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The COVID‐19 pandemic had a disproportionate impact on ethnically minoritised and other marginalised communities, yet little is known about the impacts of long COVID‐19 (LC) on this group. Living with LC takes its toll both physically, emotionally and financially and even more so when a diagnosis is hard to come by. By using qualitative interviews centring the view of undiagnosed and marginalised communities already classed as 'underserved' in the medical literature, we show the range of barriers and impacts faced by these groups in the UK, and the strategies of resilience they use. Whether trapped on a 'diagnostic odyssey' at the level of primary care, struggling to maintain employment and businesses, or managing family commitments, we argue many minoritised communities are caught in a liminal space of misrecognition, invalidation and ambiguity. We show how these impacts are generated by tensions and challenges in the process and categorisation of diagnosis, and how this effects the daily lives of many individuals already on the receiving end of health inequity. We also offer some examples and suggestions for best practices. [ABSTRACT FROM AUTHOR]

Biochemical phenotyping has been the milestone for diagnosing and managing patients affected by inborn errors of intermediary metabolism (IEiM); however, identifying the genotype responsible for these monogenic disorders greatly contributes to achieving these goals. Herein, whole-exome sequencing (WES) was used to determine the genotypes of 95 unrelated Mexican pediatric patients suspected of having IEiM. They were classified into those bearing specific biochemical abnormalities (Group 1), and those presenting unspecific biochemical profiles (Group 2). The overall concordance between the initial biochemical diagnosis and final genotypic diagnoses was 72.6% (N = 69/95 patients), with the highest concordance achieved in Group 1 (91.3%, N = 63/69), whereas the concordance was limited in Group 2 (23.07%). This finding suggests that previous biochemical phenotyping correlated with the high WES diagnostic success. Concordance was high for urea cycle disorders (94.1%) and organic acid disorders (77.4%). The identified mutational spectrum comprised 83 IEiM-relevant variants (pathogenic, likely pathogenic, and variants of uncertain significance or VUS), including three novel ones, distributed among 29 different genes responsible for amino acid, organic acid, urea cycle, carbohydrate, and lipid disorders. Inconclusive WES results (7.3%, N = 7/95) relied on monoallelic pathogenic genotypes or those involving two VUS for autosomal-recessive IEiMs. A second monogenic disease was observed in 10.5% (N = 10/95) of the patients. According to the WES results, modifications in treatment had to be made in 33.6% (N = 32/95) of patients, mainly attributed to the presence of a second monogenic disease, or to an actionable trait. This study includes the largest cohort of Mexican patients to date with biochemically suspected IEiM who were genetically diagnosed through WES, underscoring its importance in medical management. [ABSTRACT FROM AUTHOR]

Background: Congenital insensitivity to pain with anhidrosis (CIPA) (OMIM 256800) is a rare autosomal‐recessive condition, also known as hereditary sensory and autonomic neuropathy type IV (HSAN‐IV). The most commonly reported features include anhidrosis, intellectual disability, self‐mutilation, febrile episodes, impaired temperature perception, recurrent infections and/or autonomic nervous system impairment. Major joint destruction and joint deformity known as Charcot (neuropathic) joints are also seen in CIPA patients attributed to insensitivity to joint pain. Methods: We present a case of a 46‐year‐old female affected with CIPA with a known NTRK1 variant and previously unidentified variant. Minigene reporter constructs were generated encompassing the exon 8 to exon 13 of the NTRK1 gene using the reference sequence and one harboring c.1483 + 5G > A variant identified in our proband. Minigene constructs were transfected into HEK293T cells, and the transcript was analysed for splicing to evaluate the effect of this variant in splicing. Results: The patient (46‐year‐old female) exhibited right ankle joint deformity around 5 years of age. Patient also experienced lumbar compression and knee damage in adulthood. She had undergone a significant number of evaluations without clear diagnosis. Her presentation lacked many of the common clinical presentations of CIPA, and therefore, the focus of her evaluation was directed towards her unexplained joint deformities. Exome sequencing revealed a known pathogenic variant in NTRK1 (c.851 ‐ 33T > A:p.? [Intron 7]) and a novel NTRK1 variant (c.1483 + 5G > A:p.? [Intron 11]), which was later re‐classified as likely pathogenic. The patient was started on a biologic disease‐modifying anti‐rheumatic medication (bDMARD) due to a possible inflammatory etiology of her joint deformity. Molecular diagnosis allowed for modification of her treatment and surveillance strategies. Our minigene splicing assay demonstrated that the presence of the c.1483 + 5G > A variant has a negative effect on splicing, supporting the pathogenicity of this novel variant. [ABSTRACT FROM AUTHOR]

Purpose: Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease characterized by the loss of motor neurons in the spinal cord and brainstem, leading to muscle atrophy and weakness. To understand the diagnostic process of Korean patients with SMA, we analyzed their clinical characteristics and challenges. Materials and Methods: We conducted a retrospective study of 38 patients with SMA (9 type II and 29 type III) between January 2000 and September 2023. Clinical, laboratory, and genetic data were reviewed. Results: The median ages at symptom onset and diagnosis were 3.0 years [interquartile range (IQR): 1.0-7.3 years] and 25.0 years (IQR: 10.5-37.3 years), respectively. The median diagnostic delay was 19.6 years (IQR: 6.4-31.0 years). A significantly longer delay was observed in SMA type III patients (median: 21.0 years, IQR: 11.0-31.0 years) compared to SMA type II patients (median: 3.0 years, IQR: 0.9-21.0 years) (p=0.021). No significant difference was observed in the number of clinic visits before diagnosis between patients with SMA type II (median: 2.0, IQR: 1.0-4.5) and those with type III (median: 2.0, IQR: 2.0-6.0, p=0.282). The number of clinic visits before diagnosis showed no significant association with the age at symptom onset and diagnosis (p=0.998 and 0.291, respectively). Conclusion: Our investigation is the first examination of the diagnostic journey of Korean patients with SMA. As treatments for SMA progress, the significance of an accurate diagnosis has increased, highlighting the importance of reviewing the diagnostic advancements made thus far. [ABSTRACT FROM AUTHOR]

Introduction: Establishing a diagnosis is paramount in medical practice as it shapes patients’ experiences and guides treatment. Patients grappling with rare diseases face a triple challenge: prolonged diagnostic journeys, limited responses to existing therapies, and the absence of effective monitoring tools. Genetic diagnosis often provides crucial diagnostic and prognostic information, opening up possibilities for genotype-targeted treatments and facilitating counselling and relative testing. The NIHR BioResource – Rare Diseases (NBR) Study and the Cohort Study in Idiopathic and Hereditary Pulmonary Arterial Hypertension (PAH Cohort study) aimed to enhance diagnosis and treatment for PAH, successfully identifying the genetic cause in 25% of idiopathic cases. However, the diagnostic and therapeutic odyssey in patients with PAH remains largely unexplored. Methods: Stakeholders from the NBR and PAH Cohort studies were recruited using purposive sampling. In-depth interviews and focus groups were recorded, transcribed, anonymised, and analysed thematically using MAXQDA software. Results: The study involved 53 interviews and focus groups with 63 participants, revealing key themes across five stages of the diagnostic odyssey: initial health concerns and interactions with general practitioners, experiences of misdiagnosis, relief upon receiving the correct diagnosis, and mixed emotions regarding genetic results and the challenges of living with the disease. Following the diagnosis, participants embarked on a therapeutic journey, facing various challenges, including the disease’s impact on professional and social lives, the learning curve associated with understanding the disease, shifts in communication dynamics with healthcare providers, therapeutic hurdles, and insurance-related issues. Building on these insights, we identified areas of unmet needs, such as improved collaboration with primary care providers and local hospitals, the provision of psychological support and counselling, and the necessity for ongoing patient education in the ever-evolving realms of research and therapy. Conclusions: The study highlights the significant challenges encountered throughout the diagnostic and therapeutic journey in PAH. To enhance patient outcomes, it is crucial to raise awareness of the disease, establish clear diagnostic pathways, and seamlessly integrate genetic diagnostics into clinical practice. Streamlining the diagnostic process can be achieved by utilising existing clinical infrastructure to support research and fostering better communication within the NHS. Moreover, there is an urgent need for more effective therapies alongside less burdensome drug delivery methods. [ABSTRACT FROM AUTHOR]

In 2023, the genetics scientific community celebrated two special anniversaries: the discovery of the double helix structure of DNA was published in 1953 and in 2003 the Human Genome Project was declared completed and made publicly available. To this day, genetics and genomics research is continuing to evolve at high pace and is identifying a steadily increasing number of genes as causal for distinct genetic diseases. The success story of genetics and genomics would not be complete without taking due account of the role of patient advocacy organizations in this process. This paper is based on the personal narrative (oral history) of a father whose daughter was born with a rare genetic disease (RGD) in the 1960s. The first-hand experience of living as a family with an RGD in those days made him a leading pioneer not only in the foundation of patient organizations at national, pan-European, and international levels but also in the development of multi-stakeholder co-operation and networking. Today, patient advocacy organizations play an active role in shaping health and research policies at national, EU, and international levels to ensure that their needs in regard to advancing RGD diagnostics, care, and treatment are addressed. [ABSTRACT FROM AUTHOR]

• Retrospective cohort to evaluate potential surgical delay among 93 pediatric DRE patients with FCD. • Unique treatment odyssey plot revealed the long patient journey to surgery in children with FCD. • Key factors for surgical delay: delayed notification of MRI abnormalities, longer time to DRE, older age at onset, use of more anti-seizure medications, and severe intellectual disability. • Early referral and accurate identification of MRI abnormalities in pediatric patients were recommended to minimize surgical delays. To elucidate the patient's journey to epilepsy surgery and identify the risk factors contributing to surgical delay in pediatric patients with drug-resistant epilepsy (DRE) due to focal cortical dysplasia (FCD). A retrospective review was conducted of 93 pediatric patients who underwent curative epilepsy surgery for FCD between January 2012 and March 2023 at a tertiary epilepsy center. The Odyssey plot demonstrated the treatment process before epilepsy surgery, including key milestones of epilepsy onset, first hospital visit, epilepsy diagnosis, MRI diagnosis, DRE diagnosis, and surgery. The primary outcome was surgical delay; the duration from DRE to surgery. Multivariate linear regression models were used to examine the association between surgical delay and clinical, investigative, and treatment characteristics. The median age at seizure onset was 1.3 years (interquartile range [IQR] 0.14–3.1), and at the time of surgery, it was 6 years (range 1–11). Notably, 46% experienced surgical delays exceeding two years. The Odyssey plot visually highlighted that surgical delay comprised a significant portion of the patient journey. Although most patients underwent MRI before referral, MRI abnormalities were identified before referral only in 39% of the prolonged group, compared to 70% of the non-prolonged group. Multivariate analyses showed that delayed notification of MRI abnormalities, longer duration from epilepsy onset to DRE, older age at onset, number of antiseizure medications tried, and moderate to severe intellectual disability were significantly associated with prolonged surgical delay. Pediatric DRE patients with FCD experienced a long journey until surgery. Early and accurate identification of MRI abnormalities is important to minimize surgical delays. [ABSTRACT FROM AUTHOR]

A genetic diagnosis of primary cardiomyopathies can be a long-unmet need in patients with complex phenotypes. We investigated a three-generation family with cardiomyopathy and various extracardiac abnormalities that had long sought a precise diagnosis. The 41-year-old proband had hypertrophic cardiomyopathy (HCM), left ventricular noncompaction, myocardial fibrosis, arrhythmias, and a short stature. His sister showed HCM, myocardial hypertrabeculation and fibrosis, sensorineural deafness, and congenital genitourinary malformations. Their father had left ventricular hypertrophy (LVH). The proband's eldest daughter demonstrated developmental delay and seizures. We performed a clinical examination and whole-exome sequencing for all available family members. All patients with HCM/LVH shared a c.4411-2A>C variant in ALPK3, a recently known HCM-causative gene. Functional studies confirmed that this variant alters ALPK3 canonical splicing. Due to extracardiac symptoms in the female patients, we continued the search and found two additional single-gene disorders. The proband's sister had a p.Trp329Gly missense in GATA3, linked to hypoparathyroidism, sensorineural deafness, and renal dysplasia; his daughter had a p.Ser251del in WDR45, associated with beta-propeller protein-associated neurodegeneration. This unique case of three monogenic disorders in one family shows how a comprehensive approach with thorough phenotyping and extensive genetic testing of all symptomatic individuals provides precise diagnoses and appropriate follow-up, embodying the concept of personalized medicine. We also present the first example of a splicing functional study for ALPK3 and describe the genotype–phenotype correlations in cardiomyopathy. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Congenital insensitivity to pain with anhidrosis (CIPA) (OMIM 256800) is a rare autosomal‐recessive condition, also known as hereditary sensory and autonomic neuropathy type IV (HSAN‐IV). The most commonly reported features include anhidrosis, intellectual disability, self‐mutilation, febrile episodes, impaired temperature perception, recurrent infections and/or autonomic nervous system impairment. Major joint destruction and joint deformity known as Charcot (neuropathic) joints are also seen in CIPA patients attributed to insensitivity to joint pain. Methods We present a case of a 46‐year‐old female affected with CIPA with a known NTRK1 variant and previously unidentified variant. Minigene reporter constructs were generated encompassing the exon 8 to exon 13 of the NTRK1 gene using the reference sequence and one harboring c.1483 + 5G > A variant identified in our proband. Minigene constructs were transfected into HEK293T cells, and the transcript was analysed for splicing to evaluate the effect of this variant in splicing. Results The patient (46‐year‐old female) exhibited right ankle joint deformity around 5 years of age. Patient also experienced lumbar compression and knee damage in adulthood. She had undergone a significant number of evaluations without clear diagnosis. Her presentation lacked many of the common clinical presentations of CIPA, and therefore, the focus of her evaluation was directed towards her unexplained joint deformities. Exome sequencing revealed a known pathogenic variant in NTRK1 (c.851 ‐ 33T > A:p.? [Intron 7]) and a novel NTRK1 variant (c.1483 + 5G > A:p.? [Intron 11]), which was later re‐classified as likely pathogenic. The patient was started on a biologic disease‐modifying anti‐rheumatic medication (bDMARD) due to a possible inflammatory etiology of her joint deformity. Molecular diagnosis allowed for modification of her treatment and surveillance strategies. Our minigene splicing assay demonstrated that the presence of the c.1483 + 5G > A variant has a negative effect on splicing, supporting the pathogenicity of this novel variant.

Abstract Background The ‘diagnostic odyssey’ is a common challenge faced by patients living with rare diseases and poses a significant burden for patients, their families and carers, and the healthcare system. The diagnosis of rare diseases in clinical settings is challenging, with patients typically experiencing a multitude of unnecessary tests and procedures. To improve diagnosis of rare disease, clinicians require evidence-based guidance on when their patient may be presenting with a rare disease. This study aims to identify common experiences amongst patients with rare diseases, to inform a series of ‘red flags’ that can aid diagnosis of rare diseases in non-specialist settings. A questionnaire was developed by Medics for Rare Diseases, informed by the experiences of clinicians, rare disease patients and patient advocates, and was shared with UK-based rare disease patient groups. Study participants were engaged via social media platforms, blogs and email newsletters of three umbrella rare disease organisations. The questionnaire, comprising 22 questions, was designed to identify typical experiences relating to physical and psychosocial manifestations and presentation of disease, patient interactions with healthcare providers, and family history. Results Questionnaire responses were received from 79 different rare disease patient groups and the common experiences identified were used to inform seven red flags of rare disease: multi-system involvement (3 or more); genetic inheritance pattern; continued presentation throughout childhood and adulthood; difficulties at school, especially relating to absences, difficulty participating in physical education and experiences of bullying or social isolation; multiple specialist referrals; extended period with unexplained symptoms; and misdiagnosis. In light of the red flags identified, recommendations for primary care and education settings have been proposed, focusing on the need for holistic assessment and awareness of both physical and psychosocial factors. Conclusions This study identified key commonalities experienced by patients with rare disease across physical and psychosocial domains, in addition to understanding patients’ history and experiences with healthcare providers. These findings could be used to develop a clinical decision‑making tool to support non-specialist practitioners to consider when their patient may have an undiagnosed rare condition, which may minimise the challenges of the ‘diagnostic odyssey’ and improve the patient experience.

This case report chronicles the diagnostic odyssey and resolution of a 27-year-old female with a complex neurodevelopmental disorder (NDD) using Whole Exome Sequencing (WES). The patient presented to a precision medicine clinic with multiple diagnoses including intellectual disability, autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), tics, seizures, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Although this patient previously had chromosomal microarray and several single-gene tests, the underlying cause of this patient's symptoms remained elusive. WES revealed a pathogenic missense mutation in the HNRNPU gene, associated with HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) and developmental and epileptic encephalopathy-54 (DEE54, OMIM: # 617391). Following this diagnoses, other treating clinicians identified additional indications for genetic testing, however, as the WES data was readily available, the clinical team was able to re-analyze the WES data to address their inquiries without requiring additional tests. This emphasizes the pivotal role of WES in expediting diagnoses, reducing costs, and providing ongoing clinical utility throughout a patient's life. Accessible WES data in primary care settings can enhance patient care by informing future genetic inquiries, enhancing coordination of care, and facilitating precision medicine interventions, thereby mitigating the burden on families and the healthcare system. [ABSTRACT FROM AUTHOR]

Background: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. Clinical trial data suggest early diagnosis and treatment are critical. The purpose of this study was to evaluate neurology appointment wait times for newborn screening identified infants, pediatric cases mirroring SMA symptomatology, and cases in which SMA is suspected by the referring physician. Approaches for triaging and expediting referrals in the US were also explored. Methods: Cure SMA surveyed healthcare professionals from two cohorts: (1) providers affiliated with SMA care centers and (2) other neurologists, pediatric neurologists, and neuromuscular specialists. Surveys were distributed directly and via Medscape Education, respectively, between July 9, 2020, and August 31, 2020. Results: Three hundred five total responses were obtained (9% from SMA care centers and 91% from the general recruitment sample). Diagnostic journeys were shorter for infants eventually diagnosed with SMA Type 1 if they were referred to SMA care centers versus general sample practices. Appointment wait times for infants exhibiting "hypotonia and motor delays" were significantly shorter at SMA care centers compared to general recruitment practices (p = 0.004). Furthermore, infants with SMA identified through newborn screening were also more likely to be seen sooner if referred to a SMA care center versus a general recruitment site. Lastly, the majority of both cohorts triaged incoming referrals. The average wait time for infants presenting at SMA care centers with "hypotonia and motor delay" was significantly shorter when initial referrals were triaged using a set of "key emergency words" (p = 0.036). Conclusions: Infants directly referred to a SMA care center versus a general sample practice were more likely to experience shorter SMA diagnostic journeys and appointment wait times. Triage guidelines for referrals specific to "hypotonia and motor delay" including use of "key emergency words" may shorten wait times and support early diagnosis and treatment of SMA. [ABSTRACT FROM AUTHOR]

Obtaining a genetic diagnosis of a primary mitochondrial disease (PMD) is often framed as a diagnostic odyssey. Yet, even after receiving a diagnosis, parents of affected children experience ongoing therapeutic and prognostic uncertainty and considerable psychosocial challenges. Semi-structured interviews (N = 24) were conducted with parents of 13 children (aged 2–19 years) with a genetically confirmed PMD. Paternal (N = 11) and maternal (N = 13) perspectives were obtained, and thematic analysis was performed on all interviews. A genetic diagnosis was valuable and empowering for parents, despite eliciting varied emotional responses. While the diagnosis helped focus management decisions, families often felt overwhelmed and unsupported in navigating the healthcare system. Most parents reported a serious impact on their romantic relationship. The sources of social support varied, with a preference for established friendship and family support networks over disease-specific community support groups. Most parents favored prenatal genetic testing in the event of a future pregnancy. This study provides insight into the lived experiences of parents after a genetic diagnosis of PMD in their children. The findings draw awareness to supportive care needs and highlight important gaps that should be addressed to ensure that parents feel supported within a holistic framework of management for PMDs. [ABSTRACT FROM AUTHOR]

Angelman syndrome (AS, MIM #105830) is a neurodevelopmental disorder characterized by severe intellectual disability, profound developmental delay, movement or balance problems, an excessively cheerful disposition, and seizures. AS results from inadequate expression of the maternal UBE3A gene (MIM #601623), which encodes an E3 ligase in the ubiquitin‐proteasome pathway. Here we present the case of two sisters with features consistent with AS who had negative methylation analyses. An autism/intellectual disability expanded panel revealed a maternally inherited novel UBE3A (NM_001354506.2) variant c.2443C>T p.(Pro815Ser) in both patients that was initially classified as a variant of uncertain significance. The patients were enrolled in Indiana University's Undiagnosed Rare Disease Clinic (URDC) to further investigate the variant. Additional data, including deep phenotyping, familial segregation analysis, and in silico studies, suggest that the variant is likely pathogenic. 3D modeling studies based on the available crystal structure revealed that the Pro815Ser variant can introduce more flexibility into the protein and alter its enzymatic activity. Recent literature confirms the pathogenic nature of the variant. Reanalysis of the UBE3A variant has heightened existing knowledge of AS and has offered this family an end to their diagnostic odyssey. [ABSTRACT FROM AUTHOR]

Background: Biochemical testing is a common first-tier approach in the setting of genetic evaluation of patients with unexplained developmental delay. However, results can be unclear, and a plan for second-tier analysis must be determined based on the patient's biochemical results and clinical presentation - in many cases, triggering a diagnostic odyssey. Case presentation: A male patient from the United States presenting with unexplained developmental delay, microcephaly, hypotonia, and feeding difficulties was referred for clinical genetic evaluation at age 8 months. Biochemical testing revealed an isolated marked elevation of glutaric acid on urine organic acid profile, without elevations of related metabolites. Further testing included GCDH sequencing, a neurometabolic gene panel, chromosomal microarray, Prader Willi/Angelman testing, and lysosomal disease enzyme panel, all of which were non-diagnostic. The patient had persistent developmental delay and hypotonia, dystonia, sensorineural hearing loss, and abnormal brain myelination on magnetic resonance imaging. Whole exome sequencing (WES) was performed and revealed a dual diagnosis of glutaric aciduria III (GA III) and BCAP31-related disorder, an X-linked intellectual disability syndrome, caused by a novel pathogenic variant. Conclusions: GA III has historically been considered clinically benign, with few reported cases. This patient's presenting symptoms were similar to those commonly seen in GA I and GA II, however the biochemical abnormalities were not consistent with these disorders, prompting additional molecular and biochemical testing. Ultimately, WES confirmed a diagnosis of BCAP31-related syndrome, a rare neurological disorder, which explained the patient's presenting symptoms. WES also identified a secondary diagnosis of GA III. We present a patient with two rare genetic conditions, highlighting the importance of deep phenotyping and the utility of WES in the setting of a patient with dual genetic diagnoses.

Abstract Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. Clinical trial data suggest early diagnosis and treatment are critical. The purpose of this study was to evaluate neurology appointment wait times for newborn screening identified infants, pediatric cases mirroring SMA symptomatology, and cases in which SMA is suspected by the referring physician. Approaches for triaging and expediting referrals in the US were also explored. Methods Cure SMA surveyed healthcare professionals from two cohorts: (1) providers affiliated with SMA care centers and (2) other neurologists, pediatric neurologists, and neuromuscular specialists. Surveys were distributed directly and via Medscape Education, respectively, between July 9, 2020, and August 31, 2020. Results Three hundred five total responses were obtained (9% from SMA care centers and 91% from the general recruitment sample). Diagnostic journeys were shorter for infants eventually diagnosed with SMA Type 1 if they were referred to SMA care centers versus general sample practices. Appointment wait times for infants exhibiting “hypotonia and motor delays” were significantly shorter at SMA care centers compared to general recruitment practices (p = 0.004). Furthermore, infants with SMA identified through newborn screening were also more likely to be seen sooner if referred to a SMA care center versus a general recruitment site. Lastly, the majority of both cohorts triaged incoming referrals. The average wait time for infants presenting at SMA care centers with “hypotonia and motor delay” was significantly shorter when initial referrals were triaged using a set of “key emergency words” (p = 0.036). Conclusions Infants directly referred to a SMA care center versus a general sample practice were more likely to experience shorter SMA diagnostic journeys and appointment wait times. Triage guidelines for referrals specific to “hypotonia and motor delay” including use of “key emergency words” may shorten wait times and support early diagnosis and treatment of SMA.

Abstract Background Familial hemophagocytic lymphohistiocytosis (FHL) is an immunological disorder characterized by overactivation of macrophages and T lymphocytes. This autosomal recessive condition has been characterized into multiple types depending on the genetic etiology. FHL type 3 is associated with bi-allelic pathogenic variants in the UNC13D gene. Case presentation We present a 12-year diagnostic odyssey for a family with FHL that signifies the advances of FHL genetic testing in a clinical genetic diagnostic laboratory setting. We describe the first case of a large UNC13D gross deletion in trans to a nonsense variant in a family with FHL3, which may have been mediated by Alu elements within introns 12 and 25 of the UNC13D gene. Conclusions This case highlights the importance of re-evaluating past genetic testing for a patient and family as test technology evolves in order to end a diagnostic odyssey.

Newborn screening (NBS) dramatically improves outcomes in severe childhood disorders by treatment before symptom onset. In many genetic diseases, however, outcomes remain poor because NBS has lagged behind drug development. Rapid whole-genome sequencing (rWGS) is attractive for comprehensive NBS because it concomitantly examines almost all genetic diseases and is gaining acceptance for genetic disease diagnosis in ill newborns. We describe prototypic methods for scalable, parentally consented, feedback-informed NBS and diagnosis of genetic diseases by rWGS and virtual, acute management guidance (NBS-rWGS). Using established criteria and the Delphi method, we reviewed 457 genetic diseases for NBS-rWGS, retaining 388 (85%) with effective treatments. Simulated NBS-rWGS in 454,707 UK Biobank subjects with 29,865 pathogenic or likely pathogenic variants associated with 388 disorders had a true negative rate (specificity) of 99.7% following root cause analysis. In 2,208 critically ill children with suspected genetic disorders and 2,168 of their parents, simulated NBS-rWGS for 388 disorders identified 104 (87%) of 119 diagnoses previously made by rWGS and 15 findings not previously reported (NBS-rWGS negative predictive value 99.6%, true positive rate [sensitivity] 88.8%). Retrospective NBS-rWGS diagnosed 15 children with disorders that had been undetected by conventional NBS. In 43 of the 104 children, had NBS-rWGS-based interventions been started on day of life 5, the Delphi consensus was that symptoms could have been avoided completely in seven critically ill children, mostly in 21, and partially in 13. We invite groups worldwide to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness.

The Kondo-Fu type of spondyloepiphyseal dysplasia (SEDKF) is a rare skeletal dysplasia caused by homozygous or compound heterozygous mutations in the MBTPS1 gene. The MBTPS1 gene encodes a protein that is involved in the regulation of cholesterol and fatty acid metabolism. Mutations in MBTPS1 can lead to reduced levels of these lipids, which can have a number of effects on development, including skeletal anomalies, growth retardation, and elevated levels of blood lysosomal enzymes. This work reports the case of a 5-year-old girl with SEDKF. The patient had a severely short stature and a number of skeletal anomalies, including kyphosis, pectus carinatum, and reduced bone mineral density. She also had early onset cataracts and inguinal hernias. Genetic testing revealed two novel compound heterozygous variants in the MBTPS1 gene. These variants are predicted to disrupt the function of the MBTPS1 protein, which is consistent with the patient's clinical presentation. This case report adds to the growing body of evidence that mutations in the MBTPS1 gene are causal of SEDKF. We summarized the features of previous reported cases (with age ranges from 4 to 24 years) and identified that 80% had low stature, 70% low weight, 80% had bilateral cataracts and 70% showed Spondyloepiphyseal dysplasia on X-rays. The findings of this study suggest that SEDKF is a clinically heterogeneous disorder that can present with a variety of features. Further studies are needed to better understand the underlying mechanisms of SEDKF and to develop more effective treatments. [ABSTRACT FROM AUTHOR]

This case report chronicles the diagnostic odyssey and resolution of a 27-year-old female with a complex neurodevelopmental disorder (NDD) using Whole Exome Sequencing (WES). The patient presented to a precision medicine clinic with multiple diagnoses including intellectual disability, autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), tics, seizures, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Although this patient previously had chromosomal microarray and several single-gene tests, the underlying cause of this patient’s symptoms remained elusive. WES revealed a pathogenic missense mutation in the HNRNPU gene, associated with HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) and developmental and epileptic encephalopathy-54 (DEE54, OMIM: # 617391). Following this diagnoses, other treating clinicians identified additional indications for genetic testing, however, as the WES data was readily available, the clinical team was able to re-analyze the WES data to address their inquiries without requiring additional tests. This emphasizes the pivotal role of WES in expediting diagnoses, reducing costs, and providing ongoing clinical utility throughout a patient’s life. Accessible WES data in primary care settings can enhance patient care by informing future genetic inquiries, enhancing coordination of care, and facilitating precision medicine interventions, thereby mitigating the burden on families and the healthcare system.

Background: Advances in genomics provide improved opportunities for diagnosis of complex neurogenetic disorders, yet the optimal approach to translate these benefits to the outpatient clinic is unclear. Aims: We retrospectively reviewed referral indications and outcomes of an integrated multidisciplinary team (MDT) clinic pathway for adults with suspected neurogenetic disorders. The associated cost implications were estimated. Methods: Consecutive patients who attended the neurogenomics clinic from January 2017 to April 2020 were included. The clinic comprised neurologists, clinical geneticists and genetic counsellors, who assessed each patient concurrently. Results: Ninety‐nine new patients were referred spanning 45 different clinical diagnoses. Following MDT clinical assessment, 23% (23/99) of referral diagnoses were revised prior to molecular testing. Eighty‐one patients (82%) underwent genetic testing, including 43 exome‐based panels, 15 whole‐genome sequencing, 14 single gene tests, 27 repeat‐primed polymerase chain reaction testing and two chromosomal microarrays. Overall, 33/99 patients (33%) received a diagnosis, either a molecular diagnosis (n = 24, of which 22 were diagnostic and two were predictive) or a clinical diagnosis (n = 9). Of the clinical diagnosis cohort, five patients received a diagnosis without molecular testing and four patients whose negative testing (one diagnostic and three predictive) allowed exclusion of genetic differentials and, hence, confirmation of clinical diagnoses. The diagnostic rate following MDT and diagnostic testing was 30% (28/94), excluding the five predictive testing cases. MDT assessment aligned with eventual molecular diagnoses in 96% of cases. The estimated average costs were AU$1386 per patient undergoing MDT assessment and AU$4159 per diagnosis achieved. Conclusions: We present an integrated multidisciplinary neurogenomics clinic pathway providing a diagnostic yield of 33% (30% excluding predictive testing cases), with costing implications. The relatively high diagnostic yield may be attributed to multidisciplinary input integrating accurate phenotyping of complex disorders and interpretation of genomic findings. [ABSTRACT FROM AUTHOR]

The diagnostic odyssey for people living with rare diseases (PLWRD) is often prolonged for myriad reasons including an initial failure to consider rare disease and challenges to systemically and systematically identifying and tracking undiagnosed diseases across the diagnostic journey. This often results in isolation, uncertainty, a delay to targeted treatments and increase in risk of complications with significant consequences for patient and family wellbeing. This article aims to highlight key time points to consider a rare disease diagnosis along with elements to consider in the potential operational classification for undiagnosed rare diseases during the diagnostic odyssey. We discuss the need to create a coding framework that traverses all stages of the diagnostic odyssey for PLWRD along with the potential benefits this will have to PLWRD and the wider community.

The diagnosis of chronic neuropathic pain requires a laborious process and can be a very long journey for the patients, one that can be characterized as an “odyssey.” Our aim was to describe the “diagnostic odyssey” associated with chronic neuropathic pain in the Greek context. Specialized clinicians working at dedicated chronic pain and palliative care centers were asked to participate in a survey regarding the diagnostic process in Greece. In total, 44 respondents provided information on the organization of their centers, the diagnostic process, and the perceived obstacles involved in the diagnosis of chronic neuropathic pain. Most respondents reported that their centers were not fully or efficiently organized and believed that additional specialized healthcare personnel should be employed. Raising public awareness about the existence of such centers was also considered key. The two main obstacles in reaching a diagnosis were the difficulty non-experts had in recognizing chronic neuropathic pain and the lack of acknowledgement that chronic neuropathic pain is a condition that needs to be addressed. When considering these responses in light of the extended socioeconomic burden associated with chronic neuropathic pain, efforts should be made to limit the “diagnostic odyssey” of chronic neuropathic pain in Greece. The aim of this study is to explore the experience of patients with chronic neuropathic pain in Greece from the viewpoint of pain specialists. A better organization of pain and palliative care centers, facilitation of communication with previously treating clinicians, increased personnel, utilization of a chronic pain registry, and guidelines development can aid in this venture. Keypoints: The diagnosis of chronic neuropathic pain in Greece is a laborious and time-consuming process that needs to be refined; Greek clinicians believe that their centers were not fully or efficiently organized and think that additional specialized healthcare personnel should be employed; Patient comorbidities and retards in visiting a clinic at the onset of symptoms delay the diagnosis of neuropathic pain and may complicate subsequent care; The diagnostic delay has been reported as three years between the onset of symptoms and seeking general medical help and another nine years before a referral to a pain specialist; Neuropathic pain is associated with patient distress and socioeconomic burdens, and diagnostic delays prolong the condition, may allow it to worsen, and utilize valuable healthcare resources without providing effective solutions.

Children with disabilities and rare or undiagnosed conditions and their families have faced numerous hardships of living during the COVID-19 pandemic. For those with undiagnosed conditions, the diagnostic odyssey can be long, expensive, and marked by uncertainty. We, therefore, sought to understand whether and how COVID-19 impacted the trajectory of children's care. We conducted semi-structured qualitative interviews with 25 caregivers who, prior to the pandemic, were on a diagnostic odyssey for their children. Most caregivers did not report any interruptions to their child's diagnostic odyssey. The greatest impact was access to therapy services, including the suspension or loss of their child's in-person therapeutic care and difficulties with virtual therapies. This therapy gap caused caregivers to fear that their children were not making progress. Although much has been written about the challenges of diagnostic odysseys for children and their families, this study illustrates the importance of expanding the focus of these studies to include therapeutic odysseys. Because therapeutic odysseys continue regardless of whether diagnoses are made, future research should investigate how to support caregivers through children's therapies within and outside of the COVID-19 context. [ABSTRACT FROM AUTHOR]

The Kondo-Fu type of spondyloepiphyseal dysplasia (SEDKF) is a rare skeletal dysplasia caused by homozygous or compound heterozygous mutations in the MBTPS1 gene. The MBTPS1 gene encodes a protein that is involved in the regulation of cholesterol and fatty acid metabolism. Mutations in MBTPS1 can lead to reduced levels of these lipids, which can have a number of effects on development, including skeletal anomalies, growth retardation, and elevated levels of blood lysosomal enzymes. This work reports the case of a 5-year-old girl with SEDKF. The patient had a severely short stature and a number of skeletal anomalies, including kyphosis, pectus carinatum, and reduced bone mineral density. She also had early onset cataracts and inguinal hernias. Genetic testing revealed two novel compound heterozygous variants in the MBTPS1 gene. These variants are predicted to disrupt the function of the MBTPS1 protein, which is consistent with the patient’s clinical presentation. This case report adds to the growing body of evidence that mutations in the MBTPS1 gene are causal of SEDKF. We summarized the features of previous reported cases (with age ranges from 4 to 24 years) and identified that 80% had low stature, 70% low weight, 80% had bilateral cataracts and 70% showed Spondyloepiphyseal dysplasia on X-rays. The findings of this study suggest that SEDKF is a clinically heterogeneous disorder that can present with a variety of features. Further studies are needed to better understand the underlying mechanisms of SEDKF and to develop more effective treatments.

Abstract Among the different etiologies for fever of unknown origin in children, infectious diseases are the most frequent final diagnosis, followed by autoimmune diseases and malignancies. Autoinflammatory diseases are relatively rare among children and are frequently overlooked as differential diagnoses for fever of unknown origin. Once the possibility of a particular autoimmune disease is considered by physicians, the diagnosis might be easily made by a genetic approach because many of autoinflammatory diseases are of monogenic origin. To reach the diagnosis, detailed history-taking, precise physical examinations, and cytokine profiling as well as extensive mutation analysis of candidate genes should be undertaken for febrile children. Such the approach will protect the patients, and their family to undergo “diagnostic odyssey” in which unnecessary and sometimes risky diagnostic and therapeutic interventions are taken. This short review discusses the clinical and laboratory features of familial Mediterranean fever and systemic juvenile idiopathic arthritis, as representative illnesses of monogenic and polygenic autoinflammatory diseases, respectively. Cytokine profiling and mutation analyses both help to understand and decipher the heterogeneous pathologies in both disease categories.

IntroductionRare genetic diseases are a major cause for severe illness in children. Whole exome sequencing (WES) is a powerful tool for identifying genetic causes of rare diseases. For a better and faster assessment of the vast number of variants that are identified in the index patient in WES, parental sequencing can be applied (“trio WES”).MethodsWe assessed the diagnostic rate of routine trio WES including analysis of copy number variants in 224 pediatric patients during an evaluation period of three years.ResultsTrio WES provided a diagnosis in 67 (30%) of all 224 analysed children. The turnaround time of trio WES analysis has been reduced significantly from 41 days in 2019 to 23 days in 2021. Copy number variants could be identified to be causative in 10 cases (4.5%), underlying the importance of copy number variant analysis. Variants in three genes which were previously not associated with a clinical condition (GAD1, TMEM222 and ZNFX1) were identified using the matching tool GeneMatcher and were part of the first description of a new syndrome.DiscussionTrio WES has proven to have a high diagnostic yield and to shorten the process of identifying the correct diagnosis in paediatric patients. Re-evaluation of all 224 trio WES 1–3 years after initial analysis did not establish new diagnoses. Initiating (trio) WES as a first-tier diagnostics including copy number variant detection should be considered as early as possible, especially for children treated in ICU, if a monogenetic disease is suspected.

The diagnosis of chronic neuropathic pain requires a laborious process and can be a very long journey for the patients, one that can be characterized as an "odyssey." Our aim was to describe the "diagnostic odyssey" associated with chronic neuropathic pain in the Greek context. Specialized clinicians working at dedicated chronic pain and palliative care centers were asked to participate in a survey regarding the diagnostic process in Greece. In total, 44 respondents provided information on the organization of their centers, the diagnostic process, and the perceived obstacles involved in the diagnosis of chronic neuropathic pain. Most respondents reported that their centers were not fully or efficiently organized and believed that additional specialized healthcare personnel should be employed. Raising public awareness about the existence of such centers was also considered key. The two main obstacles in reaching a diagnosis were the difficulty non-experts had in recognizing chronic neuropathic pain and the lack of acknowledgement that chronic neuropathic pain is a condition that needs to be addressed. When considering these responses in light of the extended socioeconomic burden associated with chronic neuropathic pain, efforts should be made to limit the "diagnostic odyssey" of chronic neuropathic pain in Greece. The aim of this study is to explore the experience of patients with chronic neuropathic pain in Greece from the viewpoint of pain specialists. A better organization of pain and palliative care centers, facilitation of communication with previously treating clinicians, increased personnel, utilization of a chronic pain registry, and guidelines development can aid in this venture. Keypoints: The diagnosis of chronic neuropathic pain in Greece is a laborious and time-consuming process that needs to be refined; Greek clinicians believe that their centers were not fully or efficiently organized and think that additional specialized healthcare personnel should be employed; Patient comorbidities and retards in visiting a clinic at the onset of symptoms delay the diagnosis of neuropathic pain and may complicate subsequent care; The diagnostic delay has been reported as three years between the onset of symptoms and seeking general medical help and another nine years before a referral to a pain specialist; Neuropathic pain is associated with patient distress and socioeconomic burdens, and diagnostic delays prolong the condition, may allow it to worsen, and utilize valuable healthcare resources without providing effective solutions. [ABSTRACT FROM AUTHOR]

Abstract Background People living with rare disease often have protracted journeys towards diagnosis. In the last decade, programs have arisen around the world that are dedicated to ending this ‘diagnostic odyssey’, including the Undiagnosed Diseases Program Western Australia (UDP-WA), which has a focus on finding diagnoses for children and young adults. To explore the lived experience of the diagnostic journey semi-structured interviews were conducted with parents of 11 children at commencement of their involvement in the UDP-WA. Results Thematic analysis revealed three main themes that captured parents’ experiences and perspectives. Parents reported (i) the need to respond to significant care needs of their children, which span not only the health system but other systems such as education and disability services. In doing so, parents become the navigator, expert and advocate for their children. Meanwhile, parents are on (ii) the diagnostic odyssey—the rollercoaster of their journey towards diagnosis, which includes various names applied to their child’s condition, and the impact of no diagnosis. Parents described their views on (iii) the value of a diagnosis and the outcomes they expect to be associated with a diagnosis. Conclusion Analysis showed an overall significant perceived value of a diagnosis. Our study provides new perspectives on the concept of diagnosis and indicates that parents may benefit from supports for their child’s care needs that are beyond the scope of the UDP-WA.

Abstract Background In order to facilitate the diagnostic process for adult patients suffering from a rare disease, the Undiagnosed Disease Program (UD-PrOZA) was founded in 2015 at the Ghent University Hospital in Belgium. In this study we report the five-year results of our multidisciplinary approach in rare disease diagnostics. Methods Patients referred by a healthcare provider, in which an underlying rare disease is likely, qualify for a UD-PrOZA evaluation. UD-PrOZA uses a multidisciplinary clinical approach combined with state-of-the-art genomic technologies in close collaboration with research facilities to diagnose patients. Results Between 2015 and 2020, 692 patients (94% adults) were referred of which 329 (48%) were accepted for evaluation. In 18% (60 of 329) of the cases a definite diagnosis was made. 88% (53 of 60) of the established diagnoses had a genetic origin. 65% (39 of 60) of the genetic diagnoses were made through whole exome sequencing (WES). The mean time interval between symptom-onset and diagnosis was 19 years. Key observations included novel genotype–phenotype correlations, new variants in known disease genes and the identification of three new disease genes. In 13% (7 of 53), identifying the molecular cause was associated with therapeutic recommendations and in 88% (53 of 60), gene specific genetic counseling was made possible. Actionable secondary findings were reported in 7% (12 of 177) of the patients in which WES was performed. Conclusion UD-PrOZA offers an innovative interdisciplinary platform to diagnose rare diseases in adults with previously unexplained medical problems and to facilitate translational research.

Purpose: The extent of comorbidity and misdiagnosis had been unclear for patients with hypermobile Ehlers-Danlos Syndrome (hEDS), a hereditary connective tissue disorder. The objectives of the study were to (1) describe the prevalence of alternative diagnoses that these patients have received, (2) assess their endorsement and rejection of these diagnoses, and (3) characterize their experience on their “diagnostic odysseys.” Methods: We circulated a survey through the Ehlers-Danlos Society’s Global Registry, asking participants which diagnoses they had received and whether they believed they were still accurate. They were also asked questions about their experience while seeking a diagnosis. Descriptive statistics and consensus clustering were then conducted. Results: A total of 505 unique individuals with clinically confirmed hEDS completed the survey. The average number of alternative diagnoses was 10.45. Anxiety, depression, and migraines were the most common. However, the diagnoses with the greatest endorsement were postural orthostatic tachycardia syndrome, cervical instability, and mast cell activation syndrome. The diagnoses with the greatest rejection were functional neurologic disorders, multiple sclerosis, and fibromyalgia. The average time to diagnosis was 10.39 years. Conclusion: An appropriate hEDS diagnosis is complex and its presentation multisystemic. Health care providers should be aware of the specific phenotypes to improve the time to diagnosis and care.

Rare diseases (RDs) cause considerable death and disability in Latin America. Still, there is no consensus on their definition across the region. Patients with RDs face a diagnostic odyssey to find a correct diagnosis, which may last many years and creates a burden for caregivers, healthcare systems, and society. These diagnostic delays have repercussions on the health and economic burden created by RDs and continue to represent an unmet medical need. This review analyzes barriers to the widespread adoption of newborn screening (NBS) programs and early diagnostic methods for RDs in Latin America and provides recommendations to achieve this critical objective. Increasing the adoption of NBS programs and promoting early diagnosis of RDs are the first steps to improving health outcomes for patients living with RDs. A coordinated, multistakeholder effort from leaders of patient organizations, government, industry, medical societies, academia, and healthcare services is required to increase the adoption of NBS programs. Patients' best interests should remain the guiding principle for decisions regarding NBS implementation and early diagnosis for RDs. [ABSTRACT FROM AUTHOR]

A twelve-year-old patient with a previous clinical diagnosis of spondylocostal skeletal dysplasia and moderate intellectual disability was genetically analyzed through next generation sequencing of a targeted gene panel of 179 genes associated to skeletal dysplasia and mucopolysaccharidosis in order to stablish a precision diagnosis. A homozygous nonsense [c.62C>G; p.(Ser21Ter)] mutation in DYM gene was identified in the patient. Null mutations in DYM have been associated to Dyggve-Melchior-Clausen syndrome, which is a rare autosomalrecessive disorder characterized by skeletal dysplasia and mental retardation, compatible with the patient's phenotype. To confirm the pathogenicity of this mutation, a segregation analysis was carried out, revealing that the mutation p(Ser21Ter) was solely inherited from the father, who is a carrier of the mutation, while the mother does not carry themutation. With the suspicion that a paternal disomy could be causing the disease, a series of microsatellite markers in chromosome 18, where the DYM gene is harbored, was analyzed in all the members of the family. Haplotype analysis provided strong evidence of paternal isodisomy and heterodisomy in that chromosome, confirming the pathological effect of this mutation. Furthermore, the patientmay have a compromised expression of the ELOA3 gene due to modifications in the genomic imprinting that may potentially increase the risk of digestive cancer. All these results highlight the importance of obtaining a precision diagnosis in rare diseases. [ABSTRACT FROM AUTHOR]

The use of facial recognition technology has diversified the diagnostic toolbelt for clinicians and researchers for the accurate diagnoses of patients with rare and challenging disorders. Specific identifiers in patient images can be grouped using artificial intelligence to allow the recognition of diseases and syndromes with similar features. Lysosomal storage disorders are rare, and some have prominent and unique features that may be used to train the accuracy of facial recognition software algorithms. Noteworthy features of lysosomal storage disorders (LSDs) include facial features such as prominent brows, wide noses, thickened lips, mouth, and chin, resulting in coarse and rounded facial features. We evaluated and report the prevalence of facial phenotypes in patients with different LSDs, noting two current examples when artificial intelligence strategies have been utilized to identify distinctive facies. Specific LSDs, including Gaucher disease, Mucolipidosis IV and Fabry disease have recently been distinguished using facial recognition software. Additional lysosomal disorders LSDs lysosomal storage disorders with unique and distinguishable facial features also merit evaluation using this technology. These tools may ultimately aid in the identification of specific LSDs and shorten the diagnostic odyssey for patients with these rare and under-recognized disorders. [ABSTRACT FROM AUTHOR]

Novel developments in genomic medicine may reduce the length of the diagnostic odyssey for patients with rare diseases. Health providers must thus decide whether to offer genome sequencing for the diagnosis of rare conditions in a routine clinical setting. We estimated the costs of singleton standard genetic testing and trio-based whole genome sequencing (WGS), in the context of the Scottish Genomes Partnership (SGP) study. We also explored what users value about genomic sequencing. Insights from the costing and value assessments will inform a subsequent economic evaluation of genomic medicine in Scotland. An average cost of £1,841 per singleton was estimated for the standard genetic testing pathway, with significant variability between phenotypes. WGS cost £6625 per family trio, but this estimate reflects the use of WGS during the SGP project and large cost savings may be realised if sequencing was scaled up. Patients and families valued (i) the chance of receiving a diagnosis (and the peace of mind and closure that brings); (ii) the information provided by WGS (including implications for family planning and secondary findings); and (iii) contributions to future research. Our costings will be updated to address limitations of the current study for incorporation in budget impact modelling and cost-effectiveness analysis (cost per diagnostic yield). Our insights into the benefits of WGS will guide the development of a discrete choice experiment valuation study. This will inform a user-perspective cost–benefit analysis of genome-wide sequencing, accounting for the broader non-health outcomes. Taken together, our research will inform the long-term strategic development of NHS Scotland clinical genetics testing services, and will be of benefit to others seeking to undertake similar evaluations in different contexts. [ABSTRACT FROM AUTHOR]

Background: Rare genetic disease studies have benefited from the era of high throughput sequencing. DNA sequencing results in genetic diagnosis of 18-40% of previously unsolved cases, while the incorporation of RNA-Seq analysis has more recently been shown to generate significant numbers of previously unattainable diagnoses. While DNA methylation remains less explored, multiple inborn diseases resulting from disorders of genomic imprinting are well characterized and a growing body of literature suggests the causative or correlative role of aberrant methylation in diverse rare inherited conditions. Complex pictures of methylation patterning are also emerging, including the association of regional, multiple specific-site or even single-site methylation, with disease. The systematic application of genomic-wide methylation-based sequencing for undiagnosed cases of rare diseases is a logical progression from current testing paradigms. Similar to the rationale previously exploited in RNA-based rare disease studies, we can assume that disease-associated or causative methylation aberrations in an individual will demonstrate significant differences from other individuals with unrelated phenotypes. Thus, aberrantly methylated sites will be outliers from a heterogeneous cohort of individuals. Methods: Based on this rationale, we present BOREALIS: Bisulfite-seq Outlie R M Ethylation At Sing Le S Ite Re Solution. BOREALIS uses a beta binomial model to identify outlier methylation at single CpG site resolution from bisulfite sequencing data. Results: Utilizing power analyses, we demonstrate that BOREALIS can identify outlier CpG methylation within a cohort of samples. Furthermore, we show that BOREALIS is tolerant to the inclusion of multiple identical outliers with sufficient cohort size and sequencing depth. Conclusions: The method demonstrates improved performance versus standard statistical testing and is suited for single or multi-site downstream analysis.

Despite affecting a small portion of the population, rare conditions have a significant impact, collectively affecting around 300 million people worldwide. Historically, early diagnosis has been impeded by failure to recognize rare conditions and order/refer for appropriate genomic testing. The advancements in genome sequencing offer a more agnostic and accelerated approach to the identification and diagnosis of rare disorders, potentially improving health outcomes, reducing the impact of disability, and reducing financial and psychological burdens on families. Due to the complex nature of these conditions, early engagement with genomic testing and clinical genetics services is key to facilitating a diagnosis. This qualitative exploration aimed to understand the journey to genomic testing and services and identify the supports families need during the diagnostic period. We conducted semi-structured interviews with 24 parents of children with a rare condition. Interviews were analyzed using inductive reflexive thematic analysis. Three themes of the parent experience were identified (1) the need for a streamlined pathway through the healthcare system, (2) the value of healthcare professionals who listen to parents, believed them, and partnered with them, and (3) the power of accurate diagnosis. Our findings indicate that providing direct and timely access to genomic testing for patients with a suspected rare condition could alleviate psychological and financial stressors. Genetic counselors are adept at supporting families affected by rare conditions and are optimally placed to facilitate timely access to genomic testing. Improving timely access may be facilitated through educating primary care physicians and embedding genetic counselors in pediatric settings., (© 2024 National Society of Genetic Counselors.)

Purpose: Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease characterized by the loss of motor neurons in the spinal cord and brainstem, leading to muscle atrophy and weakness. To understand the diagnostic process of Korean patients with SMA, we analyzed their clinical characteristics and challenges., Materials and Methods: We conducted a retrospective study of 38 patients with SMA (9 type II and 29 type III) between January 2000 and September 2023. Clinical, laboratory, and genetic data were reviewed., Results: The median ages at symptom onset and diagnosis were 3.0 years [interquartile range (IQR): 1.0-7.3 years] and 25.0 years (IQR: 10.5-37.3 years), respectively. The median diagnostic delay was 19.6 years (IQR: 6.4-31.0 years). A significantly longer delay was observed in SMA type III patients (median: 21.0 years, IQR: 11.0-31.0 years) compared to SMA type II patients (median: 3.0 years, IQR: 0.9-21.0 years) ( p =0.021). No significant difference was observed in the number of clinic visits before diagnosis between patients with SMA type II (median: 2.0, IQR: 1.0-4.5) and those with type III (median: 2.0, IQR: 2.0-6.0, p =0.282). The number of clinic visits before diagnosis showed no significant association with the age at symptom onset and diagnosis ( p =0.998 and 0.291, respectively)., Conclusion: Our investigation is the first examination of the diagnostic journey of Korean patients with SMA. As treatments for SMA progress, the significance of an accurate diagnosis has increased, highlighting the importance of reviewing the diagnostic advancements made thus far., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2024.)

Most rare diseases are genetic diseases. Due to the diversity of rare diseases and the high likelihood of patients with rare diseases to be undiagnosed or misdiagnosed, it is not unusual that these patients undergo a long diagnostic odyssey before they receive a definitive diagnosis. This situation presents a clear need to set up a dedicated clinical service to end the diagnostic odyssey of patients with rare diseases.

Abstract Background Diagnosis, treatment, and care of patients with rare diseases require multidisciplinary cooperation between medical and paramedical specialities and with patients and families. Innovative genetic diagnostics, whole exome and whole genome sequencing (WES, WGS) has enlarged the diagnostic toolkit but also increased the complexity of the endeavour. Structured multidisciplinary clinical pathways (CPW) can guide diagnosis, treatment, and care of patients with rare diseases, link scientific evidence to clinical practice and optimise clinical outcomes whilst maximising clinical efficiency. Results In contrast to the common approach of appending disease-specific CPWs to disease-specific guidelines, we suggest a generic CPW manoeuvring the patient along the way of finding the correct diagnosis by applying the best diagnostic strategy into an appropriate system of treatment and care. Available guidelines can be integrated into the generic CPW in the course of its application. The approach also applies to situations where a diagnosis remains unsolved. The backbone of the generic CPW is a set of multidisciplinary structured case conferences projecting and evaluating diagnostic and/or therapeutic steps, enforcing to integrate best scientific evidence with clinical experience. The generic CPW is stated as a flowchart and a checklist which can be used to record and document parsimoniously the structure, process and results of a patient’s pathway, but also as a data model for research. It was applied in a multicentre setting with 587 cases each with a presumptive diagnosis of a rare disease. In 369 cases (62.8%) a diagnosis could be confirmed, and multidisciplinary treatment and/or care was initiated. The median process time from first contact until confirmation of diagnosis by WES was 109 days and much shorter than diagnostic delays reported in the literature. Application of the CPW is illustrated by two case reports. Conclusions Our model is a tool to change the diagnostic odyssey into an organised and trackable route. It can also be used to inform patients and families about the stages of their individual route, to update health care providers only partially involved or attending specialised treatment and care, like the patient’s or family’s primary physician, and finally to train novices in the field.

Abstract Background Autism prevalence has increased rapidly in recent years, however, nationally representative estimates on the ages of first identification and intervention are out of date. Objectives: (1) To estimate the ages at which children with autism receive their first diagnosis, intervention plan, and developmental services; and (2) To evaluate differences in ages at events by birth cohort and sociodemographic characteristics. Methods Using cross-sectional data from the 2016–2018 National Survey of Children’s Health (NSCH), we examined associations via linear regression among a sample of 2303 children aged 2–17 years old, who had ever been diagnosed with autism and either (1) ever had a plan for special education or early intervention, or (2) ever received special services to meet developmental needs. Exposures included age cohort, child, household and healthcare provider characteristics. Results Most children in the study sample (n = 2303) were over age 6 years, male, of non-Hispanic white race/ethnicity and had mild/moderate autism. Mean ages (years) at first diagnosis was 4.56 (SE = 0.13); first plan was 4.43 (SE = 0.11); and first services was 4.10 (SE = 0.11). After adjustment for exposures and survey year, the middle childhood cohort was 18 months older at first intervention (β = 1.49, 95% CI, 1.18–1.81), and adolescents were 38 months older at first diagnosis (β = 3.16, 95% CI, 2.72–3.60) compared to those in early childhood. Younger ages at events were observed among: Hispanic/Latinx as compared to white children, those with moderate or severe symptoms as compared to mild symptoms, and children who received their diagnosis from a specialist as compared to psychologists or psychiatrists. Conclusions Children with autism receive their first diagnosis, intervention plans and developmental services at younger ages than they had in the past. Future research is needed to identify the mechanisms for these improvements in early identification and intervention to accelerate additional progress.

Rare diseases (RDs) cause considerable death and disability in Latin America. Still, there is no consensus on their definition across the region. Patients with RDs face a diagnostic odyssey to find a correct diagnosis, which may last many years and creates a burden for caregivers, healthcare systems, and society. These diagnostic delays have repercussions on the health and economic burden created by RDs and continue to represent an unmet medical need. This review analyzes barriers to the widespread adoption of newborn screening (NBS) programs and early diagnostic methods for RDs in Latin America and provides recommendations to achieve this critical objective. Increasing the adoption of NBS programs and promoting early diagnosis of RDs are the first steps to improving health outcomes for patients living with RDs. A coordinated, multistakeholder effort from leaders of patient organizations, government, industry, medical societies, academia, and healthcare services is required to increase the adoption of NBS programs. Patients’ best interests should remain the guiding principle for decisions regarding NBS implementation and early diagnosis for RDs.

While we know a lot more about Long Covid today, patients who were infected with Covid-19 early on in the pandemic and developed Long Covid had to contend with medical professionals who lacked awareness of the potential for extended complications from Covid-19. Long Covid patients have responded by labeling their contentious interactions with medical professionals, organizations, and the broader medical system as “gaslighting.” We argue that the charge of medical gaslighting can be understood as a form of ontological politics. Not only do patients demand that their version of reality be recognized, but they also blame the experts who hold gatekeeping power over their medical care for producing a distorted version of said reality. By analyzing results from an online survey of Long Covid patients active on social media in the United States (n ​= ​334), we find that experiences of contention and their reframing as “gaslighting” were common amongst our respondents. In short answer responses about their experience obtaining medical care for Long Covid, our respondents described encountering medical professionals who dismissed their experience, leading to lengthy diagnostic odysseys and lack of treatment options for Long Covid. Even though we are limited by characteristics of our sample, there is good reason to believe that these experiences and their contentious reframing as medical gaslighting are exacerbated by gender, class, and racial inequalities.

A twelve-year-old patient with a previous clinical diagnosis of spondylocostal skeletal dysplasia and moderate intellectual disability was genetically analyzed through next generation sequencing of a targeted gene panel of 179 genes associated to skeletal dysplasia and mucopolysaccharidosis in order to stablish a precision diagnosis. A homozygous nonsense [c.62C>G; p.(Ser21Ter)] mutation in DYM gene was identified in the patient. Null mutations in DYM have been associated to Dyggve-Melchior-Clausen syndrome, which is a rare autosomal-recessive disorder characterized by skeletal dysplasia and mental retardation, compatible with the patient´s phenotype. To confirm the pathogenicity of this mutation, a segregation analysis was carried out, revealing that the mutation p(Ser21Ter) was solely inherited from the father, who is a carrier of the mutation, while the mother does not carry the mutation. With the suspicion that a paternal disomy could be causing the disease, a series of microsatellite markers in chromosome 18, where the DYM gene is harbored, was analyzed in all the members of the family. Haplotype analysis provided strong evidence of paternal isodisomy and heterodisomy in that chromosome, confirming the pathological effect of this mutation. Furthermore, the patient may have a compromised expression of the ELOA3 gene due to modifications in the genomic imprinting that may potentially increase the risk of digestive cancer. All these results highlight the importance of obtaining a precision diagnosis in rare diseases.