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PubMed | KLES Prabhakar Kore Hospital, St. Mary's University, Uppsala University, Laboratoire Of Genetique Medicale and FRIGEs Institute of Human Genetics
Type: | Journal: Clinical genetics | Year: 2016

Duplications at 2q24.3 encompassing the voltage-gated sodium channel gene cluster are associated with early onset epilepsy. All cases described in the literature have presented in addition with different degrees of intellectual disability, and have involved neighbouring genes in addition to the sodium channel gene cluster. Here we report eight new cases with overlapping duplications at 2q24 ranging from 0.05Mb to 7.63Mb in size. Taken together with the previously reported cases, our study suggests that having an extra copy of SCN2A has an effect on epilepsy pathogenesis, causing benign familial infantile seizures which eventually disappear at the age of one to two years.. However, the number of copies of SCN2A does not appear to have an effect on cognitive outcome.

PubMed | Jena University Hospital and FRIGEs Institute of Human Genetics
Type: | Journal: BMC pregnancy and childbirth | Year: 2015

Children born with congenital anomalies present a very high rate of perinatal death and neonatal mortality. Cytogenetic analysis is a convincing investigation along with clinical suspicion and biochemical screening tests. The current study was designed to characterize the prevalence and types of chromosomal abnormalities in high risk prenatal samples using different cytogenetic techniques.This study was conducted on a total of 1,728 prenatal samples (1,324 amniotic fluids, 366 chorionic villi and 38 cord blood samples) from 1994 to 2014 at Institute of Human Genetics, Ahmedabad, India. Conventional karyotyping was conducted with GTG-banding. Molecular approaches were used (fluorescence in situ hybridization=FISH and/ or array-comparative genomic hybridization=aCGH) when indicated to detect karyotypic abnormalities.Abnormal karyotypes were detected in 125/1,728 (7.2%) cases. Trisomy 21 was the most common abnormality detected in 46 (2.7%) followed by trisomy 18 in 11 (0.6%) and trisomy 13 in 2 (0.1%) samples. Besides, structural abnormalities such as reciprocal and Robertsonian translocation were detected in 20 [1.2%] cases. Turner syndrome was diagnosed in seven (0.4%) cases; in six (0.34%) cases there was an inversion in the Y-chromosome. Heteromorphic variants were diagnosed in 22 (1.3%) cases. Finally, small supernumerary marker chromosomes (sSMC) were found in six (0.34%) cases.Conventional GTG-banding along with molecular cytogenetic techniques is useful in detecting genomic alterations and rearrangements. Comprehensive characterization of chromosomal rearrangements like sSMC has the potential to save potentially healthy fetuses from being terminated.

Sheth J.,Friges Institute Of Human Genetics | Mistri M.,Friges Institute Of Human Genetics | Bhavsar R.,Friges Institute Of Human Genetics | Sheth F.,Friges Institute Of Human Genetics | And 3 more authors.
Indian Pediatrics | Year: 2015

Objective: To study the etiology of neuroregression in children having deficiency of the lysosomal enzymes. Design: Review of medical records. Setting: Specialized Genetic Center. Participants: 432 children aged 3 mo-18 y having regression in a learned skill, selected from 1453 patients referred for diagnostic workup of various Lysosomal storage disorders (LSDs). Methods: Plasma chitotriosidase, quantitative and qualitative glycosaminoglycans, and mucolipidosis-II/II screening followed by confirmatory enzyme study using specific substrate was carried out; Niemann-Pick disease Type-C was studied by fillipin stain method on skin fibroblasts. Results: Total 309 children (71.5%) were diagnosed with different lysosomal storage disorders as the underlying cause of neuroregression. Plasma chitotriosidase was raised in 82 of 135; 64 (78%) of these had various LSDs. 69 out of 90 cases showed high excretion of glycoaminoglycans, and 67 (97.1%) of these were confirmed to have enzyme deficiency for various mucoplysaccharide disorders. While 3/90 children with positive I-cell screening had confirmed mucolipidosis-II/III disease. Among all, glycolipid storage disorders were the most common (50.2%) followed by mucopolysaccharidosis (MPS) (21.7%) and sulphatide degradation defect (17.5%). Neuronal ceroid lipofucinosis-1 & 2 (7.4%), mucolipidosis-II/III (1%), Sialic acid storage disorder (1%), Niemann-Pick disease type-C (1%) and Fucosidosis (0.3%) were observed with less frequency. Most common phenotypes in all subjects were cherry red spot (18.5%), hepatosplenomegaly (17.9%), coarse facies (15%), seizures (13.1%) and skeletal abnormalities (12.14%). Conclusions: Lysosomal storage disorders are considered to be one of the common causes in children with regression in learned skill, dysmorphic features and cherry red spot. Among these, glycolipid storage disorders are the most common, followed by mucopolysaccharidosis. © 2015, Indian Academy of Pediatrics.

Asadollahi R.,University of Zürich | Oneda B.,University of Zürich | Sheth F.,FRIGEs Institute of Human Genetics | Azzarello-Burri S.,University of Zürich | And 9 more authors.
European Journal of Human Genetics | Year: 2013

A chromosomal balanced translocation disrupting the MED13L (Mediator complex subunit13-like) gene, encoding a subunit of the Mediator complex, was previously associated with transposition of the great arteries (TGA) and intellectual disability (ID), and led to the identification of missense mutations in three patients with isolated TGA. Recently, a homozygous missense mutation in MED13L was found in two siblings with non-syndromic ID from a consanguineous family. Here, we describe for the first time, three patients with copy number changes affecting MED13L and delineate a recognizable MED13L haploinsufficiency syndrome. Using high resolution molecular karyotyping, we identified two intragenic de novo frameshift deletions, likely resulting in haploinsufficiency, in two patients with a similar phenotype of hypotonia, moderate ID, conotruncal heart defect and facial anomalies. In both, Sanger sequencing of MED13L did not reveal any pathogenic mutation and exome sequencing in one patient showed no evidence for a non-allelic second hit. A further patient with hypotonia, learning difficulties and perimembranous VSD showed a 1 Mb de novo triplication in 12q24.2, including MED13L and MAP1LC3B2. Our findings show that MED13L haploinsufficiency in contrast to the previously observed missense mutations cause a distinct syndromic phenotype. Additionally, a MED13L copy number gain results in a milder phenotype. The clinical features suggesting a neurocristopathy may be explained by animal model studies indicating involvement of the Mediator complex subunit 13 in neural crest induction. © 2013 Macmillan Publishers Limited.

Sheth F.,FRIGEs Institute of Human Genetics | Trivedi S.,FRIGEs Institute of Human Genetics | Andrieux J.,Jeanne Of Flandre Hospital | Blouin J.-L.,University of Geneva | Sheth J.,FRIGEs Institute of Human Genetics
Italian Journal of Pediatrics | Year: 2015

'Pure' interstitial duplication of chr6q is rare. The varying size of duplication encompassing 6q22.31 is associated with the expressivity of dysmorphism and autism. Here, we report a unique case with facial dysmorphism, developmental delay, complex neurological impairment and spasticity unrelated to autism. Genetic analysis by aCGH exhibited a 627-971 kb dup(6)(q22.31q22.31) encompassing TRDN and NKAIN2 genes. The presence of the duplication was confirmed by quantitative PCR in the proband and phenotypically normal parents. With the current techniques, we cannot exclude presence of a deleterious homozygous point mutation in the proband where each copy would have been inherited from both parents. © 2015 Sheth et al.

Sheth J.J.,FRIGEs Institute of Human Genetics | Shah A.,FRIGEs Institute of Human Genetics | Sheth F.J.,FRIGEs Institute of Human Genetics | Trivedi S.,FRIGEs Institute of Human Genetics | And 4 more authors.
BMC Endocrine Disorders | Year: 2015

Background: Vitamin D deficiency reportedly is associated with type 2 diabetes (T2DM). We aim to examine whether 25-hydroxyvitamin D (25OHD) has clinically significant influence on hemoglobin glycation (HbA1c) and insulin resistance (HOMA-IR) in T2DM subjects. Methods: Present study was carried out in 912 subjects (429 T2DM cases and 483 non-diabetic controls) from Western India. The enrolled study subjects were investigated for biochemical parameters like FBS, PPBS, HbA1c, FI, HOMA-IR and 25OHD levels in blood. Results: Vitamin D deficiency was seen in 91.4% and 93.0% of T2DM cases and control subjects respectively. There was no association of serum 25OHD deficiency on HbA1c or HOMA-IR in T2DM cases (p = 0.057 & p = 0.257 respectively) and in control subjects (p = 0.675 & p = 0.647 respectively). Conclusion: Our findings suggests that though vitamin D deficiency is prevalent in T2DM and non-diabetic subjects, its role in hemoglobin glycation and insulin resistance could not be established. © 2015 applies to the data made available in this article, unless otherwise stated.

PubMed | Clinical Geneticist, FRIGEs Institute of Human Genetics, Hiranandani Hospital, KLES Prabhakar Kore Hospital and 3 more.
Type: | Journal: Molecular genetics and metabolism reports | Year: 2016

Tay-Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of -hexosaminidase-A (EC, resulting from the mutation in

PubMed | National Health Research Institute and FRIGEs Institute of Human Genetics
Type: Journal Article | Journal: Journal of human genetics | Year: 2016

Sandhoff disease (SD) is an autosomal recessive neurodegenerative lysosomal storage disorder caused by mutations in HEXB gene. Molecular pathology is unknown in Indian patients with SD. The present study is aimed to determine mutations spectrum and molecular pathology leading to SD in 22 unrelated patients confirmed by the deficiency of -hexosaminidase-A and total-hexosaminidase in leukocytes. To date, nearly 86 mutations of HEXB have been described, including five large deletions. Over all we have identified 13 mutations in 19 patients, eight of which were novel, including two missense mutations [c.611G>A (p.G204E), c. 634A>T (p.H212Y)], two nonsense mutations [c.333G>A (p.W111X), c.298C>T (p.R100X)], one splice site mutation c.1082+5 G>T, two small in-frame deletions [c.534_541delAGTTTATC (p.V179RfsX10), c.1563_1573delTATGGATGACG (p.M522LfsX2)] and one insertion c.1553_1554insAAGA (p.D518EfsX8). We have also identified previously known, five sequence variations leading to amino acid changes [c.926G>A (p.C309Y), c.1597C>T (p.R533C)], one nonsense mutation c.850 C>T (p.R284X), one splice site mutation c.1417+1 G-A and one insertion c.1591_1592insC (p.R531TfsX22). Mutation was not identified in three patients. We observed from this study that mutation c.850C>T (p.R284X) was identified in 4/19 (21%) patients which is likely to be the most common mutation in the country. This is the first study providing insight into the molecular basis of SD in India.

PubMed | KEM Hospital, Believers Church Medical College Hospital and FRIGEs Institute of Human Genetics
Type: Journal Article | Journal: BMC medical genetics | Year: 2017

Niemann-Pick disease type C (NPC) is an inherited metabolic disorder; due to defect in cellular cholesterol trafficking. It is clinically a heterogeneous disease with variable age of onset with multiple organ systems being involved. NPC1 gene is involved in 95% cases where as remaining ~5% cases are linked with NPC2 gene.Case-1, a 14-months-old female presented with recurrent respiratory distress, failure to thrive and hepatosplenomegaly. Lung biopsy was suggestive of alveolar proteinosis and liver biopsy confirmed foamy macrophages. Molecular analysis revealed homozygous mutation c.141C>A in exon 2 of NPC2 gene. Case-2, a 3-year-old male presented with dyspnoea and hepatomegaly noticed at 1year of age. HRCT-scan of thoracic region showed consolidation with mediastinal lymphadenopathy. Broncho-alveolar lavage revealed moderate amount of foamy macrophages and bone marrow examination detected foam cells. Homozygous T>C transition in intron 1 of the NPC2 gene was identified.Our study demonstrates that NPC2 can present in early years of life with pulmonary complications like alveolar proteinosis and hepatosplenomegaly or hepatomegaly due to mutation in NPC2 gene. An early suspicion will help clinicians to clinch its diagnosis, management and genetic counselling.

PubMed | Sahyadari Medical Genetics and Tissue engineering facility SMGTEF and FRIGEs Institute of Human Genetics
Type: | Journal: BMC pediatrics | Year: 2016

GM2 gangliosidosis-AB variants a rare autosomal recessive neurodegenerative disorder occurring due to deficiency of GM2 activator protein resulting from the mutation in GM2A gene. Only seven mutations in nine cases have been reported from different population except India.Present case is a one year old male born to 3rd degree consanguineous Indian parents from Maharashtra. He was presented with global developmental delay, hypotonia and sensitive to hyperacusis. Horizontal nystagmus and cherry red spot was detected during ophthalmic examination. MRI of brain revealed putaminal hyperintensity and thalamic hypointensity with some unmyelinated white matter in T2/T1 weighted images. Initially he was suspected having Tay-Sachs disease and finally diagnosed as GM2 gangliosidosis, AB variant due to truncated protein caused by nonsense mutation c.472G>T (p.E158X) in GM2Agene.Children with phenotypic presentation as GM2 gangliosidosis (Tay-Sachs or Sandhoff disease) and normal enzyme activity of -hexosaminidase-A and -B in leucocytes need to be investigated for GM2 activator protein deficiency.

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