Advances In Genetic Testing Research Articles

Genetic Obesity—Causes and Treatments

Genetic abnormalities are responsible for up to 70% of severe, early onset obesity. With recent advances in genetic testing, more individuals with genetic etiology of excessive weight are being identified. However, treatment will need to be individualized based on the cause and underlying pathophysiology. Several treatment options are being investigated, and there are several treatment options now commercially available for some of these genetic conditions. [Pediatr Ann. 2023;52(2):e57-e61.].

Whole-Exome Sequencing Identified Rare Genetic Variants Associated with Undervirilized Genitalia in Taiwanese Pediatric Patients

Disorders/differences of sex development (DSDs) are a group of rare and phenotypically variable diseases. The underlying genetic causes of most cases of 46XY DSDs remains unknown. Despite the advent of genetic testing, current investigations of the causes of DSDs allow genetic-mechanism identification in about 20-35% of cases. This study aimed primarily to establish a rapid and high-throughput genetic test for undervirilized males with and without additional dysmorphic features. Routine chromosomal and endocrinological investigations were performed as part of DSD evaluation. We applied whole-exome sequencing (WES) complemented with multiplex ligation-dependent probe amplification to seek explainable genetic causes. Integrated computing programs were used to call and predict the functions of genetic variants. We recruited 20 patients and identified the genetic etiologies for 14 (70%) patients. A total of seven of the patients who presented isolated DSD phenotypes were found to have causative variants in the AR, MAP3K1, and FLNA genes. Moreover, the other seven patients presented additional phenotypes beyond undervirilized genitalia. Among them, two patients were compatible with CHARGE syndrome, one with Robinow syndrome, and another three with hypogonadotropic hypogonadism. One patient, who carried a heterozygous FLNA mutation, also harbored a heterozygous PTPN11 mutation and thus presented some phenotypes of Noonan syndrome. We identified several genetic variants (12 nonsense mutations and one microdeletion) that account for syndromic and nonsyndromic DSDs in the Taiwanese population. The identification of these causative genes extended our current understanding of sex development and related congenital disorders.

Inherited cardiomyopathies: how nurses can facilitate holistic care for patients and their families

This article is the second instalment of the British Journal of Cardiac Nursing's series on genetics, and will focus on inherited cardiomyopathies. Collectively, cardiomyopathies are the most common inherited cardiac condition. They affect the structure of the heart muscle, sometimes leading to heart failure or sudden cardiac death. Advances in genetic testing for cardiomyopathies mean that this can now be offered to more patients, influencing care and treatment options. This article looks at the contributions made by nurses to the care of people who have, or are at risk of, an inherited cardiomyopathy.

Challenges in the clinical understanding of genetic testing in birth defects and pediatric diseases.

Advances in prenatal/neonatal genetic screening practices and next generation sequencing (NGS) technologies have made the detection of molecular causes of pediatric diseases increasingly more affordable, accessible, and rapid in return of results. In the past, families searching for answers often required diagnostic journeys leading to delays in targeted care and missed diagnoses. Non-invasive prenatal NGS is now used routinely in pregnancy, significantly altering the obstetric approach to early screening and evaluation of fetal anomalies. Similarly, exome sequencing (ES) and genome sequencing (GS) were once only available for research but are now used in patient care, impacting neonatal care and the field of neonatology as a whole. In this review we will summarize the growing body of literature on the role of ES/GS in prenatal/neonatal care, specifically in neonatal intensive care units (NICU), and the molecular diagnostic yield. Furthermore, we will discuss the impact of advances in genetic testing in prenatal/neonatal care and discuss challenges faced by clinicians and families. Clinical application of NGS has come with many challenges in counseling families on interpretation of diagnostic results and incidental findings, as well as re-interpretation of prior genetic test results. How genetic results may influence medical decision-making is highly nuanced and needs further study. The ethics of parental consent and disclosure of genetic conditions with limited therapeutic options continue to be debated in the medical genetics community. While these questions remain unanswered, the benefits of a standardized approach to genetic testing in the NICU will be highlighted by two case vignettes.

De Sanctis - Cacchione Syndrome in a Male Ghanaian Child: A Case Report

A family was followed up after the presentation of a rare complication of xeroderma pigmentosum (De sanctis - cacchionne) syndrome in a child. A total of four children in a family of 8 developed the disease. The background of the family was explored revealing consanguinity as a result of cultural practices among the Mossi tribe in Ghana. Rare diseases are more common when there is consanguinity and this is the first report of this rare syndrome in Ghana and the West African sub region. The child showed the characteristic features of microcephaly, severe learning difficulties, cutaneous hypersensitivity, peripheral neuropathy and reported deafness. The disease predisposed the child to early squamous cell carcinoma of the eyelid. Advanced genetic testing showed complimentary group A in the sibling. Genetic counselling was offered. Management involved the dermatologists, opthalmologists and surgeons. This case report seeks to emphasise that consanguinity is linked to rare neurological diseases in Ghana and external collaborations in the field of advanced genetic testing can be mutually beneficial. The general recommended management options like sunblock, covering clothing UV film protection on windows are not possible in the tropics like Ghana. Rather support groups and genetic counselling are paramount.

Clinical Applications of Flow Cytometry in Cancer Immunotherapies: From Diagnosis to Treatments.

The scope of flow cytometry is rapidly expanding in the diagnosis of various cancers, and it is being used routinely as an aid in classifying leukemias and lymphomas. There are several applications of flow cytometry to enumerate tumorigenic anomalies in patients. The unusual distribution of cells in various locations, their DNA content, cell proliferation rate, dysregulated expression of several surface receptors, and expression of tumor antigens are some examples that can be characterized by using different flow cytometry-based techniques. For instance, the differential diagnosis between chronic lymphocytic leukemia (CLL) and various other mature B-cell neoplasms can be made by immunophenotyping in combination with absolute counting of numerous cellular subsets or by enumerating their percent distributions. Flow cytometry has several advantages over conventional techniques which include the ability to acquire a multiparametric data in a relatively shorter time and facilitate the comparative analysis of specific cellular subsets in an efficient manner.In addition to diagnosis, there are several other applications of flow cytometry in the management of various cancers which include treatment monitoring or even selecting a personalized precision-based immunotherapy in synch with advanced genetic tests to increase the chances of favorable prognosis and complete remission. The detection of chimeric antigen receptors (CARs) on various engineered effector cells can also be determined along with their specificity in engaging the targets. Furthermore, the assessment of numerous immunological parameters, their effector functions and potencies including the proliferation dynamics, cytokine secretion profiles, and activation efficiencies can also be measured before starting immunotherapies in patients.This chapter is a brief overview of flow cytometry applications in the diagnosis and treatment strategies of various cancers.

Challenging Neuromuscular Disease Cases.

The diagnosis of neuromuscular disorders requires a thorough history including family history and examination, with the next steps broadened now beyond electromyography and neuropathology to include genetic testing. The challenge in diagnosis can often be putting all the information together. With advances in genetic testing, some diagnoses that adult patients may have received as children deserve a second look and may result in diagnoses better defined or alternative diagnoses made. Clearly defining or redefining a diagnosis can result in understanding of potential other systems involved, prognosis, or potential treatments. This article presents several cases and approach to diagnosis as well as potential treatment and prognostic concerns, including seipinopathy, congenital myasthenic syndrome, central core myopathy, and myotonic dystrophy type 2.

Long-Read Sequencing Resolves Complex Structural Variants and Identifies Missing Disease-Causing Variants in Unsolved Cases of Hemophilia

Introduction: Despite recent advances in genetic testing, many individuals with inherited bleeding disorders remain unsolved after a complete clinical evaluation. In some cases, no variant is found in a particular gene or genes of interest, while in other cases a large structural variant (SV) is found or suspected that cannot be resolved using existing methods. In the large U.S. hemophilia genotyping initiative MyLifeOurFuture, ~2% of participants with hemophilia A had no F8 variant identified despite exhaustive investigation. Additionally, large SVs were common in severe hemophilia and associated with inhibitor risk but were incompletely characterized in nearly all cases. We hypothesized that long-read sequencing (LRS) would identify missing disease-causing variants and fully characterize SVs associated with hemophilia in these individuals. Methods: We performed targeted or whole-genome LRS on the Oxford Nanopore platform of 25 hemophilia cases with FVIII levels <14% in which prior testing identified no pathogenic variant or identified a suspected SV impacting F8. After basecalling with guppy and alignment to GRCh38 using minimap2, single nucleotide and insertion or deletion variants were identified with Clair3. All variant calls were refined using population frequency and pathogenicity predictions. SVs were called with Sniffles2, SVIM, and CuteSV. We performed de novo assembly of SVs and called methylation in all samples. Methylation differences were identified using an in-house developed pipeline. Results: We identified candidate pathogenic variants and previously undetected SVs in 10/10 cases with no variant found on clinical testing. Candidate intronic variants predicted to affect splicing were validated by exon trap assays. SVs identified included deletions and large inversions. Among 11 cases with suspected SVs, LRS resolved the candidate SV providing detailed genomic structure, orientation, and predicted impact of the variant. Whole genome LRS resolved SVs involving the large segmental duplication within F8 intron 22 (Int22h1), revealing variants that have not previously been observed including unsuspected orientations in the F8 intron 22 positive control sample. We analyzed four females with unexplained low FVIII levels and identified skewed methylation profiles that may help explain their phenotype. Conclusion: In a single genetic test LRS can identify disease-causing variants missed by prior genetic testing, resolve complex SVs, and identify methylation differences that explain hemophilia phenotypes. These comprehensive methods are necessary to fully understand causes of hemophilia and complications such as inhibitor development. We expect this approach will similarly resolve "missing” genetic variation in other inherited disorders. Supported and funded by the BBI at UW, WACBD, HTRS MCRA (Genentech), and NHLBI TOPMed.

UNRAVELING THE CAUSE OF A KINDRED WITH CHRONIC CANDIDIASIS

<h3>Introduction</h3> Chronic mucocutaneus candidiasis (CMC) is a clinical syndrome characterized by invasive chronic fungal infections involving skin, nails, and mucosal tissues. Advancements in genetic testing have aided in identification of underlying molecular causes; however challenges arise when variants of uncertain significance are identified in genes of interest. Our case highlights the importance of family history in genotype-phenotype correlation leading to reclassification of a novel variant in a rare immune deficiency. <h3>Case Description</h3> A 67-year-old female is referred for evaluation of chronic candidiasis including vaginitis, onychomycosis, stomatitis, gingivitis requiring teeth removal, and recurrent esophageal structuring requiring balloon dilation. She developed fluconazole resistance and treatment includes a combination of nystatin, clotrimazole, itraconazole, and in severe cases, amphotericin. She had no clinically significant history of bacterial or viral infections. Medical history included melanoma, cervical and breast cancers. Immune evaluation including HIV testing, tetanus and pneumococcal titers, total complement, lymphocyte flow cytometry and mitogen/antigen proliferation were unremarkable. Her immunoglobulins were notable for a low IgM of 43mg/dL (reference 57-237mg/dL), and diphtheria titer was low at 0.036IU/mL (reference >/= 0.100IU/mL). Gene sequencing revealed a variant of uncertain significance in STAT1 c.200A>C (p.Gln67Pro). Family history was notable for CMC in multiple relatives across four generations. Family sequencing was positive for the same STAT1 mutation in all affected members and negative for one unaffected member. <h3>Discussion</h3> Dominant STAT1 gain-of-function mutations, often in the coiled-coil domain, are an established cause of CMC. The outlined case represents a novel N-terminal domain mutation, initially classified as a variant, but reclassified as pathogenic following kindred sequencing.

Approaches to long-read sequencing in a clinical setting to improve diagnostic rate

Over the past decade, advances in genetic testing, particularly the advent of next-generation sequencing, have led to a paradigm shift in the diagnosis of molecular diseases and disorders. Despite our present collective ability to interrogate more than 90% of the human genome, portions of the genome have eluded us, resulting in stagnation of diagnostic yield with existing methodologies. Here we show how application of a new technology, long-read sequencing, has the potential to improve molecular diagnostic rates. Whole genome sequencing by long reads was able to cover 98% of next-generation sequencing dead zones, which are areas of the genome that are not interpretable by conventional industry-standard short-read sequencing. Through the ability of long-read sequencing to unambiguously call variants in these regions, we discovered an immunodeficiency due to a variant in IKBKG in a subject who had previously received a negative genome sequencing result. Additionally, we demonstrate the ability of long-read sequencing to detect small variants on par with short-read sequencing, its superior performance in identifying structural variants, and thirdly, its capacity to determine genomic methylation defects in native DNA. Though the latter technical abilities have been demonstrated, we demonstrate the clinical application of this technology to successfully identify multiple types of variants using a single test.

Maturing pharmacogenomic factors deliver improvements and cost efficiencies.

An ever-expanding annotation of the human genome sequence continues to promise a new era of precision medicine. Advances in knowledge management and the ability to leverage genetic information to make clinically relevant, predictive, diagnostic, and targeted therapeutic choices offer the ability to improve patient outcomes and reduce the overall cost of healthcare. However, numerous barriers have resulted in a modest start to the clinical use of genetics at scale. Examples of successful deployments include oncologic disease treatment with targeted prescribing; however, even in these cases, genome-informed decision-making has yet to achieve standard of care in most major healthcare systems. In the last two decades, advances in genetic testing, therapeutic coverage, and clinical decision support have resulted in early-stage adoption of pharmacogenomics - the use of genetic information to routinely determine the safety and efficacy profile of specific medications for individuals. Here, through their complicated histories, we review the current state of pharmacogenomic testing technologies, the information tools that can unlock clinical utility, and value-driving implementation strategies that represent the future of pharmacogenomics-enabled healthcare decision-making. We conclude with real-world economic and clinical outcomes from a full-scale deployment and ultimately provide insight into potential tipping points for global adoption, including recent lessons from the rapid scale-up of high-volume test delivery during the global SARS-CoV2 epidemic.

O.01 Correlating molecular genetic testing for rare genetic variants with a broad clinicopathologic spectrum of congenital myopathies

Congenital myopathies (CMs) are a group of clinically heterogeneous disorders presenting with a range of overlapping findings, making diagnosis challenging. Despite advances in genetic testing, many cases remain undiagnosed. The Beggs' laboratory CM cohort, which currently totals over 1,100 individuals, constitutes a robust dataset of existing cases. Subjects were ascertained based on clinical presentation and pathologic diagnoses suggestive of CM. We report that over 65% have been solved by a combination of single gene, panel, or genomic sequencing, and/or RNA-Seq. Of 727 solved cases, 610 had mutations in either ACTA1, DNM2, MTM1, NEB, RYR1, SELENON, TPM2, TPM3, or TTN. All these genes are well-known causes of congenital myopathy. While all patients shared a myopathic pattern of weakness and hypotonia, a wide spectrum of clinicopathologic features were appreciated among the cases. The remaining 117 cases had mutations in one of 52 different genes, including a number of rare or novel genes, as well as some more commonly mutated non-CM disease genes in patients who presented atypically for those associated conditions. Among a heterogeneous group of 96 probands with congenital myopathy with nonspecific or no pathology, 31 (32%) had SELENON mutations; 9 (9.4%) had RYR1 mutations and 6 (6.25%) had TTN mutations. This survey of the Beggs' laboratory cohort cases, accumulated over roughly 20 years, emphasizes the crucial and growing role of WES/WGS in establishing a molecular genetic diagnosis of CM, as opposed to disease-based gene panels or single-gene testing, which may miss cases where the presentation does not fit the classical description of the disorder, or where multiple genes may present with overlapping clinicopathologic diagnoses. Moreover, certain syndromes not known to present predominantly with myopathic symptoms may go undiagnosed if genetic testing is done in a more targeted fashion based on specific clinical symptoms or pathologic diagnosis alone.

P.180 Diagnostic range of targeted next-generation sequencing in a single center experience with limb-girdle muscular dystrophy

Limb-girdle muscular dystrophies (LGMDs) are clinically and genetically heterogeneous group of muscle disease characterized by proximally predominant weakness of the shoulder and hip girdle musculature. Recent advances in genetic testing have contributed to increasing diagnostic yields and better understanding each subtype of LGMDs. We investigated genetic variability and clinical manifestation among a single center study of Korean patients with LGMD. We reviewed medical records of myopathy data from January 2002 to August 2021 at Gangnam Severance Hospital. Among 1,028 patients with muscular dystrophies, we selected 334 patients with LGMD from 304 unrelated families. We investigated diagnostic rate of targeted next-generation sequencing and genotypes of 304 families with LGMD. Pathogenic/likely pathogenic variants were found in 184 (55.1%) patients out of 304 families with LGMD. Diagnostic rate of targeted next-generation sequencing in our center was 158 (52%) out of 304 families. Additionally, 16 (5.3%) families had a one heterozygous variant of recessive myopathy. <i>DYSF</i> (97 families) was the most common genetic cause in Korean patients with LGMDs, followed by <i>CAPN3</i> (25), <i>COL6A1/A2</i> (17), <i>TTN</i> (6), <i>DNAJB6</i> (4), <i>FKRP</i> (2), <i>GMPPB</i> (1), <i>LAMA2</i> (1), <i>PLEC</i> (1), <i>SGCA</i> (1), <i>SGCB</i> (1), <i>SGCG</i> (1), and <i>TNPO3</i> (1). Cases with one heterozygous variant of recessive myopathy were in <i>DYSF</i> (10 families), <i>CAPN3</i> (5), and <i>TTN</i> (1). The total 184 patients were genetically confirmed from 158 families, and comprised of 90 men and 94 women. In dysferlinopathy, we genetically verified 102 Patients from 97 families. There were 45 men and 57 women. The median age at the symptom onset and the diagnosis were 23 years [Interquartile range (IQR): 18-30 years] and 37 years [IQR: 27-47 years], respectively. In calpainopathy, 28 patients from 25 families included 18 men and 10 women. The median age at the symptom onset and the diagnosis was 18 years [IQR: 16-27 years] and 34 years [IQR: 25-45], respectively. Serum creatine kinase (CK) levels were highest in patients with dysferlinopathy. The median level of CK in dysferlinopathy was 4,871 IU/l [IQR: 2,400-8,145 IU/l]. This study showed the diagnostic rate of targeted next-generation sequencing in Korean patients with LGMD.

EVIDENCE OF THE NEED FOR INCREASING GENETICS EDUCATION AND SUPPORT FOR GAMETE DONOR RECIPIENTS: RECOMMENDATIONS FOR REPRODUCTIVE PROVIDERS

Genetic screening of gamete donors and tracking of health issues in donor-conceived offspring are performed to avoid transmission of significant health issues to donor-conceived individuals. As degree of risk is subjective, donors need not be excluded from a donor program; however, reproductive risk information will continue to grow in complexity due to advances in genetic testing and understanding of inherited susceptibilities. This study details the types of health information available on gamete donors at a sperm bank and the counseling considerations for the healthcare providers of the intended parents.

Additional value of advanced ultrasonography in pregnancies with two inconclusive cell-free DNA draws.

We aimed to evaluate the additional value of advanced fetal anatomical assessment by ultrasound in pregnancies with twice inconclusive noninvasive testing (NIPT) due to low fetal fraction (FF). We performed a multicenter-retrospective study between 2017 and 2020 including 311 pregnancies with twice inconclusive NIPT due to low FF≤1%. Women were offered invasive testing and advanced fetal anatomical assessment at ≤18weeks' gestation. Ultrasound findings, genetic testing, and pregnancy/postnatal outcomes were evaluated. Ninety-two/311 (29.6%) women underwent invasive testing. Structural anomalies were diagnosed in 13/311 (4.2%) pregnancies (nine at the first scan and four at follow-up). In 6/13 (46.2%) cases, genetic aberrations were confirmed (one case of Trisomy 13 (detectable by NIPT), two of Triploidy, one of 16q12-deletion, HCN4-mutation and UPD(16) (nondetectable by NIPT). Genetic aberrations were found in 4/298 (1.3%) structurallynormal pregnancies (one 47XYY, two microscopic aberrations, one monogenic disorder found postpartum). Structural anomalies in genetically normal fetuses (2.0%) were not more prevalent compared to the general pregnant population (OR 1.0 [0.4-2.2]). In pregnancies with twice inconclusive NIPT due to low FF, fetal structural anomalies are not more prevalent than in the general obstetric population. The detailed anatomical assessment has the added value to detect phenotypical features suggestive of chromosomal/genetic aberrations and identify pregnancies where advanced genetic testing may be indicated.

Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus.

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.

Genetics of Obesity in Humans: A Clinical Review.

Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and developing countries. The development of genome-wide association studies (GWAS) and next-generation sequencing (NGS) has increased the discovery of genetic associations and awareness of monogenic and polygenic causes of obesity. The genetics of obesity could be classified into syndromic and non-syndromic obesity. Prader–Willi, fragile X, Bardet–Biedl, Cohen, and Albright Hereditary Osteodystrophy (AHO) syndromes are examples of syndromic obesity, which are associated with developmental delay and early onset obesity. Non-syndromic obesity could be monogenic, polygenic, or chromosomal in origin. Monogenic obesity is caused by variants of single genes while polygenic obesity includes several genes with the involvement of members of gene families. New advances in genetic testing have led to the identification of obesity-related genes. Leptin (LEP), the leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PCSK1), the melanocortin 4 receptor (MC4R), single-minded homolog 1 (SIM1), brain-derived neurotrophic factor (BDNF), and the neurotrophic tyrosine kinase receptor type 2 gene (NTRK2) have been reported as causative genes for obesity. NGS is now in use and emerging as a useful tool to search for candidate genes for obesity in clinical settings.

Beyond Sarcomeric Hypertrophic Cardiomyopathy: How to Diagnose and Manage Phenocopies.

We describe the most common phenocopies of hypertrophic cardiomyopathy, their pathogenesis, and clinical presentation highlighting similarities and differences. We also suggest a step-by-step diagnostic work-up that can guide in differential diagnosis and management. In the last years, a wider application of genetic testing and the advances in cardiac imaging have significantly changed the diagnostic approach to HCM phenocopies. Different prognosis and management, with an increasing availability of disease-specific therapies, make differential diagnosis mandatory. The HCM phenotype can be the cardiac manifestation of different inherited and acquired disorders presenting different etiology, prognosis, and treatment. Differential diagnosis requires a cardiomyopathic mindset allowing to recognize red flags throughout the diagnostic work-up starting from clinical and family history and ending with advanced imaging and genetic testing. Different prognosis and management, with an increasing availability of disease-specific therapies make differential diagnosis mandatory.

C.2 Muscular MRI pattern recognition for muscular dystrophies: the era of artificial intelligence beyond a systematic review

Background: Genetic neuromuscular diseases (NMD) are a heterogeneous group of disorders comprised hundreds of genes. Despite the advanced genetic testing modalities, about 40 % of patients with NMD do not have a diagnosis. Muscle MRI has been proven as a useful tool to orientate the genetic testing by looking at the muscle involvement severity pattern. Moreover, muscle MRI patterns can be specific and informative for muscular dystrophies and yet can be characteristic and diagnostic. Methods: Systematic review was conducted to review muscle MRI patters for all Limb Girdle Muscle Dystrophies (LGMD). Then, we applied artificial intelligence (AI) on muscle MRI patterns for LGMDs and other NMDs using open database containing muscle MRIs Mercuri scores from 950 individuals. Results: AI and machine learning were applied on 10 types of NMD muscle MRI Mercuri scores that represented muscle involvement based on the degree of fatty infiltration. Different models were generated, the one with highest accuracy was used. When tested on new patients, it achieved a 90% accuracy. Subsequently, was turned into a mobile application. Conclusions: Muscle MRI is a valuable tool to help in NMD diagnosis. Specific muscle involvement pattern can be predictive. Besides, AI facilitates the interpretation and comprehension of muscle imagining in NMD.

The potential of RNA-based therapy for kidney diseases.

Inherited kidney diseases (IKDs) are a large group of disorders affecting different nephron segments, many of which progress towards kidney failure due to the absence of curative therapies. With the current advances in genetic testing, the understanding of the molecular basis and pathophysiology of these disorders is increasing and reveals new potential therapeutic targets. RNA has revolutionized the world of molecular therapy and RNA-based therapeutics have started to emerge in the kidney field. To apply these therapies for inherited kidney disorders, several aspects require attention. First, the mRNA must be combined with a delivery vehicle that protects the oligonucleotides from degradation in the blood stream. Several types of delivery vehicles have been investigated, including lipid-based, peptide-based, and polymer-based ones. Currently, lipid nanoparticles are the most frequently used formulation for systemic siRNA and mRNA delivery. Second, while the glomerulus and tubules can be reached by charge- and/or size-selectivity, delivery vehicles can also be equipped with antibodies, antibody fragments, targeting peptides, carbohydrates or small molecules to actively target receptors on the proximal tubule epithelial cells, podocytes, mesangial cells or the glomerular endothelium. Furthermore, local injection strategies can circumvent the sequestration of RNA formulations in the liver and physical triggers can also enhance kidney-specific uptake. In this review, we provide an overview of current and potential future RNA-based therapies and targeting strategies that are in development for kidney diseases, with particular interest in inherited kidney disorders.