RESUMO
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.
Assuntos
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
The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.
RESUMO
Next generation sequencing (NGS)-based tests have become routine first-line investigative modalities in paediatric neurology clinics in many high-income countries (HICs). Studies from these countries show that these tests are both cost-effective and reliable in diagnosing many complex childhood neurological diseases. However, NGS-based testing in low-and middle-income countries (LMICs) is limited due to affordability constraints. The primary objective of this study was to evaluate the diagnostic yield and impact of targeted gene panel sequencing in a selected paediatric cohort attending a tertiary paediatric neurology clinic in the Western Cape Province of South Africa. This retrospective study included 124 consecutive paediatric patients with neurological disease, aged 6 weeks to 17 years, referred for NGS-based multi-gene panel testing over a 41-month period. Twenty-four different disease group-specific panels were utilized. A caregiver experience questionnaire was administered when a pathogenic variant was identified. The overall study diagnostic yield (DY) was 45% (56/124 patients). The diagnostic yield in this study is similar to previously reported paediatric cohorts in HICs. The high yields for neuromuscular disorders (52%) and early epileptic encephalopathies (41%) suggest that NGS-based panels may be more cost-effective as first-line testing in well-defined phenotypes. The latter finding argues for early inclusion of all children with developmental epileptic encephalopathies (DEE), as early diagnosis leads to better treatment and avoidance of unnecessary investigations.
RESUMO
Next-generation phenotyping (NGP) can be used to compute the similarity of dysmorphic patients to known syndromic diseases. So far, the technology has been evaluated in variant prioritization and classification, providing evidence for pathogenicity if the phenotype matched with other patients with a confirmed molecular diagnosis. In a Nigerian cohort of individuals with facial dysmorphism, we used the NGP tool GestaltMatcher to screen portraits prior to genetic testing and subjected individuals with high similarity scores to exome sequencing (ES). Here, we report on two individuals with global developmental delay, pulmonary artery stenosis, and genital and limb malformations for whom GestaltMatcher yielded Cornelia de Lange syndrome (CdLS) as the top hit. ES revealed a known pathogenic nonsense variant, NM_133433.4: c.598C>T; p.(Gln200*), as well as a novel frameshift variant c.7948dup; p.(Ile2650Asnfs*11) in NIPBL. Our results suggest that NGP can be used as a screening tool and thresholds could be defined for achieving high diagnostic yields in ES. Training the artificial intelligence (AI) with additional cases of the same ethnicity might further increase the positive predictive value of GestaltMatcher.
Assuntos
Síndrome de Cornélia de Lange , Fenótipo , Humanos , Síndrome de Cornélia de Lange/genética , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/patologia , Masculino , Feminino , Criança , Nigéria , Pré-Escolar , Proteínas de Ciclo Celular/genética , Sequenciamento do Exoma , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , LactenteRESUMO
Artificial intelligence (AI) for facial diagnostics is increasingly used in the genetics clinic to evaluate patients with potential genetic conditions. Current approaches focus on one type of AI called Deep Learning (DL). While DL- based facial diagnostic platforms have a high accuracy rate for many conditions, less is understood about how this technology assesses and classifies (categorizes) images, and how this compares to humans. To compare human and computer attention, we performed eye-tracking analyses of geneticist clinicians (n = 22) and non-clinicians (n = 22) who viewed images of people with 10 different genetic conditions, as well as images of unaffected individuals. We calculated the Intersection-over-Union (IoU) and Kullback-Leibler divergence (KL) to compare the visual attentions of the two participant groups, and then the clinician group against the saliency maps of our deep learning classifier. We found that human visual attention differs greatly from DL model's saliency results. Averaging over all the test images, IoU and KL metric for the successful (accurate) clinician visual attentions versus the saliency maps were 0.15 and 11.15, respectively. Individuals also tend to have a specific pattern of image inspection, and clinicians demonstrate different visual attention patterns than non-clinicians (IoU and KL of clinicians versus non-clinicians were 0.47 and 2.73, respectively). This study shows that humans (at different levels of expertise) and a computer vision model examine images differently. Understanding these differences can improve the design and use of AI tools, and lead to more meaningful interactions between clinicians and AI technologies.
Assuntos
Inteligência Artificial , Computadores , Humanos , Simulação por ComputadorRESUMO
We report on a female neonate with a clinico-radiological presentation in keeping with a lethal form of prenatal Caffey disease (PCH). She had antenatal and postnatal features of severely bowed long bones, small chest, diaphyseal hyperostosis and polyhydramnios and died shortly after birth. Initial testing excluded COL1A1-related PCH, as an OI gene panel, consisting of COL1A1, COL1A2, CRTAP, and P3H1 genes, was negative. Targeted sequencing using a gene panel was performed and a de novo heterozygous, likely pathogenic variant in IFITM5: c.119C > T(p.Ser40Leu) was identified, which was previously described to cause a severe form of progressively deforming osteogenesis imperfect (OI). To our knowledge, variants in IFITM5 have not been reported in infantile Caffey disease (ICH) or PCH. Given that the pathogenesis of PCH is largely unknown, we postulate that a subset of PCH may be associated with variants in IFITM5.
Assuntos
Doenças Fetais , Hiperostose Cortical Congênita , Osteogênese Imperfeita , Recém-Nascido , Humanos , Feminino , Gravidez , Osteogênese Imperfeita/genética , Mutação , Proteínas de Membrana/genética , Colágeno Tipo I/genética , Osso e Ossos/patologiaRESUMO
Dysmorphologists sometimes encounter challenges in recognizing disorders due to phenotypic variability influenced by factors such as age and ethnicity. Moreover, the performance of Next Generation Phenotyping Tools such as GestaltMatcher is dependent on the diversity of the training set. Therefore, we developed GestaltMatcher Database (GMDB) - a global reference for the phenotypic variability of rare diseases that complies with the FAIR-principles. We curated dysmorphic patient images and metadata from 2,224 publications, transforming GMDB into an online dynamic case report journal. To encourage clinicians worldwide to contribute, each case can receive a Digital Object Identifier (DOI), making it a citable micro-publication. This resulted in a collection of 2,312 unpublished images, partly with longitudinal data. We have compiled a collection of 10,189 frontal images from 7,695 patients representing 683 disorders. The web interface enables gene- and phenotype-centered queries for registered users (https://db.gestaltmatcher.org/). Despite the predominant European ancestry of most patients (59%), our global collaborations have facilitated the inclusion of data from frequently underrepresented ethnicities, with 17% Asian, 4% African, and 6% with other ethnic backgrounds. The analysis has revealed a significant enhancement in GestaltMatcher performance across all ethnic groups, incorporating non-European ethnicities, showcasing a remarkable increase in Top-1-Accuracy by 31.56% and Top-5-Accuracy by 12.64%. Importantly, this improvement was achieved without altering the performance metrics for European patients. GMDB addresses dysmorphology challenges by representing phenotypic variability and including underrepresented groups, enhancing global diagnostic rates and serving as a vital clinician reference database.
RESUMO
Osteogenesis imperfecta (OI) is a clinically heterogeneous disorder characterised by skeletal fragility and an increased fracture incidence. It occurs in approximately one in every 15-20,000 births and is known to vary considerably in its severity. This report aimed to use next-generation sequencing (NGS) technology to identify disease genes and causal variants in South African patients with clinical-radiological features of OI. A total of 50 affected individuals were recruited at Tygerberg Hospital's Medical Genetics clinic. Patients were selected for a gene panel test (n = 39), a single variant test (n = 1) or exome sequencing (ES) (n = 12, 7 singletons, 1 affected duo, and 1 trio), depending on funding eligibility. An in-house genomic bioinformatics pipeline was developed for the ES samples using open-source software and tools. This study's 100% diagnostic yield was largely attributable to an accurate clinical diagnosis. A causal variant in COL1A1 or COL1A2 was identified in 94% of this patient cohort, which is in line with previous studies. Interestingly, this study was the first to identify the common South African pathogenic FKBP10 variant in a patient of mixed ancestry, adding to what was previously known about this variant in our population. Additionally, a recurrent variant in COL1A2: c.1892G>T was discovered in 27 individuals (25 from three large unrelated families and two further individuals), facilitating the establishment of local testing for this variant in South African patients.
RESUMO
Spondyloepimetaphyseal dysplasia with severe short stature, RPL13-related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by short stature and skeletal changes such as mild spondylar and epimetaphyseal dysplasia affecting primarily the lower limbs. The genetic cause was first reported in 2019 by Le Caignec et al., and six disease-causing variants in the gene coding for a ribosomal protein, RPL13 (NM_000977.3) have been identified to date. This study presents clinical and radiographic data from 12 affected individuals aged 2-64 years from seven unrelated families, showing highly variable manifestations. The affected individuals showed a range from mild to severe short stature, retaining the same radiographic pattern of spondylar- and epi-metaphyseal dysplasia, but with varying severity of the hip and knee deformities. Two new missense variants, c.548 G>A, p.(Arg183His) and c.569 G>T, p.(Arg190Leu), and a previously known splice variant c.477+1G>A were identified, confirming mutational clustering in a highly specific RNA binding motif. Structural analysis and interpretation of the variants' impact on the protein suggests that disruption of extra-ribosomal functions of the protein through binding of mRNA may play a role in the skeletal phenotype of SEMD-RPL13. In addition, we present gonadal and somatic mosaicism for the condition.
RESUMO
The linkeropathies are a group of rare disorders, characterized by overlapping clinical features involving the skeletal and connective tissues. Each "linker" gene encodes an enzyme responsible for the addition of glycosaminoglycan chains to proteoglycans via a common tertrasaccharine linker region. The original descriptions of the autosomal recessive B3GALT6-related disorder showed that the associated clinical features are pleiotropic, spanning the skeletal dysplasia (Spondyloepimetaphyseal dysplasia with joint laxity) (SEMD-JL1) and connective tissue disorder (Ehlers-Danlos syndrome) (EDS spondylodysplastic Type 2) spectrum. Here, we describe three patients with biallelic B3GALT6 variants: each had different clinical presentations, and the two older patients initially received alternative clinical diagnoses (Larsen syndrome and Osteogenesis imperfecta, respectively). We describe the clinico-radiological features of these patients to highlight the spectrum of disease associated with the B3GALT6-linkeropathy.
RESUMO
Deep learning (DL) and other types of artificial intelligence (AI) are increasingly used in many biomedical areas, including genetics. One frequent use in medical genetics involves evaluating images of people with potential genetic conditions to help with diagnosis. A central question involves better understanding how AI classifiers assess images compared to humans. To explore this, we performed eye-tracking analyses of geneticist clinicians and non-clinicians. We compared results to DL-based saliency maps. We found that human visual attention when assessing images differs greatly from the parts of images weighted by the DL model. Further, individuals tend to have a specific pattern of image inspection, and clinicians demonstrate different visual attention patterns than non-clinicians.
RESUMO
ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.
Assuntos
Exorribonucleases , Histonas , Humanos , Exorribonucleases/genética , Histonas/genética , Mutação de Sentido Incorreto/genética , RNA Ribossômico 5,8S , RNA , RNA Mensageiro/genéticaRESUMO
Aicardi-Goutières syndrome (AGS) refers to a group of genetic diseases characterised by severe inflammatory encephalopathy that usually present within the first year of life, resulting in progressive loss of cognition, spasticity, dystonia and motor disability. Pathogenic variants in the adenosine deaminase acting on RNA (Adar) enzyme have been linked to AGS type 6 (AGS6, Online Mendelian Inheritance in Man (OMIM) 615010). In knockout mouse models, loss of Adar activates the interferon (IFN) pathway and causes autoimmune pathogenesis in the brain or liver. Bilateral striatal necrosis (BSN) has previously been reported in case series of children with biallelic pathogenic variants in Adar We describe a unique, previously unreported case of a child with AGS6, with clinical manifestations of BSN and recurrent transient episodes of transaminitis. The case highlights the importance of Adar in protecting the brain and liver from IFN-induced inflammation. Adar-related disease should therefore be considered in the differential diagnosis of BSN accompanied by recurrent episodes of transaminitis.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Pessoas com Deficiência , Transtornos Motores , Malformações do Sistema Nervoso , Animais , Camundongos , Humanos , Criança , Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Malformações do Sistema Nervoso/genética , Necrose , MutaçãoRESUMO
The field of clinical genetics and genomics continues to evolve. In the past few decades, milestones like the initial sequencing of the human genome, dramatic changes in sequencing technologies, and the introduction of artificial intelligence, have upended the field and offered fascinating new insights. Though difficult to predict the precise paths the field will follow, rapid change may continue to be inevitable. Within genetics, the practice of dysmorphology, as defined by pioneering geneticist David W. Smith in the 1960s as "the study of, or general subject of abnormal development of tissue form" has also been affected by technological advances as well as more general trends in biomedicine. To address possibilities, potential, and perils regarding the future of dysmorphology, a group of clinical geneticists, representing different career stages, areas of focus, and geographic regions, have contributed to this piece by providing insights about how the practice of dysmorphology will develop over the next several decades.
Assuntos
Inteligência Artificial , Genômica , Humanos , Genoma HumanoRESUMO
OBJECTIVES: The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of rare neurodevelopmental disorders, characterised by early-onset seizures that are often intractable, electroencephalographic abnormalities, and developmental delay or regression. There is a paucity of data from sub-Saharan Africa on the genetic basis of DEE. The aim of this study was to investigate the genetic background of DEE using targeted next generation sequencing (NGS) analysis in a tertiary pediatric neurology outpatient department at Tygerberg Hospital, South Africa. In addition, we assessed the value of the genetic results to the parents and managing physicians. METHODS: A prospective cohort study of 41 consecutive children with DEE (onset before 3 years of age) that were recruited over a 2-year period (2019-2021). Pre- and post-test genetic counselling were offered to all study participants. The results were categorized as either: positive (pathogenic/likely pathogenic variant identified), inconclusive (variant(s) of unknown significance identified), or negative (no variants identified). Result interpretation and careful matching of the variant to the clinical phenotype was performed. Subsequently, questionnaires were administered to both the physicians and the parents. RESULTS: A genetic underlying cause for DEE was identified in 18 of 41 children (diagnostic yield 43.9%). Variants in SCN1A (n=7), KANSL1 (n=2), KCNQ2 (n=2) and CDKL5 (n=2) were identified in more than one patient. Rarer genes included IQSEC2, SMC1A and STXBP1. All of the identified pathogenic variants fully explained and matched the respective phenotypic description of the patient at the time of clinical diagnosis. In 26% of patients the genetic result facilitated precision medicine management changes to anti-seizure medication. Both parents and physicians expressed benefit of genetic testing in patients with DEE. CONCLUSION: Targeted NGS analysis proved an efficient diagnostic tool in detection of a genetic cause of DEE in a large proportion of South African children. The 43.9% diagnostic yield is similar to previously reported international pediatric cohorts. Additionally, the genetic findings proved useful for targeted therapeutic decision-making and accurate genetic counseling.
Assuntos
Espasmos Infantis , Testes Genéticos/métodos , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Estudos Prospectivos , África do Sul , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Centros de Atenção TerciáriaRESUMO
Renal cell carcinoma is rarely described in paediatric patients with tuberous sclerosis complex. This report describes a case of an 11-year-old male with tuberous sclerosis-associated renal cell carcinoma.
RESUMO
The Undiagnosed Disease Program in South Africa (UDP) sought to prospectively evaluate the clinical utility of exome sequencing (ES) in a phenotypically diverse, multi-ethnic cohort of South African patients with suspected rare genetic disorders. ES was undertaken in 100 sequential patients (93 singletons, 3 duos, and 4 trios) recruited to the UDP at Stellenbosch University. The data were analyzed through two separate bioinformatics pipelines (EVIDENCE from 3 billion and our in-house pipeline). A definitive diagnosis could be reached in 51% (51/100) patients, with 46% (46/100) patients having either pathogenic or likely pathogenic single-nucleotide variants/indels (SNVs/indels), and 5 patients with likely-pathogenic copy number variants (CNVs) (5/100). The CNVs were subsequently confirmed on microarray or MLPA analysis. Detailed phenotyping and HPO terms enabled analysis and variant identification. Twenty-five novel variants in 22 genes are reported here. We provide data from the first year of this UDP and show that even amongst mainly singletons from an understudied, diverse African population, ES is a valuable diagnostic tool, especially if it includes CNV analysis. The remaining undiagnosed patients present a unique opportunity for further research and novel gene discovery.
Assuntos
Exoma , Doenças não Diagnosticadas , Variações do Número de Cópias de DNA/genética , Exoma/genética , Humanos , África do Sul/epidemiologia , Difosfato de UridinaRESUMO
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.
Assuntos
Inteligência Artificial , Doenças Raras , Face , Humanos , Redes Neurais de Computação , Fenótipo , Doenças Raras/genéticaRESUMO
Short stature is one of the most common reasons for a referral to the pediatric endocrinology clinic. Thousands of patients with short stature are assessed annually at the Department of Endocrine and Metabolic Diseases (DEMD) at Bab el Oued University Hospital in Algiers, Algeria. However, diagnostic rates in patients with syndromic short stature are not optimal due to the unavailability of next generation sequencing (NGS) technology. Here, we enrolled 10 Algerian patients with syndromic short stature in a pilot study to test the impact of genetic and genomic approaches in the DEMD. Using a combination of two different NGS modalities, namely exome sequencing and the Mendeliome (TruSight™ One sequencing panel) along with single gene testing, we were able to establish a confirmed molecular diagnosis in 7/10 patients (70%) and to identify strong likely disease-causing variants in a further two patients. Novel variants in NPR2 and VPS13B were identified. Using copy number variation analysis on the exome data, we also identified a de novo deletion of the short arm of chromosome X. These definitive diagnoses have made a substantial impact on patient treatment, management and genetic counseling. Genomic testing has the ability to transform clinical practice, and is an essential diagnostic tool in any tertiary pediatric clinic, particularly in resource limited settings.
Assuntos
Variações do Número de Cópias de DNA , Nanismo , Argélia/epidemiologia , Criança , Variações do Número de Cópias de DNA/genética , Nanismo/diagnóstico , Nanismo/genética , Exoma/genética , Humanos , Projetos PilotoRESUMO
Hemizygous loss-of-function variants in the non-POU domain-containing, octamer-binding gene, NONO, cause X-linked mental retardation syndrome 34 (MRXS34). Here, we describe the 12th patient in the literature with this rare syndrome, the first affected male from sub-Saharan Africa. This South African patient presented with dysmorphic features, congenital cardiac abnormalities (Ebstein's anomaly, left ventricular non-compaction, and a VSD), and developmental delay. He was enrolled in our "Undiagnosed Disease Programme." Exome sequencing identified a novel hemizygous 14bp deletion in NONO, which he inherited from his unaffected, healthy mother. His features overlap with the previous patients described, lending more support to the assertion that MRXS34 is a recognizable, albeit rare, syndrome. The cardiac anomalies are particularly distinctive, which combined with a variety of other associated features, should prompt the inclusion of NONO-associated MRXS34 in the differential diagnosis.