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Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams.
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Sequenciamento de Nucleotídeos em Larga Escala , Fenótipo , Humanos , Feminino , Masculino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Criança , Alemanha , Sequenciamento do Exoma/métodos , Adolescente , Estudos de Associação Genética/métodos , Testes Genéticos/métodos , Pré-Escolar , Estudos Prospectivos , Adulto , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Lactente , Adulto JovemRESUMO
In the era of high throughput sequencing, special software is required for the clinical evaluation of genetic variants. We developed REEV (Review, Evaluate and Explain Variants), a user-friendly platform for clinicians and researchers in the field of rare disease genetics. Supporting data was aggregated from public data sources. We compared REEV with seven other tools for clinical variant evaluation. REEV (semi-)automatically fills individual ACMG criteria facilitating variant interpretation. REEV can store disease and phenotype data related to a case to use these for phenotype similarity measures. Users can create public permanent links for individual variants that can be saved as browser bookmarks and shared. REEV may help in the fast diagnostic assessment of genetic variants in a clinical as well as in a research context. REEV (https://reev.bihealth.org/) is free and open to all users and there is no login requirement.
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Variação Genética , Software , Humanos , Fenótipo , Sequenciamento de Nucleotídeos em Larga Escala , Doenças Raras/genética , Doenças Raras/diagnóstico , Bases de Dados GenéticasRESUMO
The Niger Delta in Nigeria is a complex and heavily contaminated area with over 150,000 interconnected contaminated sites. This intricate issue is compounded by the region's strong hydrological processes and high-energy environment, necessitating a science-based approach for effective contamination assessment and management. This study introduces the concept of sub-catchment contamination assessment and management, providing an overarching perspective rather than addressing each site individually. A description of the sub-catchment delineation process using the digital elevation model data from an impacted area within the Delta is provided. Additionally, the contamination status from the delineated sub-catchment is reported. Sediment, surface water and groundwater samples from the sub-catchment were analyzed for total petroleum hydrocarbons (TPH) and polycyclic aromatic hydrocarbons (PAHs), respectively. Surface sediment TPH concentrations ranged from 129 to 20,600 mg/kg, with subsurface (2-m depth) concentrations from 15.5 to 729 mg/kg. PAHs in surface and subsurface sediment reached 9.55 mg/kg and 0.46 mg/kg, respectively. Surface water exhibited TPH concentrations from 10 to 620 mg/L, while PAHs ranged from below detection limits to 1 mg/L. Groundwater TPH concentrations spanned 3 to 473 mg/L, with total PAHs varying from below detection limits to 0.28 mg/L. These elevated TPH and PAH levels indicate extensive petroleum contamination in the investigated sediment and water environment. Along with severe impacts on large areas of mangroves and wetlands, comparison of TPH and PAH concentrations with sediment and water quality criteria found 54 to 100% of stations demonstrated exceedances, suggesting adverse biological effects on aquatic and sediment biota are likely occurring.
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Monitoramento Ambiental , Sedimentos Geológicos , Água Subterrânea , Poluição por Petróleo , Petróleo , Hidrocarbonetos Policíclicos Aromáticos , Poluentes Químicos da Água , Monitoramento Ambiental/métodos , Petróleo/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Nigéria , Poluentes Químicos da Água/análise , Poluição por Petróleo/análise , Sedimentos Geológicos/química , Água Subterrânea/químicaRESUMO
A lot of underdeveloped nations particularly in Africa struggle with cancer-related, deadly diseases. Particularly in women, the incidence of breast cancer is rising daily because of ignorance and delayed diagnosis. Only by correctly identifying and diagnosing cancer in its very early stages of development can be effectively treated. The classification of cancer can be accelerated and automated with the aid of computer-aided diagnosis and medical image analysis techniques. This research provides the use of transfer learning from a Residual Network 18 (ResNet18) and Residual Network 34 (ResNet34) architectures to detect breast cancer. The study examined how breast cancer can be identified in breast mammography pictures using transfer learning from ResNet18 and ResNet34, and developed a demo app for radiologists using the trained models with the best validation accuracy. 1, 200 datasets of breast x-ray mammography images from the National Radiological Society's (NRS) archives were employed in the study. The dataset was categorised as implant cancer negative, implant cancer positive, cancer negative and cancer positive in order to increase the consistency of x-ray mammography images classification and produce better features. For the multi-class classification of the images, the study gave an average accuracy for binary classification of benign or malignant cancer cases of 86.7% validation accuracy for ResNet34 and 92% validation accuracy for ResNet18. A prototype web application showcasing ResNet18 performance has been created. The acquired results show how transfer learning can improve the accuracy of breast cancer detection, providing invaluable assistance to medical professionals, particularly in an African scenario.
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Neoplasias da Mama , Feminino , Humanos , Mamografia/métodos , Mama/diagnóstico por imagem , Diagnóstico por Computador , Aprendizado de MáquinaRESUMO
Pathogenic variants in TRIO, encoding the guanine nucleotide exchange factor, are associated with two distinct neurodevelopmental delay phenotypes: gain-of-function missense mutations within the spectrin repeats are causative for a severe developmental delay with macrocephaly (MIM: 618825), whereas loss-of-function missense variants in the GEF1 domain and truncating variants throughout the gene lead to a milder developmental delay and microcephaly (MIM: 617061). In three affected family members with mild intellectual disability/NDD and microcephaly, we detected a novel heterozygous TRIO variant at the last coding base of exon 31 (NM_007118.4:c.4716G>A). RNA analysis from patient-derived lymphoblastoid cells confirmed aberrant splicing resulting in the skipping of exon 31 (r.4615_4716del), leading to an in-frame deletion in the first Pleckstrin homology subdomain of the GEF1 domain: p.(Thr1539_Lys1572del). To test for a distinct gestalt, facial characteristics of the family members and 41 previously published TRIO cases were systematically evaluated via GestaltMatcher. Computational analysis of the facial gestalt suggests a distinguishable facial TRIO-phenotype not outlined in the existing literature.
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Fatores de Troca do Nucleotídeo Guanina , Linhagem , Fenótipo , Sítios de Splice de RNA , Humanos , Fatores de Troca do Nucleotídeo Guanina/genética , Masculino , Feminino , Sítios de Splice de RNA/genética , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Microcefalia/genética , Microcefalia/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Éxons/genética , Splicing de RNA/genética , Fácies , Proteínas Serina-Treonina QuinasesRESUMO
BACKGROUND: While characteristic facial features provide important clues for finding the correct diagnosis in genetic syndromes, valid assessment can be challenging. The next-generation phenotyping algorithm DeepGestalt analyzes patient images and provides syndrome suggestions. GestaltMatcher matches patient images with similar facial features. The new D-Score provides a score for the degree of facial dysmorphism. OBJECTIVE: We aimed to test state-of-the-art facial phenotyping tools by benchmarking GestaltMatcher and D-Score and comparing them to DeepGestalt. METHODS: Using a retrospective sample of 4796 images of patients with 486 different genetic syndromes (London Medical Database, GestaltMatcher Database, and literature images) and 323 inconspicuous control images, we determined the clinical use of D-Score, GestaltMatcher, and DeepGestalt, evaluating sensitivity; specificity; accuracy; the number of supported diagnoses; and potential biases such as age, sex, and ethnicity. RESULTS: DeepGestalt suggested 340 distinct syndromes and GestaltMatcher suggested 1128 syndromes. The top-30 sensitivity was higher for DeepGestalt (88%, SD 18%) than for GestaltMatcher (76%, SD 26%). DeepGestalt generally assigned lower scores but provided higher scores for patient images than for inconspicuous control images, thus allowing the 2 cohorts to be separated with an area under the receiver operating characteristic curve (AUROC) of 0.73. GestaltMatcher could not separate the 2 classes (AUROC 0.55). Trained for this purpose, D-Score achieved the highest discriminatory power (AUROC 0.86). D-Score's levels increased with the age of the depicted individuals. Male individuals yielded higher D-scores than female individuals. Ethnicity did not appear to influence D-scores. CONCLUSIONS: If used with caution, algorithms such as D-score could help clinicians with constrained resources or limited experience in syndromology to decide whether a patient needs further genetic evaluation. Algorithms such as DeepGestalt could support diagnosing rather common genetic syndromes with facial abnormalities, whereas algorithms such as GestaltMatcher could suggest rare diagnoses that are unknown to the clinician in patients with a characteristic, dysmorphic face.
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Algoritmos , Benchmarking , Humanos , Feminino , Masculino , Estudos Retrospectivos , Área Sob a Curva , ComputadoresRESUMO
Clinical exome and genome sequencing have revolutionized the understanding of human disease genetics. Yet many genes remain functionally uncharacterized, complicating the establishment of causal disease links for genetic variants. While several scoring methods have been devised to prioritize these candidate genes, these methods fall short of capturing the expression heterogeneity across cell subpopulations within tissues. Here, we introduce single-cell tissue-specific gene prioritization using machine learning (STIGMA), an approach that leverages single-cell RNA-seq (scRNA-seq) data to prioritize candidate genes associated with rare congenital diseases. STIGMA prioritizes genes by learning the temporal dynamics of gene expression across cell types during healthy organogenesis. To assess the efficacy of our framework, we applied STIGMA to mouse limb and human fetal heart scRNA-seq datasets. In a cohort of individuals with congenital limb malformation, STIGMA prioritized 469 variants in 345 genes, with UBA2 as a notable example. For congenital heart defects, we detected 34 genes harboring nonsynonymous de novo variants (nsDNVs) in two or more individuals from a set of 7,958 individuals, including the ortholog of Prdm1, which is associated with hypoplastic left ventricle and hypoplastic aortic arch. Overall, our findings demonstrate that STIGMA effectively prioritizes tissue-specific candidate genes by utilizing single-cell transcriptome data. The ability to capture the heterogeneity of gene expression across cell populations makes STIGMA a powerful tool for the discovery of disease-associated genes and facilitates the identification of causal variants underlying human genetic disorders.
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Cardiopatias Congênitas , Transcriptoma , Humanos , Animais , Camundongos , Exoma/genética , Cardiopatias Congênitas/genética , Sequenciamento do Exoma , Aprendizado de Máquina , Análise de Célula Única/métodos , Enzimas Ativadoras de Ubiquitina/genéticaRESUMO
BACKGROUND/OBJECTIVES: Tooth agenesis (TA) is among the most common malformations in humans. Although several causative mutations have been described, the genetic cause often remains elusive. Here, we test whether whole genome sequencing (WGS) could bridge this diagnostic gap. METHODS: In four families with TA, we assessed the dental phenotype using the Tooth Agenesis Code after intraoral examination and radiographic and photographic documentation. We performed WGS of index patients and subsequent segregation analysis. RESULTS: We identified two variants of uncertain significance (a potential splice variant in PTH1R, and a 2.1 kb deletion abrogating a non-coding element in FGF7) and three pathogenic variants: a novel frameshift in the final exon of PITX2, a novel deletion in PAX9, and a known nonsense variant in WNT10A. Notably, the FGF7 variant was found in the patient, also featuring the WNT10A variant. While mutations in PITX2 are known to cause Axenfeld-Rieger syndrome 1 (ARS1) predominantly featuring ocular findings, accompanied by dental malformations, we found the PITX2 frameshift in a family with predominantly dental and varying ocular findings. CONCLUSION: Severe TA predicts a genetic cause identifiable by WGS. Final exon PITX2 frameshifts can cause a predominantly dental form of ARS1.
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Valosin-containing protein (VCP) is an AAA+ ATPase that plays critical roles in multiple ubiquitin-dependent cellular processes. Dominant pathogenic variants in VCP are associated with adult-onset multisystem proteinopathy (MSP), which manifests as myopathy, bone disease, dementia, and/or motor neuron disease. Through GeneMatcher, we identified 13 unrelated individuals who harbor heterozygous VCP variants (12 de novo and 1 inherited) associated with a childhood-onset disorder characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly. Trio exome sequencing or a multigene panel identified nine missense variants, two in-frame deletions, one frameshift, and one splicing variant. We performed in vitro functional studies and in silico modeling to investigate the impact of these variants on protein function. In contrast to MSP variants, most missense variants had decreased ATPase activity, and one caused hyperactivation. Other variants were predicted to cause haploinsufficiency, suggesting a loss-of-function mechanism. This cohort expands the spectrum of VCP-related disease to include neurodevelopmental disease presenting in childhood.
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Doenças Musculares , Transtornos do Neurodesenvolvimento , Adulto , Humanos , Proteína com Valosina/genética , Hipotonia Muscular , Mutação de Sentido Incorreto/genéticaRESUMO
PURPOSE: HOXD13 is an important regulator of limb development. Pathogenic variants in HOXD13 cause synpolydactyly type 1 (SPD1). How different types and positions of HOXD13 variants contribute to genotype-phenotype correlations, penetrance, and expressivity of SPD1 remains elusive. Here, we present a novel cohort and a literature review to elucidate HOXD13 phenotype-genotype correlations. METHODS: Patients with limb anomalies suggestive of SPD1 were selected for analysis of HOXD13 by Sanger sequencing, repeat length analysis, and next-generation sequencing. Literature was reviewed for HOXD13 heterozygotes. Variants were annotated for phenotypic data. Severity was calculated, and cluster and decision-tree analyses were performed. RESULTS: We identified 98 affected members of 38 families featuring 11 different (likely) causative variants and 4 variants of uncertain significance. The most frequent (25/38) were alanine repeat expansions. Phenotypes ranged from unaffected heterozygotes to severe osseous synpolydactyly, with intra- and inter-familial heterogeneity and asymmetry. A literature review provided 160 evaluable affected members of 49 families with SPD1. Computer-aided analysis only corroborated a positive correlation between alanine repeat length and phenotype severity. CONCLUSION: Our findings support that HOXD13-protein condensation in addition to haploinsufficiency is the molecular pathomechanism of SPD1. Our data may, also, facilitate the interpretation of synpolydactyly radiographs by future automated tools.
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Proteínas de Homeodomínio , Sindactilia , Humanos , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Sindactilia/genética , Genótipo , Fenótipo , Linhagem , Alanina/genética , MutaçãoRESUMO
This study evaluated the effects of neem seed biochar, poultry manure, and their combinations at varying rates of 15 and 25% (w/w) on potentially toxic elements (PTEs) in soils. Afterward, the suitability of Manihot esculenta and Jatropha curcas in removing Cd, As, Zn, Pb, and Hg from mine spoils were appraised in a 270-day outdoor pot experiment. Using ICP-Mass Spectrometry, the elemental contents of target PTE in the shoot, root, and soil specimens were determined for each treatment. The obtained average values were further subjected to a nonparametric test of samples using IBM SPSS Statistic 29. The applied organic amendments resulted in significant differences p < 0.05 in PTE availability for plant uptake after the Independent-Samples Kruskal-Wallis Test was made. Nonetheless, applying a 25% (w/w) mixture of neem seed biochar and poultry manure was efficient in immobilizing more PTEs in soils which caused lower PTEs presence in plants. Organic amendments further significantly enhanced the fertility of the mine soils leading to about a 6- 25.00% increase in the biomass yield (p < 0.05) of both plants. No significant difference (p > 0.05) was however observed between the phytoremediation potentials of both plants after the Independent-Sample Mann-Whitney U test. Even that, Manihot esculenta was averagely more efficient in PTE uptake than Jatropha curcas. Larger portions of the bioaccumulated PTEs were stored in the roots of both plants leading to high bioconcentration factors of 1.94- 2.47 mg/kg and 1.27- 4.70 mg/kg, respectively, for Jatropha curcas and Manihot esculenta. A transfer factor < 1 was achieved for all PTEs uptake by both plants and indicated their suitability for phytostabilization. Techniques for easy cultivation of root-storing PTEs are required to enhance their large-scale use as their biomass could further be used in clean energy production.
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Jatropha , Manihot , Metais Pesados , Poluentes do Solo , Animais , Biodegradação Ambiental , Metais Pesados/análise , Esterco/análise , Poluentes do Solo/análise , Solo/química , Aves Domésticas , Monitoramento Ambiental , Sementes/químicaRESUMO
Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1-3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6-8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.
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Nucléolo Celular , Proteína HMGB1 , Humanos , Arginina/genética , Arginina/metabolismo , Nucléolo Celular/genética , Nucléolo Celular/metabolismo , Nucléolo Celular/patologia , Proteína HMGB1/química , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/genética , Proteínas Intrinsicamente Desordenadas/metabolismo , Síndrome , Mutação da Fase de Leitura , Transição de FaseRESUMO
This study answered the question of whether mine spoils occurring in a common geological location had similarities in their contaminant load and associated health risks. Using inductively coupled plasma mass spectrometry, the total contents of Cd, Pb, As, Hg, Zn, Fe, and Al were determined for 110 digested soil samples obtained from underground rock ore (URS), oxide ore (OXS), and alluvial ore (AVS) mine spoils. Independent sample Kruskal-Wallis test and pairwise comparisons of sources were used to ascertain the variation in elemental load between the mine spoil investigated. The results showed that mine spoil contaminations and their ecological and health risk significantly varied (p < 0.01) from each other and fell in the order OXS > URS > AVS > forest soils because of their geochemistry. Determined enrichment and geo-accumulation indices revealed that OXS and URS sites were severely-extremely polluted with Cd, Hg, and As, while AVS mine spoils were only moderately contaminated by Cd and As contents. Children had the highest tendency for developing noncarcinogenic health defects largely due to toxic contents of As, Cd, and Hg in soil materials near them than adult men and women would after obtaining a hazard index of 73.5 and 67.7 (unitless) at both OXS and URS sites. Mine spoils especially where hard rocks and oxide ores were processed are not fit for agricultural use or human habitation. The restriction of human access and sustainable remediation approaches are required to avert health defects. Even so, area-specific potentially toxic elements must be targeted during soil cleaning due to the significant variations in contaminant load between mined sites.
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Mercúrio , Metais Pesados , Poluentes do Solo , Criança , Humanos , Feminino , Ouro/análise , Cádmio/análise , Monitoramento Ambiental/métodos , Mercúrio/análise , Solo/química , Poluentes do Solo/análise , Metais Pesados/análise , Medição de RiscoRESUMO
The properties of oxide dispersion-strengthened steels are highly dependent on the nature and size distribution of their constituting nano-oxide precipitates. A fine control of the processes of synthesis would enable the optimization of pertinent properties for use in various energy systems. This control, however, requires knowledge of the precise mechanisms of nucleation and growth of the nanoprecipitates, which are still a matter of debate. In the present study, nano-oxide precipitates were produced via the implantation of Y, Ti, and O ions in two different sequential orders in an Fe-10%Cr matrix that was subsequently thermally annealed. The results show that the oxides that precipitate are not necessarily favoured thermodynamically, but rather result from complex kinetics aspects related to the interaction between the implanted elements and induced defects. When Y is implanted first, the formation of nanoprecipitates with characteristics similar to those in conventionally produced ODS steels, especially with a core/shell structure, is evidenced. In contrast, when implantation starts with Ti, the precipitation of yttria during subsequent high-temperature annealing is totally suppressed, and corundum Cr2O3 precipitates instead. Moreover, the systematic involvement of {110} matrix planes in orientation relationships with the precipitates, independently of the precipitate nature, suggests matrix restriction effects on the early stages of precipitation.
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BACKGROUND: Variants in genes of the nucleotide excision repair (NER) pathway have been associated with heterogeneous clinical presentations ranging from xeroderma pigmentosum to Cockayne syndrome and trichothiodystrophy. NER deficiencies manifest with photosensitivity and skin cancer, but also developmental delay and early-onset neurological degeneration. Adult-onset neurological features have been reported in only a few xeroderma pigmentosum cases, all showing at least mild skin manifestations. OBJECTIVE: The aim of this multicenter study was to investigate the frequency and clinical features of patients with biallelic variants in NER genes who are predominantly presenting with neurological signs. METHODS: In-house exome and genome datasets of 14,303 patients, including 3543 neurological cases, were screened for deleterious variants in NER-related genes. Clinical workup included in-depth neurological and dermatological assessments. RESULTS: We identified 13 patients with variants in ERCC4 (n = 8), ERCC2 (n = 4), or XPA (n = 1), mostly proven biallelic, including five different recurrent and six novel variants. All individuals had adult-onset progressive neurological deterioration with ataxia, dementia, and frequently chorea, neuropathy, and spasticity. Brain magnetic resonance imaging showed profound global brain atrophy in all patients. Dermatological examination did not show any skin cancer or pronounced ultraviolet damage. CONCLUSIONS: We introduce NERDND as adult-onset neurodegeneration (ND ) within the spectrum of autosomal recessive NER disorders (NERD). Our study demonstrates that NERDND is probably an underdiagnosed cause of neurodegeneration in adulthood and should be considered in patients with overlapping cognitive and movement abnormalities. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Síndrome de Cockayne , Neoplasias Cutâneas , Xeroderma Pigmentoso , Adulto , Síndrome de Cockayne/complicações , Síndrome de Cockayne/genética , Reparo do DNA/genética , Humanos , Pele , Neoplasias Cutâneas/genética , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/metabolismo , Xeroderma Pigmentoso/patologia , Proteína Grupo D do Xeroderma Pigmentoso/genética , Proteína Grupo D do Xeroderma Pigmentoso/metabolismoRESUMO
Many monogenic disorders cause a characteristic facial morphology. Artificial intelligence can support physicians in recognizing these patterns by associating facial phenotypes with the underlying syndrome through training on thousands of patient photographs. However, this 'supervised' approach means that diagnoses are only possible if the disorder was part of the training set. To improve recognition of ultra-rare disorders, we developed GestaltMatcher, an encoder for portraits that is based on a deep convolutional neural network. Photographs of 17,560 patients with 1,115 rare disorders were used to define a Clinical Face Phenotype Space, in which distances between cases define syndromic similarity. Here we show that patients can be matched to others with the same molecular diagnosis even when the disorder was not included in the training set. Together with mutation data, GestaltMatcher could not only accelerate the clinical diagnosis of patients with ultra-rare disorders and facial dysmorphism but also enable the delineation of new phenotypes.
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Inteligência Artificial , Doenças Raras , Face , Humanos , Redes Neurais de Computação , Fenótipo , Doenças Raras/genéticaRESUMO
Bilateral laryngeal abductor paralysis is a rare entity and the second most common cause of stridor in newborns. So far, no conclusive genetic or chromosomal aberration has been reported for X-linked isolated bilateral vocal cord paralysis, also referred to as Plott syndrome. Via whole genome sequencing (WGS), we identified a complex interchromosomal insertion in a large family with seven affected males. The 404 kb inserted fragment originates from chromosome 10q21.3, contains no genes and is inserted inversionally into the intergenic chromosomal region Xq27.1, 82 kb centromeric to the nearest gene SOX3. The patterns found at the breakpoint junctions resemble typical characteristics that arise in replication-based mechanisms with long-distance template switching. Non protein-coding insertions into the same genomic region have been described to result in different phenotypes, indicating that the phenotypic outcome likely depends on the introduction of regulatory elements. In conclusion, our data adds Plott syndrome as another entity, likely caused by the insertion of non-coding DNA into the intergenic chromosomal region Xq27.1. In this regard, we demonstrate the importance of WGS as a powerful diagnostic test in unsolved genetic diseases, as this genomic rearrangement has not been detected by current first-line diagnostic tests, i.e., exome sequencing and chromosomal microarray analysis.
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Doenças Genéticas Ligadas ao Cromossomo X , Deficiência Intelectual , Paralisia das Pregas Vocais , Aberrações Cromossômicas , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Paralisia das Pregas Vocais/genéticaRESUMO
Copy Number Variants (CNVs) are deletions, duplications or insertions larger than 50 base pairs. They account for a large percentage of the normal genome variation and play major roles in human pathology. While array-based approaches have long been used to detect them in clinical practice, whole-genome sequencing (WGS) bears the promise to allow concomitant exploration of CNVs and smaller variants. However, accurately calling CNVs from WGS remains a difficult computational task, for which a consensus is still lacking. In this paper, we explore practical calling options to reach the best compromise between sensitivity and sensibility. We show that callers based on different signal (paired-end reads, split reads, coverage depth) yield complementary results. We suggest approaches combining four selected callers (Manta, Delly, ERDS, CNVnator) and a regenotyping tool (SV2), and show that this is applicable in everyday practice in terms of computation time and further interpretation. We demonstrate the superiority of these approaches over array-based Comparative Genomic Hybridization (aCGH), specifically regarding the lack of resolution in breakpoint definition and the detection of potentially relevant CNVs. Finally, we confirm our results on the NA12878 benchmark genome, as well as one clinically validated sample. In conclusion, we suggest that WGS constitutes a timely and economically valid alternative to the combination of aCGH and whole-exome sequencing.