Over 100 genetically distinct causal known loci for hereditary ataxia phenotype poses a challenge for diagnostic work‐up for ataxia patients in a clinically relevant time and precision. In the present study using next‐generation sequencing, we have investigated pathogenic variants in early‐onset cerebellar ataxia cases using whole exome sequencing in singleton/family‐designed and targeted gene‐panel sequencing. A total of 98 index patients were clinically and genetically (whole exome sequencing (WES) in 16 patients and targeted gene panel of 41 ataxia causing genes in 82 patients) evaluated. Four families underwent WES in family based design. Overall, we have identified 24 variants comprising 20 pathogenic and four likely‐pathogenic both rare/novel, variations in 21 early onset cerebellar ataxia patients. Among the identified variations, SACS (n = 7) and SETX (n = 6) were frequent, while ATM (n = 2), TTPA (n = 2) and other rare loci were observed. We have prioritized novel pathogenic variants in RARS2 and FA2H loci through family based design in two out of four families.

ObjectivesThe primary objective of this study was to determine the prevalence of BRAFV600E and TERTpromoter mutations in paediatric and young adult patients with papillary thyroid carcinoma (PTC) and the secondary objective, to assess their association with clinicopathological features.MethodsPatients ≤20 years who underwent surgery for differentiated thyroid cancer (DTC) from 2005 to 2018 were consecutively enrolled for BRAFV600E and TERTpromoter mutations analysis and records analysed for the association of aggressive features. Univariate analysis and multivariate logistic regression were used to identify the independent predictors of BRAFV600E mutations.ResultsAmong 100 patients with DTC, 68 patients were ≤18 years and the remaining 30 patients were >18 years of age with a median age of 17 years (IQR 14–19 years) 98 patients had PTC and 2 had FTC. BRAFV600E mutation was present in 14/98 (14.3%) PTC and TERTpromoter mutation noted in none. Multivariate analysis identified RAI refractoriness (OR:10.57, 95% CI: 2.6 to 41.6, P-0.0008) as an independent factor associated with BRAFV600E mutation. 17 patients with distant metastases were negative for both BRAFV600E or TERTpromoter mutation. No significant association was observed between age, gender, PTC variants, extra-thyroidal extension, lymphovascular invasion, multifocality, RAI administration and event rate with BRAFV600E mutation. Irrespective of BRAFV600E mutation, radioiodine refractory status (p-0.0001) had a reduced EFS probability.ConclusionIn paediatric & young adult PTC, TERTpromoter mutation is absent and BRAFV600E mutation is not associated with distant metastasis. The prevalence rate of the BRAFV600E mutation is much lower compared to adult PTC patients.

Cerebellar ataxias (CAs) represent a group of autosomal dominant and recessive neurodegenerative disorders affecting cerebellum with or without spinal cord. Overall, CAs have preponderance for tandem nucleotide repeat expansions as an etiological factor (10 TREs explain nearly 30–40% of ataxia cohort globally). The experience of 10 years of common genetic ataxia subtypes for ≈5600 patients’ referrals (Pan‐India) received at a single center is shared herein. Frequencies (in %, n) of SCA types and FRDA in the sample cohort are observed as follows: SCA12 (8.6%, 490); SCA2 (8.5%, 482); SCA1 (4.8%, 272); SCA3 (2%, 113); SCA7 (0.5%, 28); SCA6 (0.1%, 05); SCA17 (0.1%, 05), and FRDA (2.2%, 127). A significant amount of variability in TRE lengths at each locus is observed, we noted presence of biallelic expansion, co‐occurrence of SCA‐subtypes, and the presence of premutable normal alleles. The frequency of mutated GAA‐FRDA allele in healthy controls is 1/158 (0.63%), thus an expected FRDA prevalence of 1:100 000 persons. The data of this study are relevant not only for clinical decision making but also for guidance in direction of genetic investigations, transancestral comparison of genotypes, and lastly provide insight for policy decision for the consideration of SCAs under rare disease category.

Objective Medullary thyroid carcinoma is a rare, potentially aggressive tumour, with relatively worse prognosis than well-differentiated thyroid cancer. We evaluated the long-term outcomes and prognosis of medullary thyroid carcinoma patients at a single institution in India and compared outcomes based on results of RET protooncogene mutation analysis. Methods Data were retrieved through a prospectively maintained thyroid cancer database from 1998 to June 2019, and medullary thyroid carcinoma patients were recruited. RET gene mutation status (exon 10–16) was assessed. Patient with a minimum follow-up of 12 months was eligible to be part of the long-term outcome analysis. Results Out of 149 peripheral blood samples, 42 were positive for RET gene mutation (prevalence of 28.1%). The median follow-up duration was 48 months, ranging from 12 to 240 months. Long-term clinical outcomes of 113 patients were assessed. Two deaths were noted in this series. Both 5- and 10-year survival was cent per cent. Overall survival was 98.2% (97.3% in RET positive and 98.7% in RET negative group). Progression-free survival was 55.4% in total (60% in RET positive and 53.3% in RET negative group). No statistically significant difference was found between RET positive and RET negative groups concerning overall survival (P = 0.6011) and progression-free survival (P = 0.5140). Univariate analysis revealed high calcitonin (>10 pg/mL), stage IV disease, and presence of lymph nodal metastasis to be significant predictors of disease recurrence, however, multivariate analysis demonstrated the presence of lymph node metastases as the only significant predictor of recurrence (P = 0.0005). Conclusions Medullary thyroid carcinoma patients had relatively favourable long-term outcomes. Long-term survival was similar irrespective of RET mutation status. Presence of lymph node metastases appeared to be the strongest predictor of overall and progression-free survival, followed by Calcitonin level and stage of the disease.