The Undiagnosed Diseases Network is a National Institutes of Health funded research study that aims to solve a broad clinical spectrum of challenging rare disease cases. Participants receive care from multiple clinical specialists, who collaborate to perform deep phenotyping and state-of-the-art multiomics analyses. As bioinformatics of short-read sequencing has matured, the discovery of repeat expansion disorders (REDs) is accelerating. REDs comprise approximately 60 characterized disorders, which exhibit a broad spectrum of phenotypes. Thus, a largely unbiased genome-wide approach in a phenotypically diverse sample will add to the diagnostic depth, explore the limits of short-read genome analysis, and establish novel candidate RED loci. Here, we present a genome-wide analysis of repeat expansions conducted on 1018 genomes from the Undiagnosed Diseases Network. By leveraging 2 distinct bioinformatics tools, ExpansionHunter Denovo and STRling, we showed that repeat expansions can be accurately detected in short-read genomes. We demonstrated that a genotype-first approach can diagnose atypical cases of known REDs and provide valuable clinical insights. We present clinical details on participants with expansions in ATXN7, DMPK, FMR1, GLS, HTT, RFC1, AFF3, and MARCH6. Importantly, we highlight 2 cases of juvenile Huntington disease that were discovered through our analysis. Finally, we present a list of novel candidate short tandem repeats (TR) that could potentially be pathogenic if expanded. Importantly, our approach showcases the bioinformatic advancements in genome analysis for RED detection and highlights its practical applications.

Huntington disease, an autosomal dominant inherited neurodegenerative disorder, is characterized by the clinical triad of involuntary choreiform movements with cognitive and behavioral disturbances. It occurs due to cytosine, adenine, and guanine (CAG) trinucleotide repeats on the short arm of chromosome 4p16.3 in the Huntingtin (HTT) gene. This mutation leads to an abnormally long polyglutamine expansion in the HTT protein's N-terminal fragment, which leads to neurodegeneration. The expansion also causes the HTT protein to be more prone to aggregation and accumulation, which mitigates protein folding. Huntington disease commonly affects patients between the ages of 30 to 50. However, the longer the CAG repeats, the earlier the onset of symptoms. The term juvenile Huntington disease refers to the onset of illness before the age of 20 and is characterized by learning difficulties as well as behavioral disturbances at school. Diagnosis can be made clinically in a patient with motor and or cognitive and behavioral disturbances with a parent diagnosed with Huntington disease and can be confirmed by DNA determination. Premanifest diagnosis can determine if they carry the gene in patients at risk for the disease. The disease has no cure, and affected patients tend to be entirely dependent on their caregivers as the disease progresses. Therefore, treatment aims to improve the quality of life and decrease complications. Pneumonia is a common cause of death, followed by suicide.

Managing severe obesity in youth with chronic, progressive conditions, such as juvenile Huntington disease, presents unique challenges. Juvenile Huntington disease, is characterized by rapid neurodegeneration, with most patients experiencing a significant decline in motor and cognitive functions within 10-20 years of symptom onset, leading to reduced life expectancy. Obesity further complicates these conditions, reducing quality of life and exacerbating physical, cognitive, and metabolic dysfunctions. A multidisciplinary approach is essential to address these complex issues. A 17-year-old Hispanic male with juvenile Huntington disease and a body mass index of 44 kg/m2 (190% of the 95th percentile) presented for obesity management. He experienced extreme food cravings and difficulty with portion control. After thorough discussions with the patient and his family, and with ethics consultation, a treatment plan was developed that included pharmacological and surgical interventions. Semaglutide was initiated at 0.25 mg weekly, titrating up to 1 mg. After 3 months, his body mass index reduced by 7% (40 kg/m2). Despite this, he continued to experience obesity-related complications, including elevated liver enzymes and obstructive sleep apnea, and underwent laparoscopic sleeve gastrectomy at 18 years old. Six-months postoperatively, his body mass index decreased to 33 kg/m2, liver enzyme levels improved, and his sleep apnea resolved. Additionally, he reported improved physical activity and enhanced quality of life. This case illustrates the ethical considerations and challenges of managing severe obesity in juvenile Huntington disease. The decision to proceed with bariatric surgery prioritized improving quality of life, given the patient's limited life expectancy. The use of a multimodal treatment approach, including semaglutide and laparoscopic sleeve gastrectomy, significantly improved both physical health and psychosocial well-being. This case highlights the importance of shared decision-making in managing complex obesity cases in pediatric populations with neurodegenerative diseases.

The rarity of Huntington's disease (HD) parturients implies that anesthesiologists have little exposure to the management of these patients. We explore techniques for the management of a 21-year-old parturient with symptomatic HD who underwent successful neuraxial anesthesia for labor and subsequent cesarean delivery. We provide guidance on perioperative medications for comorbidities associated with HD. Dexmedetomidine, which we administered neuraxially, appears to have significant potential for the perioperative diminution of choreiform movements. Current anesthetic management of HD cannot be informed by traditional research methodology and therefore much information must be gleaned from the limited available case reports.