Niu, Zhiyv

ABSTRACT Background Agrin‐congenital myasthenic syndrome ( AGRN ‐CMS) is a rare, heterogeneous genetic disorder of the neuromuscular transmission that can present from infancy to adulthood. The clinical phenotype includes distal weakness mimicking distal myopathies. Additionally, electromyography and muscle biopsy may demonstrate myopathic features, increasing the diagnostic challenge. Mitochondrial dysfunction has not been reported in the muscle of AGRN ‐CMS patients. Methods We report the clinical, electrophysiological, radiological, myopathological, and genetic findings of a patient with AGRN‐ CMS. Results A 47‐year‐old male presented at age 18 with sudden onset of eyelid ptosis, weakness, and fatigue, followed by dysphagia, dyspnea on exertion, exercise intolerance, and myalgias. Three sisters had similar symptoms. Neurological examination showed lower limb weakness, predominantly affecting the calf muscles with associated atrophy. Tendon reflexes were normal but absent at the ankles. Creatine kinase levels were normal. Electromyography demonstrated myopathic changes in distal muscles with fibrillation potentials in the gastrocnemius. 2 Hz‐Repetitive nerve stimulation of the fibular nerve revealed a 32% decrement in the extensor digitorum brevis without facilitation. Tibialis anterior biopsy showed non‐specific myopathic changes, neurogenic features, and histological evidence of mitochondrial dysfunction, as suggested by the scattered cytochrome c oxidase‐negative fibers. Whole exome sequencing detected a homozygous pathogenic AGRN variant (c.5012G>A, p.Arg1671Gln). No pathogenic or suspected pathogenic variants were detected in muscle mitochondrial DNA or in nuclear genes affecting mitochondrial function. Conclusions This patient expands the pathological spectrum of AGRN ‐CMS to include mitochondrial dysfunction and highlights the importance of low‐frequency repetitive nerve stimulation in the assessment of patients with distal weakness for differentiating myopathies from CMS.

ABSTRACT Background Li Fraumeni syndrome (LFS) is a hereditary multi‐cancer syndrome caused by alterations in TP53 (MIM# 151623). Next generation sequencing (NGS) allows for the detection of TP53 variants at lower variant allele frequencies (VAFs). A TP53 variant with a VAF < 50% may represent mosaic LFS, aberrant clonal expansion (ACE), or possible circulating tumor DNA. Differentiation among these conditions is important for optimal patient management. Methods Genetic testing was performed using a custom gene panel, with an average read depth of 350× (range 166–553×). DNA extracted from four different tissues (blood, saliva, cultured skin fibroblasts, and colon) was sequenced. Results Here, we describe an adult female patient with a history of an adrenocortical neoplasm and osteosarcoma, diagnosed at 2 and 16 years of age, respectively. Testing of peripheral blood identified a pathogenic TP53 variant, c.733G>A, p.(Gly245Ser) (NM_000546.6); however, subsequent in vitro fertilization with preimplantation genetic testing for monogenic disorders (PGT‐M) did not identify this TP53 variant in any of nine embryos tested. Testing for possible mosaicism in the proband was performed on four different specimens, revealing variable VAFs of the TP53 variant (saliva: 44%; blood: 31%; cultured skin fibroblasts: 18%; and colon tissue: 9%). These results suggest a post‐zygotic event, consistent with mosaic LFS rather than ACE. Conclusion This case highlights the complexity of interpreting mosaic variants in the TP53 gene, and we propose a testing algorithm to aid in the delineation of this phenomenon when relaying cancer and reproductive risk information in the context of mosaicism.

Abstract Background X and Y chromosome analysis is a critical component of genetic testing, used both diagnostically and as a quality control (QC) metric. Discordances between expected and observed sex chromosome data can arise due to mislabeling, demographic data errors, transplant history, or biological variations. Such discordances pose challenges to laboratories and affect patient care, particularly in marginalized populations and unique clinical contexts. Methods We reviewed cases of sex chromosome discordance identified at our laboratory from January 2021 through August 2023. Cases spanned various testing methods and were categorized by the root cause, including mislabeling, sample mix-ups, transgender individuals, stem cell transplants, and unexplained causes. Case outcomes were assessed, and potential resolutions were analyzed. Results Among 65 cases identified, the leading cause of discordance was mislabeling (n = 20, 31%), followed by other/not identified (n = 16, 25%), sample mix-ups (n = 13, 20%), transgender individuals (n = 9, 14%), and stem cell transplants (n = 7, 11%). Cases required additional QC processes such as reanalysis, clinician contact, and occasionally sample re-collection. The process extended turnaround times by up to 13 business days. Detailed case reviews highlighted the challenges and implications of managing these discordances, emphasizing the importance of accurate data transmission and inclusive practices. Conclusion Using X and Y chromosome data as a QC metric can identify critical errors but also introduces limitations and bias. Improved standardization, inclusive practices, and alternative QC methods are necessary to ensure accuracy and equitable patient care. Collaborative efforts are required to address demographic complexities and reduce testing delays.

ABSTRACTBackground and AimsChronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is difficult to distinguish from mimicking disorders, with misdiagnosis resulting in IVIG overutilization. We evaluate a clinical‐electrophysiological model to facilitate CIDP versus mimic neuropathy prediction.MethodsUsing the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) 2021 CIDP guidelines we derived 26 clinical and 144 nerve conduction variables. The model was generated and validated utilizing total CIDP (n = 129) and mimics (n = 309); including (1) IgG4‐nodopathies; (2) POEMS (polyneuropathy–organomegaly–endocrinopathy–monoclonal protein‐skin changes); (3) anti‐myelin‐associated‐glycoprotein; (4) paraneoplastic; (5) Waldenström B‐cell lymphoma; (6) diabetic neuropathies; (7) amyloidosis; (8) Charcot–Marie–Tooth; (9) motor neuropathies/neuronopathies; and (10) idiopathic‐inflammatory‐myopathies.ResultsWe analyzed 9282 clinical and 51 408 electrophysiological data points. Univariate analysis identified 11 of 26 clinical variables with significant odds ratios. A multivariate regression model using four clinical and two electrophysiologic variables achieved 93% area‐under‐curve (95% CI 91–95): progression over 8 weeks (OR 40.66, 95% CI 5.31–311.36), absent autonomic involvement (OR 17.82, 95% CI 2.93–108.24), absent muscle atrophy (OR 16.65, 95% CI 3.27–84.73), proximal weakness (OR 3.63, 95% CI 1.58–8.33), ulnar motor conduction velocity slowing < 35.7 m/s (OR 5.21, 95% CI 2.13–12.76), and ulnar motor conduction block (OR 13.37, 95% CI 2.47–72.40). A web‐based probability calculator (https://news.mayocliniclabs.com/cidp‐calculator/) was developed, with 100% sensitivity and 68% specificity at a 92% probability threshold. Specificity improved to 93% when considering “red flags,” electrophysiologic criteria, and laboratory testing.InterpretationA probability calculator using clinical electrophysiological variables assists CIDP differentiation from mimics, with scores below 92% unlikely to have CIDP. The highest specificity is achieved by considering clinical “red flags,” electrophysiologic demyelination, and laboratory testing.