Determinant genes that effect the central nervous system and their antenatal identification

Background: The central nervous system is an intricate networking of electric signals that intertwines the functioning of all senses of speech, thoughts etc. A genetic mutation in this complex structure is known to cause many neurological diseases.Methods: Records of the genetic analysis reports of patients were studied. Patients with CNS genetic syndromes or tubulinopathies in fetus of the present pregnancy or previous pregnancy who presented themselves only for genetic counseling with the genetic analysis report done at an outside diagnostic center were selected.Results: Ten patients presented with history congenital abnormalities of the structure of the central nervous system in pregnancy. Non-invasive investigations in the first child led to the need for genetic analysis of the present foetus. EEG showing independent S2 foci and left central parietal and right temporal region with bilateral synchronous discharge was noticed. MRI findings such as chronic infarct with encephalomalacia were seen.Conclusions: Our study identified genes responsible for CNS abnormalities in structure and function and the Exom sequence in which they occurred. We were able to observe various types of clinical presentations of the syndromes on MRI/USG

A novel mutation 5' to the HMG box of the SRY gene in a case of Swyer syndrome

We describe a novel mutation in the coding region of the SRY gene in a 46,XY female with Swyer syndrome. Analysis of SRY was carried out by direct sequencing of a 780-bp PCR product that included the SRY open reading frame (ORF). This revealed the presence of a point mutation, ins108A, in the coding region 50 to the HMG box which results in a frame shift and premature termination of the encoded protein. No other mutation was found in the SRY ORF. We infer that sex reversal in this individual is a result of this insertion. In none of the 13 other 46, XY females that were studied was a mutation detected in SRY, confirming earlier findings that most cases of XY femaleness are due to causes other than mutation in SRY. These observations and those of others are discussed in relation to the aetiology of XY sex reversal

Karyotyping and counseling in bad obstetric history and infertility

Background: Division of Human Genetics (DHG) is a referral center for karyotyping and counseling to the couples as well as to the individuals referred with bad obstetric history and infertility. Materials and Methods: From 1972 to 2003, overall 1666 couples and 131 female partners with bad obstetric history (BOH) such as; spontaneous abortions, live births with congenital malformations and still born and 73 infertile male partners have been referred for chromosomal analysis. Results: The chromosomal abnormality was found in 4.4% (83) of the sample studied. Chromosomal abnormality was seen in 56 couples (3.4%), 15 female (11.5%) and 12 male (16.4%) partners. The numerical chromosomal abnormality were seen in 34 (41%) and the structural abnormalities in 49 (59%) cases. The numerical chromosomal abnormalities were associated with sex chromosomes as follows (the number of cases are shown in parenthesis): 47, XXY (9); 46, XY/ 47, XXY (2); 46, XY/ 48, XXXY (1); 46, XY/ 47, XYY (2) and X mosaicism; 45, X/ 46, XX (14); 46, XX/ 47, XXX (6). The structural anomalies were 40 translocations and 9 duplication/ deletion/ marker/ iso chromosome for the X chromosome; Male: 46,XY/ 47,XY+ mar (1); Female: 45,X/ 47,XX+mar (1); 46,XX/ 47,XX+mar (1); 47,XX+frag (1); 46,X,Xq- (2); 46,X,Xp- (1); 46,X,Xp+ (1); 45,X/46,X,i(Xq)(1). The frequently involved chromosomes in the translocations were 4, 11, 15 and X. There were three X; autosomal translocations and a unique combination of translocation 1; 15 in the parents of a female carrier and 13; 14 in a non- consanguineous couple. On the whole, 57.5% of the females (23/ 40) were translocation carriers. Non-significant chromosome polymorphisms were observed in 79 cases (4.2%). Conclusion: The current study has demonstrated the presence of the chromosomal abnormality and its influence in reproductive failure. On an average, in this study one in 56 couple and one in 12 males with infertility or one in 15 females with BOH has had a chromosomal abnormality as the genetic cause. The identification of chromosomal abnormality as the etiology has facilitated the counseling and appropriate management

sY116, a human Y-linked polymorphic STS

During a study of deletions of Y-chromosomal DNA in infertile males, sY116, a Y-linked STS, showed different electrophoretic mobilities in three males, two infertile and one fertile. A study of this STS among 35 other normal males showed that this locus is polymorphic. sY116 has a polya-rich stretch whose instability appears to be the most likely cause of this polymorphism. The possible usefulness of sY116 polymorphism in the detection of subtle genome-wide instabilities in some types of cancer is discussed

A novel mutation 5' to the HMG box of the SRY gene in a case of Swyer syndrome

We describe a novel mutation in the coding region of the SRY gene in a 46,XY female with Swyer syndrome. Analysis of SRY was carried out by direct sequencing of a 780-bp PCR product that included the SRY open reading frame (ORF). This revealed the presence of a point mutation, ins108A, in the coding region 50 to the HMG box which results in a frame shift and premature termination of the encoded protein. No other mutation was found in the SRY ORF. We infer that sex reversal in this individual is a result of this insertion. In none of the 13 other 46,XY females that were studied was a mutation detected in SRY, confirming earlier findings that most cases of XY femaleness are due to causes other than mutation in SRY. These observations and those of others are discussed in relation to the aetiology of XY sex reversal

Multi-gene testing in neurological disorders showed an improved diagnostic yield: data from over 1000 Indian patients

Background Neurological disorders are clinically heterogeneous group of disorders and are major causes of disability and death. Several of these disorders are caused due to genetic aberration. A precise and confirmatory diagnosis in the patients in a timely manner is essential for appropriate therapeutic and management strategies. Due to the complexity of the clinical presentations across various neurological disorders, arriving at an accurate diagnosis remains a challenge. Methods We sequenced 1012 unrelated patients from India with suspected neurological disorders, using TruSight One panel. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. Results We were able to detect mutations in 197 genes in 405 (40%) cases and 178 mutations were novel. The highest diagnostic rate was observed among patients with muscular dystrophy (64%) followed by leukodystrophy and ataxia (43%, each). In our cohort, 26% of the patients who received definitive diagnosis were primarily referred with complex neurological phenotypes with no suggestive diagnosis. In terms of mutations types, 62.8% were truncating and in addition, 13.4% were structural variants, which are also likely to cause loss of function. Conclusion In our study, we observed an improved performance of multi-gene panel testing, with an overall diagnostic yield of 40%. Furthermore, we show that NGS (next-generation sequencing)-based testing is comprehensive and can detect all types of variants including structural variants. It can be considered as a single-platform genetic test for neurological disorders that can provide a swift and definitive diagnosis in a cost-effective manner