Ducts pathology, Translocation, Genetic, Exome Sequencing, 46, XX Disorders of Sex Development genetics, Congenital Abnormalities genetics, Mullerian Ducts abnormalities, Uterus abnormalities, Vagina abnormalities
- Abstract
Purpose: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome consists of congenital absence of the uterus and vagina and is often associated with renal, skeletal, cardiac, and auditory defects. The genetic basis is largely unknown except for rare variants in several genes. Many candidate genes have been suggested by mouse models and human studies. The purpose of this study was to narrow down the number of candidate genes., Methods: Whole exome sequencing was performed on 111 unrelated individuals with MRKH; variant analysis focused on 72 genes suggested by mouse models, human studies of physiological candidates, or located near translocation breakpoints in t(3;16). Candidate variants (CV) predicted to be deleterious were confirmed by Sanger sequencing., Results: Sanger sequencing verified 54 heterozygous CV from genes identified through mouse (13 CV in 6 genes), human (22 CV in seven genes), and translocation breakpoint (19 CV in 11 genes) studies. Twelve patients had ≥ 2 CVs, including four patients with two variants in the same gene. One likely digenic combination of LAMC1 and MMP14 was identified., Conclusion: We narrowed 72 candidate genes to 10 genes that appear more likely implicated. These candidate genes will require further investigation to elucidate their role in the development of MRKH.
- Published
- 2021
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34. Missed diagnoses: Clinically relevant lessons learned through medical mysteries solved by the Undiagnosed Diseases Network.
- Author
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Cope H, Spillmann R, Rosenfeld JA, Brokamp E, Signer R, Schoch K, Glanton E, Sullivan JA, Macnamara E, Lincoln S, Golden-Grant K, Orengo JP, Clark G, Burrage LC, Posey JE, Punetha J, Robertson A, Cogan J, Phillips JA 3rd, Martinez-Agosto J, and Shashi V
- Subjects
- Adolescent, Child, Child, Preschool, Female, Genetic Diseases, Inborn genetics, Genetic Testing standards, Humans, Information Dissemination, Male, Middle Aged, National Institutes of Health (U.S.), Phenotype, Precision Medicine methods, Undiagnosed Diseases genetics, United States, Young Adult, Databases, Factual, Diagnosis, Computer-Assisted methods, Genetic Diseases, Inborn diagnosis, Genetic Testing methods, Missed Diagnosis, Undiagnosed Diseases diagnosis
- Abstract
Background: Resources within the Undiagnosed Diseases Network (UDN), such as genome sequencing (GS) and model organisms aid in diagnosis and identification of new disease genes, but are currently difficult to access by clinical providers. While these resources do contribute to diagnoses in many cases, they are not always necessary to reach diagnostic resolution. The UDN experience has been that participants can also receive diagnoses through the thoughtful and customized application of approaches and resources that are readily available in clinical settings., Methods: The UDN Genetic Counseling and Testing Working Group collected case vignettes that illustrated how clinically available methods resulted in diagnoses. The case vignettes were classified into three themes; phenotypic considerations, selection of genetic testing, and evaluating exome/GS variants and data., Results: We present 12 participants that illustrate how clinical practices such as phenotype-driven genomic investigations, consideration of variable expressivity, selecting the relevant tissue of interest for testing, utilizing updated testing platforms, and recognition of alternate transcript nomenclature resulted in diagnoses., Conclusion: These examples demonstrate that when a diagnosis is elusive, an iterative patient-specific approach utilizing assessment options available to clinical providers may solve a portion of cases. However, this does require increased provider time commitment, a particular challenge in the current practice of genomics., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
- Published
- 2020
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35. Limitations of exome sequencing in detecting rare and undiagnosed diseases.
- Author
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Burdick KJ, Cogan JD, Rives LC, Robertson AK, Koziura ME, Brokamp E, Duncan L, Hannig V, Pfotenhauer J, Vanzo R, Paul MS, Bican A, Morgan T, Duis J, Newman JH, Hamid R, and Phillips JA 3rd
- Subjects
- Exome genetics, Genetic Testing, Humans, Rare Diseases genetics, Rare Diseases pathology, Undiagnosed Diseases diagnosis, Undiagnosed Diseases epidemiology, Whole Genome Sequencing, Genetic Predisposition to Disease, Rare Diseases diagnosis, Undiagnosed Diseases genetics, Exome Sequencing standards
- Abstract
While exome sequencing (ES) is commonly the final diagnostic step in clinical genetics, it may miss diagnoses. To clarify the limitations of ES, we investigated the diagnostic yield of genetic tests beyond ES in our Undiagnosed Diseases Network (UDN) participants. We reviewed the yield of additional genetic testing including genome sequencing (GS), copy number variant (CNV), noncoding variant (NCV), repeat expansion (RE), or methylation testing in UDN cases with nondiagnostic ES results. Overall, 36/54 (67%) of total diagnoses were based on clinical findings and coding variants found by ES and 3/54 (6%) were based on clinical findings only. The remaining 15/54 (28%) required testing beyond ES. Of these, 7/15 (47%) had NCV, 6/15 (40%) CNV, and 2/15 (13%) had a RE or a DNA methylation disorder. Thus 18/54 (33%) of diagnoses were not solved exclusively by ES. Several methods were needed to detect and/or confirm the functional effects of the variants missed by ES, and in some cases by GS. These results indicate that tests to detect elusive variants should be considered after nondiagnostic preliminary steps. Further studies are needed to determine the cost-effectiveness of tests beyond ES that provide diagnoses and insights to possible treatment., (© 2020 Wiley Periodicals, Inc.)
- Published
- 2020
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36. Development and Progression of Radiologic Abnormalities in Individuals at Risk for Familial Interstitial Lung Disease.
- Author
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Salisbury ML, Hewlett JC, Ding G, Markin CR, Douglas K, Mason W, Guttentag A, Phillips JA 3rd, Cogan JD, Reiss S, Mitchell DB, Wu P, Young LR, Lancaster LH, Loyd JE, Humphries SM, Lynch DA, Kropski JA, and Blackwell TS
- Subjects
- Adult, Aged, Cigarette Smoking epidemiology, Cohort Studies, Disease Progression, Environmental Exposure statistics & numerical data, Female, Forced Expiratory Volume, Genetic Predisposition to Disease, Genotype, Humans, Longitudinal Studies, Lung physiopathology, Lung Diseases, Interstitial epidemiology, Lung Diseases, Interstitial genetics, Lung Diseases, Interstitial physiopathology, Male, Middle Aged, Mucin-5B genetics, Pulmonary Diffusing Capacity, Tomography, X-Ray Computed, Total Lung Capacity, Vital Capacity, Lung diagnostic imaging, Lung Diseases, Interstitial diagnostic imaging
- Abstract
Rationale: The preclinical natural history of progressive lung fibrosis is poorly understood. Objectives: Our goals were to identify risk factors for interstitial lung abnormalities (ILA) on high-resolution computed tomography (HRCT) scans and to determine progression toward clinical interstitial lung disease (ILD) among subjects in a longitudinal cohort of self-reported unaffected first-degree relatives of patients with familial interstitial pneumonia. Methods: Enrollment evaluation included a health history and exposure questionnaire and HRCT scans, which were categorized by visual assessment as no ILA, early/mild ILA, or extensive ILA. The study endpoint was met when ILA were extensive or when ILD was diagnosed clinically. Among subjects with adequate study time to complete 5-year follow-up HRCT, the proportion with ILD events (endpoint met or radiographic ILA progression) was calculated. Measurements and Main Results: Among 336 subjects, the mean age was 53.1 (SD, 9.9) years. Those with ILA (early/mild [ n = 74] or extensive [ n = 3]) were older, were more likely to be ever smokers, had shorter peripheral blood mononuclear cell telomeres, and were more likely to carry the MUC5B risk allele. Self-reported occupational or environmental exposures, including aluminum smelting, lead, birds, and mold, were independently associated with ILA. Among 129 subjects with sufficient study time, 25 (19.4%) had an ILD event by 5 years after enrollment; of these, 12 met the study endpoint and another 13 had radiologic progression of ILA. ILD events were more common among those with early/mild ILA at enrollment (63.3% vs. 6.1%; P < 0.0001). Conclusions: Rare and common environmental exposures are independent risk factors for radiologic abnormalities. In 5 years, progression of ILA occurred in most individuals with early ILA detected at enrollment.
- Published
- 2020
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37. Defining the clinical phenotype of Saul-Wilson syndrome.
- Author
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Ferreira CR, Zein WM, Huryn LA, Merker A, Berger SI, Wilson WG, Tiller GE, Wolfe LA, Merideth M, Carvalho DR, Duker AL, Bratke H, Haug MG, Rohena L, Hove HB, Xia ZJ, Ng BG, Freeze HH, Gabriel M, Russi AHS, Brick L, Kozenko M, Earl DL, Tham E, Nishimura G, Phillips JA 3rd, Gahl WA, Hamid R, Jackson AP, Grigelioniene G, and Bober MB
- Subjects
- Adult, Female, Humans, Phenotype, Retrospective Studies, Dwarfism
- Abstract
Purpose: Four patients with Saul-Wilson syndrome were reported between 1982 and 1994, but no additional individuals were described until 2018, when the molecular etiology of the disease was elucidated. Hence, the clinical phenotype of the disease remains poorly defined. We address this shortcoming by providing a detailed characterization of its phenotype., Methods: Retrospective chart reviews were performed and primary radiographs assessed for all 14 individuals. Four individuals underwent detailed ophthalmologic examination by the same physician. Two individuals underwent gynecologic evaluation. Z-scores for height, weight, head circumference and body mass index were calculated at different ages., Results: All patients exhibited short stature, with sharp decline from the mean within the first months of life, and a final height Z-score between -4 and -8.5 standard deviations. The facial and radiographic features evolved over time. Intermittent neutropenia was frequently observed. Novel findings included elevation of liver transaminases, skeletal fragility, rod-cone dystrophy, and cystic macular changes., Conclusions: Saul-Wilson syndrome presents a remarkably uniform phenotype, and the comprehensive description of our cohort allows for improved understanding of the long-term morbidity of the condition, establishment of follow-up recommendations for affected individuals, and documentation of the natural history into adulthood for comparison with treated patients, when therapeutics become available.
- Published
- 2020
- Full Text
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38. IgG4-related disease: Association with a rare gene variant expressed in cytotoxic T cells.
- Author
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Newman JH, Shaver A, Sheehan JH, Mallal S, Stone JH, Pillai S, Bastarache L, Riebau D, Allard-Chamard H, Stone WM, Perugino C, Pilkinton M, Smith SA, McDonnell WJ, Capra JA, Meiler J, Cogan J, Xing K, Mahajan VS, Mattoo H, Hamid R, and Phillips JA 3rd
- Subjects
- Adolescent, CD4-Positive T-Lymphocytes metabolism, Genetic Variation genetics, Humans, Immunoglobulin G metabolism, Male, Middle Aged, T-Lymphocytes, Cytotoxic physiology, Immunoglobulin G genetics, Immunoglobulin G4-Related Disease genetics
- Abstract
Background: Family screening of a 48-year-old male with recently diagnosed IgG4-related disease (IgG4-RD) revealed unanticipated elevations in plasma IgG4 in his two healthy teenaged sons., Methods: We performed gene sequencing, immune cell studies, HLA typing, and analyses of circulating cytotoxic CD4+ T lymphocytes and plasmablasts to seek clues to pathogenesis. DNA from a separate cohort of 99 patients with known IgG4-RD was also sequenced for the presence of genetic variants in a specific gene, FGFBP2., Results: The three share a previously unreported heterozygous single base deletion in fibroblast growth factor binding protein type 2 (FGFBP2), which causes a frameshift in the coding sequence. The FGFBP2 protein is secreted by cytotoxic T-lymphocytes and binds fibroblast growth factor. The variant sequence in the FGFBP2 protein is predicted to form a disordered random coil rather than a helical-turn-helix structure, unable to adopt a stable conformation. The proband and the two sons had 5-10-fold higher numbers of circulating cytotoxic CD4 + T cells and plasmablasts compared to matched controls. The three members also share a homozygous missense common variant in FGFBP2 found in heterozygous form in ~40% of the population. This common variant was found in 73% of an independent, well characterized IgG4-RD cohort, showing enrichment in idiopathic IgG4-RD., Conclusions: The presence of a shared deleterious variant and homozygous common variant in FGFBP2 in the proband and sons strongly implicates this cytotoxic T cell product in the pathophysiology of IgG4-RD. The high prevalence of a common FGFBP2 variant in sporadic IgG4-RD supports the likelihood of participation in disease., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
- Published
- 2019
- Full Text
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39. Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.
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Karolak JA, Vincent M, Deutsch G, Gambin T, Cogné B, Pichon O, Vetrini F, Mefford HC, Dines JN, Golden-Grant K, Dipple K, Freed AS, Leppig KA, Dishop M, Mowat D, Bennetts B, Gifford AJ, Weber MA, Lee AF, Boerkoel CF, Bartell TM, Ward-Melver C, Besnard T, Petit F, Bache I, Tümer Z, Denis-Musquer M, Joubert M, Martinovic J, Bénéteau C, Molin A, Carles D, André G, Bieth E, Chassaing N, Devisme L, Chalabreysse L, Pasquier L, Secq V, Don M, Orsaria M, Missirian C, Mortreux J, Sanlaville D, Pons L, Küry S, Bézieau S, Liet JM, Joram N, Bihouée T, Scott DA, Brown CW, Scaglia F, Tsai AC, Grange DK, Phillips JA 3rd, Pfotenhauer JP, Jhangiani SN, Gonzaga-Jauregui CG, Chung WK, Schauer GM, Lipson MH, Mercer CL, van Haeringen A, Liu Q, Popek E, Coban Akdemir ZH, Lupski JR, Szafranski P, Isidor B, Le Caignec C, and Stankiewicz P
- Subjects
- DNA Copy Number Variations genetics, Female, Fibroblast Growth Factor 10 metabolism, Gene Expression Regulation, Gestational Age, Humans, Infant, Newborn, Infant, Newborn, Diseases metabolism, Infant, Newborn, Diseases pathology, Lung embryology, Lung growth & development, Lung Diseases metabolism, Lung Diseases pathology, Male, Maternal Inheritance, Organogenesis, Paternal Inheritance, Pedigree, Polymorphism, Single Nucleotide genetics, Receptor, Fibroblast Growth Factor, Type 2 metabolism, T-Box Domain Proteins metabolism, Fibroblast Growth Factor 10 genetics, Infant, Newborn, Diseases genetics, Infant, Newborn, Diseases mortality, Lung Diseases genetics, Lung Diseases mortality, Signal Transduction genetics, T-Box Domain Proteins genetics
- Abstract
Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
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40. Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease.
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Splinter K, Adams DR, Bacino CA, Bellen HJ, Bernstein JA, Cheatle-Jarvela AM, Eng CM, Esteves C, Gahl WA, Hamid R, Jacob HJ, Kikani B, Koeller DM, Kohane IS, Lee BH, Loscalzo J, Luo X, McCray AT, Metz TO, Mulvihill JJ, Nelson SF, Palmer CGS, Phillips JA 3rd, Pick L, Postlethwait JH, Reuter C, Shashi V, Sweetser DA, Tifft CJ, Walley NM, Wangler MF, Westerfield M, Wheeler MT, Wise AL, Worthey EA, Yamamoto S, and Ashley EA
- Subjects
- Adult, Animals, Child, Diagnosis, Differential, Drosophila, Exome, Female, Health Care Costs statistics & numerical data, Humans, Male, Models, Animal, National Institutes of Health (U.S.), Rare Diseases diagnosis, Syndrome, United States, Genetic Testing economics, Rare Diseases genetics, Sequence Analysis, DNA
- Abstract
Background: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added., Methods: We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care., Results: A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes., Conclusions: The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).
- Published
- 2018
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41. A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation.
- Author
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Ferreira CR, Xia ZJ, Clément A, Parry DA, Davids M, Taylan F, Sharma P, Turgeon CT, Blanco-Sánchez B, Ng BG, Logan CV, Wolfe LA, Solomon BD, Cho MT, Douglas G, Carvalho DR, Bratke H, Haug MG, Phillips JB, Wegner J, Tiemeyer M, Aoki K, Nordgren A, Hammarsjö A, Duker AL, Rohena L, Hove HB, Ek J, Adams D, Tifft CJ, Onyekweli T, Weixel T, Macnamara E, Radtke K, Powis Z, Earl D, Gabriel M, Russi AHS, Brick L, Kozenko M, Tham E, Raymond KM, Phillips JA 3rd, Tiller GE, Wilson WG, Hamid R, Malicdan MCV, Nishimura G, Grigelioniene G, Jackson A, Westerfield M, Bober MB, Gahl WA, and Freeze HH
- Subjects
- Adult, Amino Acid Substitution genetics, Animals, Animals, Genetically Modified genetics, Cell Line, Child, Child, Preschool, Endoplasmic Reticulum genetics, Extracellular Matrix genetics, Female, Fibroblasts pathology, Glycosylation, Golgi Apparatus genetics, Heterozygote, Humans, Infant, Male, Zebrafish, Fragile X Syndrome genetics, Protein Transport genetics, Proteoglycans genetics, Vesicular Transport Proteins genetics
- Abstract
The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG., (Published by Elsevier Inc.)
- Published
- 2018
- Full Text
- View/download PDF
42. Phenotypic heterogeneity of ZMPSTE24 deficiency.
- Author
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Cassini TA, Robertson AK, Bican AG, Cogan JD, Hannig VL, Newman JH, Hamid R, and Phillips JA 3rd
- Subjects
- Alleles, Child, Preschool, DNA Mutational Analysis, Female, Genotype, Humans, Mutation, Exome Sequencing, Biological Variation, Population genetics, Genetic Association Studies methods, Genetic Predisposition to Disease, Membrane Proteins deficiency, Metalloendopeptidases deficiency, Phenotype
- Abstract
A 4-year-old girl was referred to the Undiagnosed Diseases Network with a history of short stature, thin and translucent skin, macrocephaly, small hands, and camptodactyly. She had been diagnosed with possible Hallerman-Streiff syndrome. Her evaluation showed that she was mosaic for uniparental isodisomy of chromosome 1, which harbored a pathogenic c.1077dupT variant in ZMPSTE24 which predicts p.(Leu362fsX18). ZMPSTE24 is a zinc metalloproteinase that is involved in processing farnesylated proteins and pathogenic ZMPSTE24 variants cause accumulation of abnormal farnesylated forms of prelamin A. This, in turn, causes a spectrum of disease severity which is based on enzyme activity. The current patient has an intermediate form, which is a genocopy of severe Progeria., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
- Full Text
- View/download PDF
43. Clinical heterogeneity of mitochondrial NAD kinase deficiency caused by a NADK2 start loss variant.
- Author
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Pomerantz DJ, Ferdinandusse S, Cogan J, Cooper DN, Reimschisel T, Robertson A, Bican A, McGregor T, Gauthier J, Millington DS, Andrae JLW, Tschannen MR, Helbling DC, Demos WM, Denis S, Wanders RJA, Newman JN, Hamid R, and Phillips JA 3rd
- Subjects
- Adolescent, Alleles, Amino Acid Sequence, Amino Acid Substitution, Biomarkers, Brain pathology, DNA Mutational Analysis, Female, Genotype, Humans, Magnetic Resonance Imaging, Male, Mitochondrial Proteins chemistry, Mitochondrial Proteins metabolism, Phosphotransferases (Alcohol Group Acceptor) chemistry, Phosphotransferases (Alcohol Group Acceptor) metabolism, Genes, Mitochondrial, Genetic Association Studies, Mitochondrial Proteins deficiency, Mitochondrial Proteins genetics, Mutation, Phenotype, Phosphotransferases (Alcohol Group Acceptor) deficiency, Phosphotransferases (Alcohol Group Acceptor) genetics
- Abstract
Mitochondrial NAD kinase deficiency (NADK2D, OMIM #615787) is a rare autosomal recessive disorder of NADPH biosynthesis that can cause hyperlysinemia and dienoyl-CoA reductase deficiency (DECRD, OMIM #616034). NADK2 deficiency has been reported in only three unrelated patients. Two had severe, unremitting disease; one died at 4 months and the other at 5 years of age. The third was a 10 year old female with CNS anomalies, ataxia, and incoordination. In two cases mutations in NADK2 have been demonstrated. Here, we report the fourth known case, a 15 year old female with normal intelligence and a mild clinical and biochemical phenotype presumably without DECRD. Her clinical symptoms, which are now stable, became evident at the age of 9 with the onset of decreased visual acuity, bilateral optic atrophy, nystagmus, episodic lower extremity weakness, peripheral neuropathy, and gait abnormalities. Plasma amino acid levels were within normal limits except for mean lysine and proline levels that were 3.7 and 2.5 times the upper limits of normal. Whole exome sequencing (WES) revealed homozygosity for a g.36241900 A>G p. Met1Val start loss mutation in the primary NADK2 transcript (NM_001085411.1) encoding the 442 amino acid isoform. This presumed hypomorphic mutation has not been previously reported and is absent from the v1000GP, EVS, and ExAC databases. Our patient's normal intelligence and stable disease expands the clinical heterogeneity and the prognosis associated with NADK2 deficiency. Our findings also clarify the mechanism underlying NADK2 deficiency and suggest that this disease should be ruled out in cases of hyperlysinemia, especially those with visual loss, and neurological phenotypes., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
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44. Rare Genetic Variants in PARN Are Associated with Pulmonary Fibrosis in Families.
- Author
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Kropski JA, Reiss S, Markin C, Brown KK, Schwartz DA, Schwarz MI, Loyd JE, Phillips JA 3rd, Blackwell TS, and Cogan JD
- Subjects
- Humans, Genetic Variation genetics, Pulmonary Fibrosis genetics
- Published
- 2017
- Full Text
- View/download PDF
45. Nano-Calorimetry based point of care biosensor for metabolic disease management.
- Author
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Kazura E, Lubbers BR, Dawson E, Phillips JA 3rd, and Baudenbacher F
- Subjects
- Equipment Design, Limit of Detection, Phenylalanine blood, Phenylalanine Ammonia-Lyase metabolism, Phenylketonurias diagnosis, Biosensing Techniques instrumentation, Calorimetry instrumentation, Nanotechnology instrumentation, Phenylketonurias blood, Point-of-Care Systems
- Abstract
Point of care (POC) diagnostics represents one of the fastest growing health care technology segments. Developments in microfabrication have led to the development of highly-sensitive nanocalorimeters ideal for directly measuring heat generated in POC biosensors. Here we present a novel nano-calorimeter-based biosensor design with differential sensing to eliminate common mode noise and capillary microfluidic channels for sample delivery to the thermoelectric sensor. The calorimeter has a resolution of 1.4 ± 0.2 nJ/(Hz)
1/2 utilizing a 27 junction bismuth/titanium thermopile, with a total Seebeck coefficient of 2160 μV/K. Sample is wicked to the calorimeter through a capillary channel making it suitable for monitoring blood obtained through a finger prick (<1 μL sample required). We demonstrate device performance in a model assay using catalase, achieving a threshold for hydrogen peroxide quantification of 50 μM. The potential for our device as a POC blood test for metabolic diseases is shown through the quantification of phenylalanine (Phe) in serum, an unmet necessary service in the management of Phenylketonuria (PKU). Pegylated phenylalanine ammonia-lyase (PEG-PAL) was utilized to react with Phe, but reliable detection was limited to <5 mM due to low enzymatic activity. The POC biosensor concept can be multiplexed and adapted to a large number of metabolic diseases utilizing different immobilized enzymes.- Published
- 2017
- Full Text
- View/download PDF
46. Genetic analysis of Mayer-Rokitansky-Kuster-Hauser syndrome in a large cohort of families.
- Author
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Williams LS, Demir Eksi D, Shen Y, Lossie AC, Chorich LP, Sullivan ME, Phillips JA 3rd, Erman M, Kim HG, Alper OM, and Layman LC
- Subjects
- Adult, Cohort Studies, Family, Genetic Markers genetics, Genetic Predisposition to Disease epidemiology, Genetic Predisposition to Disease genetics, Humans, Internationality, Prevalence, Risk Factors, Young Adult, 46, XX Disorders of Sex Development epidemiology, 46, XX Disorders of Sex Development genetics, Congenital Abnormalities epidemiology, Congenital Abnormalities genetics, Hepatocyte Nuclear Factor 1-beta genetics, LIM-Homeodomain Proteins genetics, Mullerian Ducts abnormalities, Polymorphism, Single Nucleotide genetics, Transcription Factors genetics, Wnt4 Protein genetics
- Abstract
Objective: To study the genetic cause of Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). Although a few candidate genes and genomic domains for have been reported for MRKH, the genetic underpinnings remain largely unknown. Some of the top candidate genes are WNT4, HNF1B, and LHX1. The goals of this study were to: 1) determine the prevalence of WNT4, HNF1B, and LHX1 point mutations, as well as new copy number variants (CNVs) in people with MRKH; and 2) identify and characterize MRKH cohorts., Design: Laboratory- and community-based study., Setting: Academic medical centers., Patient(s): A total of 147 MRKH probands and available family members., Interventions(s): DNA sequencing of WNT4, HNF1B, and LHX1 in 100 MRKH patients, chromosomal microarray analysis in 31 North American MRKH patients, and characterization and sample collection of 147 North American and Turkish MRKH probands and their families., Main Outcome Measure(s): DNA sequence variants and CNVs; pedigree structural analysis., Result(s): We report finding CNVs in 6/31 people (∼19%) with MRKH, but no point mutations or small indels in WNT4, HNF1B, or LHX1 in 100 MRKH patients. Our MRKH families included 43 quads, 26 trios, and 30 duos. Of our MRKH probands, 87/147 (59%) had MRKH type 1 and 60/147 (41%) had type 2 with additional anomalies., Conclusion(s): Although the prevalence of WNT4, HNF1B, and LHX1 point mutations is low in people with MRKH, the prevalence of CNVs was ∼19%. Further analysis of our large familial cohort of patients will facilitate gene discovery to better understand the complex etiology of MRKH., (Copyright © 2017 American Society for Reproductive Medicine. All rights reserved.)
- Published
- 2017
- Full Text
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47. Genetic Evaluation and Testing of Patients and Families with Idiopathic Pulmonary Fibrosis.
- Author
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Kropski JA, Young LR, Cogan JD, Mitchell DB, Lancaster LH, Worrell JA, Markin C, Liu N, Mason WR, Fingerlin TE, Schwartz DA, Lawson WE, Blackwell TS, Phillips JA 3rd, and Loyd JE
- Subjects
- DNA Mutational Analysis, Genetic Testing, Humans, Mutation, Idiopathic Pulmonary Fibrosis genetics
- Published
- 2017
- Full Text
- View/download PDF
48. Cystic fibrosis in Afro-Brazilians: XK haplotypes analysis supports the European origin of p.F508del mutation.
- Author
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de Souza DA, Faucz FR, de Alexandre RB, Santana MA, de Souza EL, Reis FJ, Pereira-Ferrari L, Sotomaior VS, Culpi L, Phillips JA 3rd, and Raskin S
- Subjects
- Alleles, Brazil, Case-Control Studies, Gene Frequency, Genetics, Population, Humans, Male, Cystic Fibrosis genetics, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Ethnicity genetics, Haplotypes, Mutation
- Abstract
Cystic fibrosis (CF) is a common autosomal recessive disorder, being the p.F508del the most frequent mutation. Also, a nearby restriction fragment length polymorphism (RFLP) named XK (KM19 and XV2C) is non-randomly associated with specific CF alleles. Our aim was to analyze the occurrence of the p.F508del mutation and XK haplotypes in Afro-Brazilians CF patients and controls, since these data is available for the other two main ethnic groups found in Brazil (Euro-Brazilians and Brazilian Amerindians), contributing for the whole comprehension of these haplotypes in the Brazilian population. A total of 103 patients and 54 controls were studied. PCR and PCR-RFLP methodologies were used to identify the presence of the p.F508del and the XK haplotype in the subjects. The combined data show that 84.2% of p.F508del mutation is associated with haplotype B and only 15.8% with haplotype A; no other haplotypes were found to be associated with this mutation. Our data suggest that the occurrence of p.F508del mutation and haplotype B in Afro-Brazilian patients occurs probably due to admixture with Euro-descendants. Therefore this mutation and haplotype could be used as a admixture marker.
- Published
- 2017
- Full Text
- View/download PDF
49. Whole exome sequencing identifies multiple diagnoses in congenital glaucoma with systemic anomalies.
- Author
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Reis LM, Tyler RC, Weh E, Hendee KE, Schilter KF, Phillips JA 3rd, Sequeira S, Schinzel A, and Semina EV
- Subjects
- Alleles, Cytochrome P-450 CYP1B1 chemistry, Cytochrome P-450 CYP1B1 genetics, DNA Mutational Analysis, Exome, Female, Forkhead Transcription Factors chemistry, Forkhead Transcription Factors genetics, Glaucoma congenital, Heterozygote, Humans, Infant, Male, Membrane Proteins chemistry, Membrane Proteins genetics, Pedigree, Sequence Analysis, DNA, Glaucoma genetics
- Abstract
The genetic basis of congenital glaucoma with systemic anomalies is largely unknown. Whole exome sequencing (WES) in 10 probands with congenital glaucoma and variable systemic anomalies identified pathogenic or likely pathogenic variants in three probands; in two of these, a combination of two Mendelian disorders was found to completely explain the patients' features whereas in the third case only the ocular findings could be explained by the genetic diagnosis. The molecular diagnosis for glaucoma included two cases with compound heterozygous or homozygous pathogenic alleles in CYP1B1 and one family with a dominant pathogenic variant in FOXC1; the second genetic diagnosis for the additional systemic features included compound heterozygous mutations in NPHS1 in one family and a heterozygous 18q23 deletion in another pedigree. These findings show the power of WES in the analysis of complex conditions and emphasize the importance of CYP1B1 screening in patients with congenital glaucoma regardless of the presence/absence of other systemic anomalies., Competing Interests: The authors declare that they have no conflict of interest., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2016
- Full Text
- View/download PDF
50. Answers to Epilogue questions.
- Author
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Maalouf FI, Coggins SA, Phillips JA 3rd, Stefanescu BM, and Weitkamp JH
- Subjects
- Humans, Alkaline Phosphatase blood, Alkaline Phosphatase genetics, Calcification, Physiologic genetics, Hypophosphatasia diagnosis, Hypophosphatasia genetics, Mutation
- Published
- 2016
- Full Text
- View/download PDF
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