Genetic association studies have implicated the TSNAX/DISC1 (disrupted in schizophrenia 1) in schizophrenia (SCZ), bipolar affective disorder (BPAD) and major depression. This study was performed to assess the possible involvement of TSNAX/DISC1 locus in the aetiology of BPAD and SCZ in the Southern Indian population. We genotyped seven single nucleotide polymorphism (SNPs) from TSNAX/DISC1 region in 1252 individuals (419 BPAD patients, 408 SCZ patients and 425 controls). Binary logistic regression revealed a nominal association for rs821616 in DISC1 for BPAD and also combined cases of BPAD or SCZ, but after correcting for multiple testing, these results were non-significant. However, significant association was observed with BPAD, as well as combined cases of BPAD or SCZ, within the female subjects for the rs766288 after applying false discovery rate corrections at the 0.05 level. Two-locus analysis showed C-C (rs766288-rs2812393) as a risk combination in BPAD, and G-T (rs2812393-rs821616) as a protective combination in SCZ and combined cases of BPAD or SCZ. Female-specific associations were observed for rs766288-rs2812393, rs766288-rs821616 and rs8212393-rs821616 in two-locus analysis. Our results provide further evidence for sex-dependent effects of the TSNAX/DISC1 locus in the aetiology of SCZ and BPAD. INTRODUCTION Schizophrenia (SCZ) and bipolar affective disorder (BPAD) are severe psychiatric disorders, each affecting approximately 1% of the population worldwide. 1 Family, twin and adoption studies confirm that genetic factors have a significant role in the aetiology of these disorders. 2 Several putative susceptibility loci and genes have been implicated, of which the TSNAX/DISC1 locus has shown encouraging results. The gene disrupted in schizophrenia 1 (DISC1) was first identified in a large Scottish family with a balanced translocation t (1, 11) (q42.2, q14.3) segregating with major mental illness, including SCZ, BPAD and recurrent major depression. [3][4][5] The translinassociated factor X (TRAX; TSNAX) gene is located adjacent to the DISC1 towards the 5 0 region. Subsequently several linkage studies have observed linkage near 1q42, which harbours DISC1, to SCZ 6-9 and BPAD. 10-12 Several population-based and family-based association studies have supported the role of the TSNAX/DISC1 locus in SCZ and/or BPAD in Caucasian 13-25 and Asian 26-28 populations. However, other studies have failed to replicate association between TSNAX/DISC1

Huntington's disease (HD), an autosomal dominant neurodegenerative syndrome, has a world-wide distribution. An estimated 2.5-10/100,000 people of European ancestry are affected with HD, while the Asian populations have lower prevalence (0.6-3.8/100,000). The epidemiology of HD is not well described in India, and the distribution of the pathogenic CAG expansion, and the associated haplotype, in this population needs to be better understood. This study demonstrates a distribution of CAG repeats, at the HTT locus, comparable to the European population in both normal and HD affected chromosomes. Further, we provide an evidence for similarity of the HD halpotype in Indian sample to the European HD haplogroup. Funding StatementThis study is supported by Indian Council of Medical Research (ICMR/002/208/2012/00126). The sponsor of this study had no role in study design, data collection, analysis, interpretation, or writing of the report. No private corporations or other agency paid to write this article. All the authors had full access to all the data in the study. All authors have seen and given their approval for submission of the manuscript. All the authors declare no conflict of interest in study undertaken. IntroductionThe diagnosis of Huntington's disease (HD) is based on estimation of the CAG repeat length at the HTT locus 1 . The normal HTT gene contains less than 27 CAG repeats 2 , 3 , and a few normal individuals have intermediate CAG (27)(28)(29)(30)(31)(32)(33)(34)(35) repeat expansion 2 and display no symptoms suggestive of HD. Subjects with borderline CAG (36)(37)(38)(39) repeats may or may not develop symptoms. Individuals affected with HD typically have at least one HTT allele containing CAG repeat size of 40 or greater 2 , 4 .The age at onset (AAO) is inversely correlated with length of the pathogenic CAG stretch in the HTT gene 5 . Almost 50-70% of the variation observed is determined by the CAG repeat length, the remaining maybe explained by the additional influence of other cis and trans elements, as well as environmental factors 5 . Highly expanded CAG sequences cause disease onset at a younger age 6 . The fundamental mechanisms of CAG repeat instability are poorly understood.The prevalence of HD varies among different populations, with prevalence rates of 2.5 -10 per 100,000 in people of European ancestry, while the Japanese (0.11-0.45 per 100,000), Chinese ( 0.5-1 per 100,000) and African populations (<0.01 per 100, 000) show significantly lower prevalence 7 . Indian and other South Asian populations are expected to have intermediate prevalence of HD. Prevalence studies of Indian immigrants in UK, predominantly from the northern regions of the Indian subcontinent 8 suggest that HD occurs in 1.75 per 100,000 individuals. It is generally accepted from clinical experience, and family studies of different geographical regions, that HD is distributed widely in India 9 , 10 , 11 , 12 . The origin of the pathogenic CAG expansion in India is not well understood. Multiple founder effects, and admix...

No abstract

No abstract

Calpainopathy is caused by mutations in the CAPN3. There is only one clinical and genetic study of CAPN3 from India and none from South India. A total of 72 (male[M]:female [F] = 34:38) genetically confirmed probands from 72 independent families are included in this study. Consanguinity was present in 54.2%. The mean age of onset and duration of symptoms are 13.5 ± 6.4 and 6.3 ± 4.7 years, respectively. Positive family history occurred in 23.3%. The predominant initial symptoms were proximal lower limb weakness (52.1%) and toe walking (20.5%). At presentation, 97.2% had hip girdle weakness, 69.4% had scapular winging, and 58.3% had contractures. Follow-up was available in 76.4%, and 92.7% were ambulant at a mean age of 23.7 ± 7.6 years and duration of 4.5 years, remaining 7.3% became wheelchair-bound at 25.5 ± 5.7 years of age (mean duration = 13.5 ± 4.6), 4.1% were aged more than 40 years (duration range = 5–20). The majority remained ambulant 10 years after disease onset. Next-generation sequencing (NGS) detected 47 unique CAPN3 variants in 72 patients, out of which 19 are novel. Missense variants were most common occurring in 59.7% (homozygous = 29; Compound heterozygous = 14). In the remaining 29 patients (40.3%), at least one suspected loss of function variant was present. Common recurrent variants were c.2051–1G > T and c.2338G > C in 9.7%, c.1343G > A, c.802–9G > A, and c.1319G > A in 6.9% and c.1963delC in 5.5% of population. Large deletions were observed in 4.2%. Exon 10 mutations accounted for 12 patients (16.7%). Our study highlights the efficiency of NGS technology in screening and molecular diagnosis of limb-girdle muscular dystrophy with recessive form (LGMDR1) patients in India.