Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia

Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified in hereditary ataxia, a heterogeneous group of disorders characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants in more than 300 genes have been described, leading to a detailed genetic classification partitioned by age-of-onset. Despite these advances, up to 75% of patients with ataxia remain molecularly undiagnosed even following whole genome sequencing, as exemplified in the 100,000 Genomes Project. This study aimed to understand whether we can improve our knowledge of the genetic architecture of hereditary ataxia by leveraging functional genomic annotations, and as a result, generate insights and strategies that raise the diagnostic yield. To achieve these aims, we used publicly-available multi-omics data to generate 294 genic features, capturing information relating to a gene's structure, genetic variation, tissue-specific, cell-type-specific and temporal expression, as well as protein products of a gene. We studied these features across genes typically causing childhood-onset, adult-onset or both types of disease first individually, then collectively. This led to the generation of testable hypotheses which we investigated using whole genome sequencing data from up to 2,182 individuals presenting with ataxia and 6,658 non-neurological probands recruited in the 100,000 Genomes Project. Using this approach, we demonstrated a high short tandem repeat (STR) density within childhood-onset genes suggesting that we may be missing pathogenic repeat expansions within this cohort. This was verified in both childhood- and adult-onset ataxia patients from the 100,000 Genomes Project who were unexpectedly found to have a trend for higher repeat sizes even at naturally-occurring STRs within known ataxia genes, implying a role for STRs in pathogenesis. Using unsupervised analysis, we found significant similarities in genomic annotation across the gene panels, which suggested adult- and childhood-onset patients should be screened using a common diagnostic gene set. We tested this within the 100,000 Genomes Project by assessing the burden of pathogenic variants among childhood-onset genes in adult-onset patients and vice versa. This demonstrated a significantly higher burden of rare, potentially pathogenic variants in conventional childhood-onset genes among individuals with adult-onset ataxia. Our analysis has implications for the current clinical practice in genetic testing for hereditary ataxia. We suggest that the diagnostic rate for hereditary ataxia could be increased by removing the age-of-onset partition, and through a modified screening for repeat expansions in naturally-occurring STRs within known ataxia-associated genes, in effect treating these regions as candidate pathogenic loci

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Vision specific quality of life in children with optic pathway gliomas.

Children with optic pathway gliomas (OPGs) frequently experience vision loss from their tumors. Most pediatric OPG research has focused on radiographic and visual outcomes, yet the impact of vision loss on quality of life (QOL) in children with OPGs has not been studied. The present study prospectively recruited children ≤ 10 years of age with sporadic or neurofibromatosis type 1 (NF1) -related OPGs. Vision specific QOL was assessed by parent proxy using the Children’s Visual Function Questionnaire (CVFQ), and scores were analyzed according to magnitude of visual acuity (VA) loss and presence of visual field (VF) loss. Thirty-six subjects completed the study (53% female) with median age of 4.6 years. Children with mild, moderate and severe vision loss have lower CVFQ subscale scores, indicating a lower vision specific QOL, compared to those with normal vision. Lower Competence scores were noted in participants with more profound vision loss (P < .05), reflecting a decreased ability to complete activities of daily living (e.g. feeding, grooming). Children with two visually impaired eyes were rated as having greater difficulty with social interactions and pleasurable activities (Personality subscale, p=.039) compared to those with only one impaired eye. In summary, our findings demonstrate that children with vision loss secondary to their OPG have a decreased vision specific QOL compared to those with normal vision. Measuring vision specific QOL may be considered a meaningful secondary outcome measure for pediatric OPG clinical trials

Sluggish Cognitive Tempo in Pediatric Sickle Cell Disease

Background: Sickle cell disease (SCD) imparts risk for a range of neurodevelopmental and neurocognitive disorders. Sluggish cognitive tempo (SCT) is a distinct syndrome that often co-occurs with attention-deficit/hyperactivity disorder (ADHD) but has not been described in SCD. We investigated the reliability and validity of a SCT measure in SCD and examined associations with biopsychosocial risk factors and functional outcomes. Materials and Methods: Caregivers ( = 85) of children with SCD ages 7-16 reported on socio-demographics and the Kiddie-Sluggish Cognitive Tempo (K-SCT) measure, Behavior Rating Inventory of Executive Function, and Conners 3. Disease-related characteristics were extracted from health records. Results: The K-SCT demonstrated excellent internal consistency (α = 0.92) and test-retest reliability ( = 0.82, \u3c 0.001). K-SCT scores were correlated with ADHD-Inattention ( = 0.64, \u3c 0.001) and ADHD-Hyperactive/Impulsive ( = 0.46, \u3c 0.001) scores, as well as functional outcomes, including learning problems ( = 0.69, \u3c 0.001). In multivariate analyses controlling for ADHD symptoms, SCT accounted for unique variance in learning ( = 9.67, \u3c 0.01) and executive functioning ( = 5.93, \u3c 0.01). Nearly all participants (93%) with elevated levels of co-occurring SCT and ADHD-Inattention symptoms had significant learning problems. Conclusion: The K-SCT is a reliable and valid measure of SCT in SCD. SCT symptoms are associated with learning difficulties even after controlling for ADHD symptoms. Further research is needed to understand the biopsychosocial factors that lead to SCT symptoms in SCD and examine long-term implications of SCT