Genetics of kidney disorders in Phelan-McDermid syndrome: evidence from 357 registry participants.

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder caused by SHANK3 pathogenic variants or chromosomal rearrangements affecting the chromosome 22q13 region. Previous research found that kidney disorders, primarily congenital anomalies of the kidney and urinary tract, are common in people with PMS, yet research into candidate genes has been hampered by small study sizes and lack of attention to these problems. METHODS: We used a cohort of 357 people from the Phelan-McDermid Syndrome Foundation International Registry to investigate the prevalence of kidney disorders in PMS using a cross-sectional design and to identify 22q13 genes contributing to these disorders. RESULTS: Kidney disorders reported included vesicoureteral reflux (n = 37), hydronephrosis (n = 36), dysplastic kidneys (n = 19), increased kidney size (n = 19), polycystic kidneys (15 cases), and kidney stones (n = 4). Out of 315 subjects with a 22q13 deletion, 101 (32%) had at least one kidney disorder, while only one out of 42 (2%) individuals with a SHANK3 pathogenic variant had a kidney disorder (increased kidney size). We identified two genomic regions that were significantly associated with having a kidney disorder with the peak associations observed near positions approximately 5 Mb and 400 Kb from the telomere. CONCLUSIONS: The candidate genes for kidney disorders include FBLN1, WNT7B, UPK3A, CELSR1, and PLXNB2. This study demonstrates the utility of patient registries for uncovering genetic contributions to rare diseases. Future work should focus on functional studies for these genes to assess their potential pathogenic contribution to the different subsets of kidney disorders.

Lymphedema is associated with CELSR1 in Phelan-McDermid syndrome.

Lymphedema is a troubling condition present in many disorders including the rare genetic disorder known as Phelan-McDermid syndrome (PMS). The neurobehavioral features of PMS, also known as 22q13.3 deletion syndrome, have been investigated, but little research exists on lymphedema in PMS. In this investigation, clinical and genetic data from 404 people with PMS were reviewed from the PMS-International Registry revealing a prevalence of 5% with lymphedema. Lymphedema was reported in 1 out of 47 people (2.1%) with PMS due to a SHANK3 variant and 19 out of 357 people (5.3%) with PMS due to 22q13.3 deletions. Lymphedema was more common among those in their teens or adulthood (p = 0.0011) and those with deletions >4 Mb. People with lymphedema had significantly larger deletions (mean 5.375 Mb) than those without lymphedema (mean 3.464 Mb, p = 0.00496). Association analysis identified a deletion of the CELSR1 gene to be the biggest risk factor (OR = 12.9 95% CI [2.9-56.2]). Detailed assessment of 5 subjects identified all had deletions of CELSR1, developed symptoms of lymphedema starting at age 8 or older, and typically responded well to standard therapy. In conclusion, this is the largest assessment of lymphedema in PMS to date and our results suggest that individuals with deletions >4 Mb or those with CELSR1 deletions should be assessed for lymphedema.

Sleep disturbances in Phelan-McDermid syndrome: Clinical and metabolic profiling of 56 individuals.

Phelan-McDermid Syndrome (PMS) is caused by deletions at chromosome 22q13.3 or pathogenic/likely pathogenic SHANK3 variants. The clinical presentation is extremely variable and includes global developmental delay/intellectual disability (ID), seizures, neonatal hypotonia, and sleep disturbances, among others. This study investigated the prevalence of sleep disturbances, and the genetic and metabolic features associated with them, in a cohort of 56 individuals with PMS. Sleep data were collected via standardized observer/caregiver questionnaires, while genetic data from array-CGH and sequencing of 9 candidate genes within the 22q13.3 region, and metabolic profiling utilized the Biolog Phenotype Mammalian MicroArray plates. Sleep disturbances were present in 64.3% of individuals with PMS, with the most common problem being waking during the night (39%). Sleep disturbances were more prevalent in individuals with a SHANK3 pathogenic variant (89%) compared to subjects with 22q13.3 deletions of any size (59.6%). Distinct metabolic profiles for individuals with PMS with and without sleep disturbances were also identified. These data are helpful information for recognizing and managing sleep disturbances in individuals with PMS, outlining the main candidate gene for this neurological manifestation, and highlighting potential biomarkers for early identification of at-risk subjects and molecular targets for novel treatment approaches.

Genetic and metabolic profiling of individuals with Phelan-McDermid syndrome presenting with seizures.

Phelan-McDermid syndrome (PMS) (OMIM*606232) is a rare genetic disorder characterized by intellectual disability, autistic features, speech delay, minor dysmorphia, and seizures. This study was conducted to investigate the prevalence of seizures and the association with genetic and metabolic features since there has been little research related to seizures in PMS. For 57 individuals, seizure data was collected from caregiver interviews, genetic data from existing cytogenetic records and Sanger sequencing for nine 22q13 genes, and metabolic profiling from the Phenotype Mammalian MicroArray (PM-M) developed by Biolog. Results showed that 46% of individuals had seizures with the most common type being absence and grand-mal seizures. Seizures were most prevalent in individuals with pathogenic SHANK3 mutations (70%), those with deletion sizes >4 Mb (16%), and those with deletion sizes <4 Mb (71%) suggesting involvement of genes in addition to SHANK3. Additionally, a 3 Mb genomic region on 22q13.31 containing the gene TBC1D22A, was found to be significantly associated with seizure prevalence. A distinct metabolic profile was identified for individuals with PMS with seizures and suggested among other features a disrupted utilization of main energy sources using Biolog plates. The results of this study will be helpful for clinicians and families in anticipating seizures in these children and for researchers to identify candidate genes for the seizure phenotype.

Factors related to initial treatment for adhesive capsulitis in the medicare population.

BACKGROUND: Primary adhesive capsulitis (AC) is not well understood, and controversy remains about the most effective treatment approaches. Even less is known about the treatment of AC in the Medicare population. We aimed to fully characterize initial treatment for AC in terms of initial treatment utilization, timing of initial treatments and treatment combinations. METHODS: Using United States Medicare claims from 2010-2012, we explored treatment utilization and patient characteristics associated with initial treatment for primary AC among 7,181 Medicare beneficiaries. Patients with primary AC were identified as patients seeking care for a new shoulder complaint in 2011, with the first visit related to shoulder referred to as the index date, an x-ray or MRI of the shoulder region, and two separate diagnoses of AC (ICD-9-CM codes: 726.00). The treatment period was defined as the 90 days immediately following the index shoulder visit. A multivariable logistic model was used to assess baseline patient factors associated with receiving surgery within the treatment period. RESULTS: Ninety percent of beneficiaries with primary AC received treatment within 90 days of their index shoulder visit. Physical therapy (PT) alone (41%) and injection combined with PT (34%) were the most common treatment approaches. Similar patient profiles emerged across treatment groups, with higher proportions of racial minorities, socioeconomically disadvantaged and more frail patients favoring injections or watchful waiting. Black beneficiaries (OR = 0.37, [0.16, 0.86]) and those residing in the northeast (OR = 0.36, [0.18, 0.69]) had significantly lower odds of receiving surgery in the treatment period. Conversely, younger beneficiaries aged 66-69 years (OR = 6.75, [2.12, 21.52]) and 70-75 years (OR = 5.37, [1.67, 17.17]) and beneficiaries with type 2 diabetes had significantly higher odds of receiving surgery (OR = 1.41, [1.03, 1.92]). CONCLUSIONS: Factors such as patient baseline health and socioeconomic characteristics appear to be important for physicians and Medicare beneficiaries making treatment decisions for primary AC.

TOMM40 genetic variants associated with healthy aging and longevity: a systematic review.

INTRODUCTION: Healthy aging relies on mitochondrial functioning because this organelle provides energy and diminishes oxidative stress. Single nucleotide polymorphisms (SNPs) in TOMM40, a critical gene that produces the outer membrane protein TOM40 of mitochondria, have been associated with mitochondrial dysfunction and neurodegenerative processes. Yet it is not clear whether or how the mitochondria may impact human longevity. We conducted this review to ascertain which SNPs have been associated with markers of healthy aging. METHODS: Using the PRISMA methodology, we conducted a systematic review on PubMed and Embase databases to identify associations between TOMM40 SNPs and measures of longevity and healthy aging. RESULTS: Twenty-four articles were selected. The TOMM40 SNPs rs2075650 and rs10524523 were the two most commonly identified and studied SNPs associated with longevity. The outcomes associated with the TOMM40 SNPs were changes in BMI, brain integrity, cognitive functions, altered inflammatory network, vulnerability to vascular risk factors, and longevity. DISCUSSIONS: Our systematic review identified multiple TOMM40 SNPs potentially associated with healthy aging. Additional research can help to understand mechanisms in aging, including resilience, prevention of disease, and adaptation to the environment.

Genetics providers' experiences using telehealth: A grounded theory approach.

There was a paucity of research describing the perspectives and experiences of clinical genetics providers in telehealth prior to the SARS-CoV-2 pandemic. The available literature focused primarily on provider satisfaction and offered limited insight into genetics providers' work in telehealth. The purpose of this study, conducted just prior to the widespread knowledge of SARS-CoV-2 in the United States and mass transition to telehealth, was to understand the telehealth process from the vantage of genetics providers working in telehealth practice settings. This research employed grounded theory using the constant comparative method in coding and analysis of data to generate theory. Ten genetics providers were interviewed over the phone about their experiences, specifically the efficacy of telehealth work, providers' perspectives of patient outcomes, and personal fulfillment derived from telehealth patient care. Six themes emerged in the study: Making Professional Choices, Increasing Patient Access, Providing Effective Services, Understanding Telehealth Limits, Feelings about Telehealth Consultations, and Deepening Personal Fulfillment. These major themes guided the creation of the Theoretical Model of Telehealth Providers in Genetics, which depicts the connections between providers' personal fulfillment in telehealth, commitment to patient services, and the provision of telehealth to the public. This model may help others who are working on telehealth initiatives or developing telehealth programs. Findings from this study can support the current use and the growth of telehealth in genetics as a result of the SARS-CoV-2 pandemic. Future research is needed to describe the telehealth process and develop valid instruments for assessing and measuring the constructs of the Theoretical Model of Telehealth Providers in Genetics.

The impact of pharmacogenetic testing in patients exposed to polypharmacy: a scoping review.

Polypharmacy poses a significant risk for adverse reactions. While there are clinical decision support tools to assist clinicians in medication management, pharmacogenetic testing to identify potential drug-gene or drug-drug-gene interactions is not widely implemented in the clinical setting. A PRISMA-compliant scoping review was performed to determine if pharmacogenetic testing for absorption, distribution, metabolism, and excretion (ADME)-related genetic variants is associated with improved clinical outcomes in patients with polypharmacy. Six studies were reviewed. Five reported improved clinical outcomes, reduced side effects, reduction in the number of drugs used, or reduced healthcare utilization. The reviewed studies varied in methodological quality, risk of bias, and outcome measures. Age, diet, disease state, and treatment adherence also influence drug response, and may confound the relationship between genetic polymorphisms and treatment outcomes. Further studies using a randomized control design are needed. We conclude that pharmacogenetic testing represents an opportunity to improve health outcomes in patients exposed to polypharmacy, particularly in patients with psychiatric disorders and the elderly.

Comprehensive investigation of the phenotype of MEF2C-related disorders in human patients: A systematic review.

MEF2C-related disorders (aka MEF2C-haploinsufficiency) are caused by variations in or involving the MEF2C gene and are characterized by intellectual disability, developmental delay, lack of speech, limited walking, and seizures. Despite these findings, the disorder is not easily recognized clinically. We performed a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to assemble the most comprehensive list of patients and their phenotypes. Through searching PubMed, Web of Science, and MEDLINE, 43 articles met the inclusion criteria and were fully reviewed. One hundred and seventeen patients were identified from these publications with most having a phenotype of intellectual disability, developmental delay, seizures, hypotonia, absent speech, inability to walk, stereotypic movements, and MRI abnormalities. Nonclassical findings included one patient with a question mark ear, two patients with a jugular pit, one patient with a unique neuroendocrine finding, and nine patients that did not have MEF2C deletions or disruptions but may be affected due to a positional effect on MEF2C. This systematic review characterizes the phenotype of MEF2C-related disorders, documents the severity of this condition, and will help providers to better diagnose and care for patients and their families. Additionally, this compiled information provides a comprehensive resource for investigators interested in pursuing specific genotype-phenotype correlations.

The epidemiology and etiology of adhesive capsulitis in the U.S. Medicare population.

BACKGROUND: Adhesive capsulitis (AC) of the shoulder, also known as frozen shoulder, causes substantial pain and disability. In cases of secondary AC, the inflammation and fibrosis of the synovial joint can be triggered by trauma or surgery to the joint followed by extended immobility. However, for primary AC the inciting trigger is unknown. The burden of the disorder among the elderly is also unknown leading to this age group being left out of therapeutic research studies, potentially receiving delayed diagnoses, and unknown financial costs to the Medicare system. The purpose of this analysis was to describe the epidemiology of AC in individuals over the age of 65, an age group little studied for this disorder. The second purpose was to investigate whether specific medications, co-morbidities, infections, and traumas are risk factors or triggers for primary AC in this population. METHODS: We used Medicare claims data from 2010-2012 to investigate the prevalence of AC and assess comorbid risk factors and seasonality. Selected medications, distal trauma, and classes of infections as potential inflammatory triggers for primary AC were investigated using a case-control study design with patients with rotator cuff tears as the comparison group. Medications were identified from National Drug codes and translated to World Health Organization ATC codes for analysis. Health conditions were identified using ICD9-CM codes. RESULTS: We found a one-year prevalence rate of AC of approximately 0.35% among adults aged 65 years and older which translates to approximately 142,000 older adults in the United States having frozen shoulder syndrome. Diabetes and Parkinson's disease were significantly associated with the diagnosis of AC in the elderly. Cases were somewhat more common from August through December, although a clear seasonal trend was not observed. Medications, traumas, and infections were similar for cases and controls. CONCLUSIONS: This investigation identified the burden of AC in the US elderly population and applied case-control methodology to identify triggers for its onset in this population. Efforts to reduce chronic health conditions such as diabetes may reduce seemingly unrelated conditions such as AC. The inciting trigger for this idiopathic condition remains elusive.

When folic acid fails: Insights from 20 years of neural tube defect surveillance in South Carolina.

Neural tube defects (NTDs) are the most common of the severe malformations of the brain and spinal cord. Increased maternal intake of folic acid (FA) during the periconceptional period is known to reduce NTD risk. Data from 1046 NTD cases in South Carolina were gathered over 20 years of surveillance. It was possible to determine maternal periconceptional FA use in 615 NTD-affected pregnancies. In 163 occurrent (26.9%) and two recurrent (22%) NTD cases, the mothers reported periconceptional FA use. These women were older and more likely to be white. Maternal periconceptional FA usage was reported in 40.4% of cases of spina bifida with other anomalies but in only 25.2% of isolated spina bifida cases (P = 0.02). This enrichment for associated anomalies was not noted among cases of anencephaly or of encephalocele. Among the 563 subsequent pregnancies to mothers with previous NTD-affected pregnancies, those taking FA had a 0.4% NTD recurrence rate, but the recurrence without FA was 8.5%. NTDs with other associated findings were less likely to be prevented by FA, suggesting there is a background NTD rate that cannot be further reduced by FA. Nonetheless, the majority (73.9%) of NTDs in pregnancies in which the mothers reported periconceptional FA use were isolated NTDs of usual types. Cases in which FA failed in prevention of NTDs provide potential areas for further study into the causation of NTDs. The measures and techniques implemented in South Carolina can serve as an effective and successful model for prevention of NTD occurrence and recurrence.

Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome.

This study is the first to describe age-related changes in a large cohort of patients with Phelan-McDermid syndrome (PMS), also known as 22q13 deletion syndrome. Over a follow-up period of up to 12 years, physical examinations and structured interviews were conducted for 201 individuals diagnosed with PMS, 120 patients had a focused, high-resolution 22q12q13 array CGH, and 92 patients' deletions were assessed for parent-of-origin. 22q13 genomic anomalies include terminal deletions of 22q13 (89 %), terminal deletions and interstitial duplications (9 %), and interstitial deletions (2 %). Considering different age groups, in older patients, behavioral problems tended to subside, developmental abilities improved, and some features such as large or fleshy hands, full or puffy eyelids, hypotonia, lax ligaments, and hyperextensible joints were less frequent. However, the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age. Some neurologic and dysmorphic features such as speech and developmental delay and macrocephaly correlated with deletion size. Deletion sizes in more recently diagnosed patients tend to be smaller than those diagnosed a decade earlier. Seventy-three percent of de novo deletions were of paternal origin. Seizures were reported three times more often among patients with a de novo deletion of the maternal rather than paternal chromosome 22. This analysis improves the understanding of the clinical presentation and natural history of PMS and can serve as a reference for the prevalence of clinical features in the syndrome.

22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome.

PURPOSE: Phelan-McDermid syndrome is a developmental disability syndrome with varying deletions of 22q13 and varying clinical severity. We tested the hypothesis that, in addition to loss of the telomeric gene SHANK3, specific genomic regions within 22q13 are associated with important clinical features. METHODS: We used a customized oligo array comparative genomic hybridization of 22q12.3-terminus to obtain deletion breakpoints in a cohort of 70 patients with terminal 22q13 deletions. We used association and receiver operating characteristic statistical methods in a novel manner and also incorporated protein interaction networks to identify 22q13 genomic locations and genes associated with clinical features. RESULTS: Specific genomic regions and candidate genes within 22q13.2q13.32 were associated with severity of speech/language delay, neonatal hypotonia, delayed age at walking, hair-pulling behaviors, male genital anomalies, dysplastic toenails, large/fleshy hands, macrocephaly, short and tall stature, facial asymmetry, and atypical reflexes. We also found regions suggestive of a negative association with autism spectrum disorders. CONCLUSION: This work advances the field of research beyond the observation of a correlation between deletion size and phenotype and identifies candidate 22q13 loci, and in some cases specific genes, associated with singular clinical features observed in Phelan-McDermid syndrome. Our statistical approach may be useful in genotype-phenotype analyses for other microdeletion or microduplication syndromes.

Inclusion of the severe and enduring anorexia nervosa phenotype in genetics research: a scoping review.

BACKGROUND: Anorexia nervosa has one of the highest mortality rates of all mental illnesses. For those who survive, less than 70% fully recover, with many going on to develop a more severe and enduring phenotype. Research now suggests that genetics plays a role in the development and persistence of anorexia nervosa. Inclusion of participants with more severe and enduring illness in genetics studies of anorexia nervosa is critical. OBJECTIVE: The primary goal of this review was to assess the inclusion of participants meeting the criteria for the severe enduring anorexia nervosa phenotype in genetics research by (1) identifying the most widely used defining criteria for severe enduring anorexia nervosa and (2) performing a review of the genetics literature to assess the inclusion of participants meeting the identified criteria. METHODS: Searches of the genetics literature from 2012 to 2023 were performed in the PubMed, PsycINFO, and Web of Science databases. Publications were selected per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). The criteria used to define the severe and enduring anorexia nervosa phenotype were derived by how often they were used in the literature since 2017. The publications identified through the literature search were then assessed for inclusion of participants meeting these criteria. RESULTS: most prevalent criteria used to define severe enduring anorexia nervosa in the literature were an illness duration of ≥ 7 years, lack of positive response to at least two previous evidence-based treatments, a body mass index meeting the Diagnostic and Statistical Manual of Mental Disorders-5 for extreme anorexia nervosa, and an assessment of psychological and/or behavioral severity indicating a significant impact on quality of life. There was a lack of consistent identification and inclusion of those meeting the criteria for severe enduring anorexia nervosa in the genetics literature. DISCUSSION: This lack of consistent identification and inclusion of patients with severe enduring anorexia nervosa in genetics research has the potential to hamper the isolation of risk loci and the development of new, more effective treatment options for patients with anorexia nervosa.

Anorexia nervosa (AN) is a serious illness with a high death rate. Many of those with AN do not recover and have continuing severe psychological and physical symptoms that greatly impact their quality of life. Research has shown that genetics plays an important role, along with environment, in the development and persistence of AN. This review highlights the continued lack of consensus on defining criteria for severe and enduring AN in the literature and the continued focus on younger females with shorter illness durations in AN genetics research. Greater efforts are needed to include older participants with severe AN of longer duration in genetics research in hopes of developing more effective treatments for this underrepresented group.

SARS-CoV-2 emergency use authorization published sensitivity differences do not correlate with positivity rate in a hospital/reference laboratory setting.

During the first year of the COVID-19 pandemic skyrocketing demand for testing in the United States, coupled with supply chain issues, necessitated the use of multiple SARS-CoV-2 molecular testing platforms at many health centers. At our institution these platforms consisted of 8 ordered services for sample triage, using 9 emergency use authorized (EUA) SARS-CoV-2 RNA nucleic acid amplification tests resulting in 10 possible ordered service/EAU combinations. Here we review the results of the first ∼2.9 million samples tested and note the variability in positivity rates. We conclude that differences in reported limit of detection did not translate to differences in positivity rate or show correlation to discordant results observed. This highlights the importance of balancing patient testing capacity needs with the desire to have more sensitive tests.

A Longitudinal Exploration of CACNA1A -related Hemiplegic Migraine in Children.

Introduction: Since the initial description of CACNA1A- related hemiplegic migraine (HM), the phenotypic spectrum has expanded from mild episodes in neurotypical individuals to potentially life-threatening events frequently seen in individuals with developmental and epileptic encephalopathies. However, the overall longitudinal course throughout childhood remains unknown. Methods: We analyzed HM and seizure history in individuals with CACNA1A -related HM, delineating frequency and severity of events in monthly increments through a standardized approach. Combining these data with medication prescription information, we assessed the response of HM to different agents. Results: Our cohort involved 15 individuals between 3 and 29 years (163 patient years) and included 11 unique and two recurrent variants (p.R1349Q and p.V1393M; both n= 2). The age of first confirmed HM ranged from 14 months to 13 years (average 3 years). 25% of all HM events were severe (lasting >3 days) and 73% of individuals had at least 1 severe occurrence. Spacing of HM events ranged from 1 month to 14 years and changes in HM severity over time of showed increases or decreases of >2 severity levels in 12/122 events. Eight individuals had epilepsy, but severity of epilepsy did not correlate with frequency and severity of HM events. While levetiracetam ( n= 6) and acetazolamide ( n= 5) were the most frequently used medications, they did not show efficacy in HM prevention or HM severity reduction. However, verapamil ( n= 3) showed efficacy in preventing HM episodes (OR 2.68, CI 1.39-5.67). Significance: The longitudinal course of CACNA1A -related HM lacks recognizable patterns for timing and severity of HM events or correlation with seizure patterns. Our data underscores the unpredictability of CACNA1A -related HM, highlighting the need for close surveillance for reoccurring HM events even in individuals with symptom-free periods. Key points: 24% of hemiplegic migraines (HM) in CACNA1A- related disorders are severe, involving cerebral edema and greater than 4 days to recover Timing and severity of HM are unpredictable, with large changes in severity between events, and age of onset ranging from 1-13 yearsEpilepsy occurred in 53% of individuals, with neither the timing nor severity of seizures correlated with HM.

Evaluating User Experience and DNA Yield from Self-Collection Devices.

BACKGROUND: The COVID-19 pandemic emphasized an urgent need for devices used in the self-collection of biospecimens in an evolving patient care system. The mailing of biospecimen self-collection kits to patients, with samples returned via mail, provides a more convenient testing regimen, but could also impart patient sampling variabilities. User compliance with device directions is central to downstream testing of collected biospecimens and clear instructions are central to this goal. METHODS: Here, we performed an evaluation of 10 oral DNA collection devices involving either swab or saliva self-collection and analyzed ease of use and comfort level with a device, as well as DNA recovery quantity/quality and sample stability. RESULTS: We show that while these DNA quality/quantity metrics are comparable between devices, users prefer direct saliva collection over swab-based devices. CONCLUSIONS: This information is useful in guiding future experiments including their use in human RNA, microbial, or viral sample collection/recovery and their use in clinical testing.

Preanalytic and Analytic Quality System Considerations in Noncoding RNA Biomarker Development for Clinical Diagnostics.

A frequent topic of biomedical research is the potential clinical use of non-coding (nc) RNAs as quantitative biomarkers for a broad spectrum of health and disease. However, ncRNA analyses have not been pressed into widespread diagnostic use. Strong preclinical evidence suggests obstacles in the translation and reproducibility of this type of biomarker which may result from preanalytical and analytical variation in the non-standardized processes used to collect, process, and store samples, as well as the substantive differences between small and long ncRNA. We performed a narrative review of selected literature, through the lens of key laboratory-developed test (LDT) regulations under the Clinical Laboratory Improvement Amendments (CLIA) in the United States, to study critical gaps in ncRNA validation studies. This review describes the leading candidate ncRNA subclasses, their biogenesis and cellular function, and identifies specific pre-analytical variables with disproportionate impact on testing performance. We summarize these findings with strategic recommendations to clinicians and biomedical scientists involved in the design, conduct, and translation of ncRNA biomarker development.

Brain Gene Co-Expression Network Analysis Identifies 22q13 Region Genes Associated with Autism, Intellectual Disability, Seizures, Language Impairment, and Hypotonia.

Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder caused by 22q13 region deletions or SHANK3 gene variants. Deletions vary in size and can affect other genes in addition to SHANK3. PMS is characterized by autism spectrum disorder (ASD), intellectual disability (ID), developmental delays, seizures, speech delay, hypotonia, and minor dysmorphic features. It is challenging to determine individual gene contributions due to variability in deletion sizes and clinical features. We implemented a genomic data mining approach for identifying and prioritizing the candidate genes in the 22q13 region for five phenotypes: ASD, ID, seizures, language impairment, and hypotonia. Weighted gene co-expression networks were constructed using the BrainSpan transcriptome dataset of a human brain. Bioinformatic analyses of the co-expression modules allowed us to select specific candidate genes, including EP300, TCF20, RBX1, XPNPEP3, PMM1, SCO2, BRD1, and SHANK3, for the common neurological phenotypes of PMS. The findings help understand the disease mechanisms and may provide novel therapeutic targets for the precise treatment of PMS.

Concomitant Calcium Channelopathies Involving CACNA1A and CACNA1F: A Case Report and Review of the Literature.

Calcium channels are an integral component in maintaining cellular function. Alterations may lead to channelopathies, primarily manifested in the central nervous system. This study describes the clinical and genetic features of a unique 12-year-old boy harboring two congenital calcium channelopathies, involving the CACNA1A and CACNA1F genes, and provides an unadulterated view of the natural history of sporadic hemiplegic migraine type 1 (SHM1) due to the patient's inability to tolerate any preventative medication. The patient presents with episodes of vomiting, hemiplegia, cerebral edema, seizure, fever, transient blindness, and encephalopathy. He is nonverbal, nonambulatory, and forced to have a very limited diet due to abnormal immune responses. The SHM1 manifestations apparent in the subject are consistent with the phenotype described in the 48 patients identified as part of a systematic literature review. The ocular symptoms of CACNA1F align with the family history of the subject. The presence of multiple pathogenic variants make it difficult to identify a clear phenotype-genotype correlation in the present case. Moreover, the detailed case description and natural history along with the comprehensive review of the literature contribute to the understanding of this complex disorder and point to the need for comprehensive clinical assessments of SHM1.