Qualification: 
DCH, MBBS
sheelanampoothiri@aims.amrita.edu

Dr. Sheela Nampoothiri currently serves as Professor at the Department of Paediatrics, Amrita School of Medicine, Kochi.

Qualification : MBBS, DCH, Dip NB (Paed), MSc Medical Genetics (Glasgow)

Publications

Publication Type: Journal Article

Year of Publication Title

2019

H. Ryung Chang, Cho, S. Yoon, Lee, J. Hoon, Lee, E., Seo, J., Lee, H. Ran, Cavalcanti, D. P., Mäkitie, O., Valta, H., Girisha, K. M., Lee, C., Neethukrishna, K., Bhavani, G. S., Shukla, A., Dr. Sheela Nampoothiri, Phadke, S. R., Park, M. Jung, Ikegawa, S., Wang, Z., Higgs, M. R., Stewart, G. S., Jung, E., Lee, M. - S., Park, J. Hoon, Lee, E. A., Kim, H., Myung, K., Jeon, W., Lee, K., Kim, D., Kim, O. - H., Choi, M., Lee, H. - W., Kim, Y., and Cho, T. - J., “Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia.”, Am J Hum Genet, vol. 104, no. 3, pp. 439-453, 2019.[Abstract]


SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors and which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of wild-type TONSL. In addition, in vitro cell-based assays and in silico analyses of TONSL structure support the pathogenicity of those TONSL variants. Intriguingly, a knock-in (KI) Tonsl mouse model leads to embryonic lethality, implying the physiological importance of TONSL. Overall, these findings indicate that genetic variants resulting in reduced function of TONSL cause SPONASTRIME dysplasia and highlight the importance of TONSL in embryonic development and postnatal growth.

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2019

J. Sheth, Bhavsar, R., Mistri, M., Pancholi, D., Bavdekar, A., Dalal, A., Ranganath, P., Girisha, K. M., Shukla, A., Phadke, S., Puri, R., Panigrahi, I., Kaur, A., Muranjan, M., Goyal, M., Ramadevi, R., Shah, R., Dr. Sheela Nampoothiri, Danda, S., Datar, C., Kapoor, S., Bhatwadekar, S., and Sheth, F., “Gaucher Disease: Single Gene Molecular Characterization of One-hundred Indian Patients Reveals Novel Variants and the Most Prevalent Mutation”, BMC Med Genet, vol. 20, no. 1, p. 31, 2019.[Abstract]


BACKGROUND: Gaucher disease is a rare pan-ethnic, lysosomal storage disorder resulting due to beta-Glucosidase (GBA1) gene defect. This leads to the glucocerebrosidase enzyme deficiency and an increased accumulation of undegraded glycolipid glucocerebroside inside the cells' lysosomes. To date, nearly 460 mutations have been described in the GBA1 gene. With the aim to determine mutations spectrum and molecular pathology of Gaucher disease in India, the present study investigated one hundred unrelated patients (age range: 1 day to 31 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality in some of the patients.

METHODS: The biochemical investigation for the plasma chitotriosidase enzyme activity and β-Glucosidase enzyme activity confirmed the Gaucher disease. The mutations were identified by screening the patients' whole GBA gene coding region using bidirectional Sanger sequencing.

RESULTS: The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all patients. Sanger sequencing established 71 patients with homozygous mutation and 22 patients with compound heterozygous mutation in GBA1 gene. Lack of identification of mutations in three patients suggests the possibility of either large deletion/duplication or deep intronic variations in the GBA1 gene. In four cases, where the proband died due to confirmed Gaucher disease, the parents were found to be a carrier. Overall, the study identified 33 mutations in 100 patients that also covers four missense mutations (p.Ser136Leu, p.Leu279Val, p.Gly383Asp, p.Gly399Arg) not previously reported in Gaucher disease patients. The mutation p.Leu483Pro was identified as the most commonly occurring Gaucher disease mutation in the study (62% patients). The second common mutations identified were p.Arg535Cys (7% patients) and RecNcil (7% patients). Another complex mutation Complex C was identified in a compound heterozygous status (3% patients). The homology modeling of the novel mutations suggested the destabilization of the GBA protein structure due to conformational changes.

CONCLUSIONS: The study reports four novel and 29 known mutations identified in the GBA1 gene in one-hundred Gaucher patients. The given study establishes p.Leu483Pro as the most prevalent mutation in the Indian patients with type 1 Gaucher disease that provide new insight into the molecular basis of Gaucher Disease in India.

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2019

K. A. Rauen, Alsaegh, A., Ben-Shachar, S., Berman, Y., Blakeley, J., Cordeiro, I., Elgersma, Y., D Evans, G., Fisher, M. J., Frayling, I. M., George, J., Huson, S. M., Kerr, B., Khire, U., Korf, B., Legius, E., Messiaen, L., van Minkelen, R., Dr. Sheela Nampoothiri, Ngeow, J., Parada, L. F., Phadke, S., Pillai, A., Plotkin, S. R., Puri, R., Raji, A., Ramesh, V., Ratner, N., Shankar, S. P., Sharda, S., Tambe, A., Vikkula, M., Widemann, B. C., Wolkenstein, P., and Upadhyaya, M., “First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and Advances of New Therapeutics”, Am J Med Genet A, vol. 179, no. 6, pp. 1091-1097, 2019.[Abstract]


The neurofibromatoses, which include neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis, are a group of syndromes characterized by tumor growth in the nervous system. The RASopathies are a group of syndromes caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. The RASopathies include NF1, Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardio-facio-cutaneous syndrome, Legius syndrome, capillary malformation arterio-venous malformation syndrome, and SYNGAP1 autism. Due to their common underlying pathogenetic etiology, all these syndromes have significant phenotypic overlap of which one common feature include a predisposition to tumors, which may be benign or malignant. Together as a group, they represent one of the most common multiple congenital anomaly syndromes estimating to affect approximately one in 1000 individuals worldwide. The subcontinent of India represents one of the largest populations in the world, yet remains underserved from an aspect of clinical genetics services. In an effort to bridge this gap, the First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and Advances of New Therapeutics was held in Kochi, Kerala, India. These proceedings chronicle this timely and topical international symposium directed at discussing the best practices and therapies for individuals with neurofibromatoses and RASopathies.

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2019

A. Shukla, Girisha, K. M., Somashekar, P. H., Dr. Sheela Nampoothiri, McClellan, R., and Vernon, H. J., “Variants in the Transcriptional Corepressor BCORL1 are Associated with an X-linked Disorder of Intellectual Disability, Dysmorphic Features, and Behavioral Abnormalities”, Am J Med Genet A, vol. 179, no. 5, pp. 870-874, 2019.[Abstract]


BCORL1, a transcriptional corepressor, is involved in negative gene regulation through associations with several protein complexes including Class II histone deacetylases (HDACs). Acquired somatic mutations in BCORL1 have been implicated in the pathogenesis of several malignancies, but germline mutations of BCORL1 have not been associated with a specific genetic syndrome. We report five individuals from three pedigrees with phenotypes including intellectual disability, behavioral difficulties, and dysmorphic features who were found via whole exome sequencing to have variants in BCORL1. In silico analysis of these variants strongly suggests pathogenicity. We propose that hemizygous pathogenic variants in BCORL1 underlie a newly identified X-linked epigenetic syndrome.

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2019

A. Ganapathy, Mishra, A., Soni, M. Rani, Kumar, P., Sadagopan, M., Kanthi, A. Vittal, Patric, I. Rosetta Pi, Sobha George, Sridharan, A., Thyagarajan, T. C., Aswathy, S. L., Vidya, H. K., Chinnappa, S. M., Nayanala, S., Prakash, M. B., Raghavendrachar, V. G., Parulekar, M., Gowda, V. K., Dr. Sheela Nampoothiri, Menon, R. N., Pachat, D., Udani, V., Naik, N., Kamate, M., A Devi, R. Rama, Kunju, P. A. Mohammed, Nair, M., Hegde, A. Udwadia, M Kumar, P., Sundaram, S., Tilak, P., Puri, R. D., Shah, K., Sheth, J., Hasan, Q., Sheth, F., Agrawal, P., Katragadda, S., Veeramachaneni, V., Chandru, V., Hariharan, R., and Mannan, A. U., “Multi-gene Testing in Neurological Disorders Showed an Improved Diagnostic Yield: Data from Over 1000 Indian Patients.”, J Neurol, 2019.[Abstract]


<p><b>BACKGROUND: </b>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.</p>

<p><b>METHODS: </b>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.</p>

<p><b>RESULTS: </b>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.</p>

<p><b>CONCLUSION: </b>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.</p>

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2019

Dr. Sheela Nampoothiri, Guillemyn, B., Elcioglu, N., Jagadeesh, S., Dhanya Yesodharan, Suresh, B., Turan, S., Symoens, S., and Malfait, F., “Ptosis as a Unique Hallmark for Autosomal Recessive WNT1-associated Osteogenesis Imperfecta”, Am J Med Genet A, vol. 179, no. 6, pp. 908-914, 2019.[Abstract]


Osteogenesis imperfecta (OI) is a heritable connective tissue disorder, mainly characterized by bone fragility and low bone mass. Defects in the type I procollagen-encoding genes account for the majority of OI, but increasingly more rare autosomal recessive (AR) forms are being identified, which are caused by defects in genes involved in collagen metabolism, bone mineralization, or osteoblast differentiation. Bi-allelic mutations in WNT1 have been associated with a rare form of AR OI, characterized by severe osteoporosis, vertebral compression, scoliosis, fractures, short stature, and variable neurological problems. Heterozygous WNT1 mutations have been linked to autosomal dominant early-onset osteoporosis. In this study, we describe the clinical and molecular findings in 10 new patients with AR WNT1-related OI. Thorough revision of the clinical symptoms of these 10 novel patients and previously published AR WNT1 OI cases highlight ptosis as a unique hallmark in the diagnosis of this OI subtype

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2019

S. P. Babu, Menon, R. N., Asranna, A., Dr. Sheela Nampoothiri, Radhakrishnan, A., Cherian, A., and Thomas, S. V., “Novel Genotype-electroclinical Phenotype Correlations in Sporadic Early-onset Childhood Myoclonic-atonic Epilepsy”, Neurol India, vol. 67, no. 1, pp. 264-267, 2019.

2018

J. Baishya, Kesav, P., Dr. Sheela Nampoothiri, Sreedharan, S. Erat, and Sylaja, P. N., “Extensive Extrapulvinar Calcification in Fabry Disease.”, Ann Indian Acad Neurol, vol. 21, no. 4, pp. 309-310, 2018.

2018

S. Sundaram, Nair, M., Dr. Sheela Nampoothiri, and Menon, R. N., “Mitochondrial Acetoacetyl-CoA Thiolase Enzyme Deficiency in a 9-month Old Boy: Atypical Urinary Metabolic Profile with a Novel Homozygous Mutation in ACAT1 Gene”, Neurol India, vol. 66, no. 6, pp. 1802-1804, 2018.

2015

K. Renugadevi, Mary, J. Asnet, Perumalsamy, V., Seshadri, S., Jagadeesh, S., Suresh, B., Dr. Sheela Nampoothiri, Shenbagarathai, R., Krishnaswamy, S., and Sundaresan, P., “Molecular Genetic Testing for Carrier-Prenatal Diagnosis and Computational Analysis of Oculocutaneous Albinism Type 1”, Genetic Disorders & Genetic Reports, vol. 2014, 2015.[Abstract]


In India epidemiological-communicable diseases are on the decline due to better living conditions and healthcare delivery in the society. On the other hand, the relative increase in the prevalence of genetic diseases threatens to be a public health problem. One such group of metabolic disorder is Albinism. General population based oculocutaneous albinism (OCA) carrier screening is controversial in all the races. Because of the occurrence of this disease in prior generations, it is necessary to create the knowledge, so that even uneducated affected family members will be willing to diagnose the disease status. As a result, the carrier detection in general population has become necessary in Indian population. More »»

2014

J. Sheth, Mistri, M., Datar, C., Kalane, U., Patil, S., Kamate, M., Shah, H., Dr. Sheela Nampoothiri, Gupta, S., and Sheth, F., “Expanding the spectrum of HEXA mutations in Indian patients with Tay–Sachs disease”, Molecular Genetics and Metabolism Reports, vol. 1, pp. 425–430, 2014.[Abstract]


Tay–Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of β-hexosaminidase-A (EC 3.2.1.52), resulting from the mutation in HEXA gene. Very little is known about the molecular pathology of TSD in Indian children except for a few mutations identified by us. The present study is aimed to determine additional mutations leading to Tay–Sachs disease in nine patients confirmed by the deficiency of β-hexosaminidase-A (C (D175A) and c.805G>C (p.G269R) in one case; and one small 1 bp deletion c.426delT (p.F142LfsX57) and one splice site mutation c.459+4A>C in the other two cases respectively. None of these mutations were detected in 100 chromosomes from healthy individuals of the same ethnic group. Three previously reported missense mutations, (i) c.532C>T (p.R178C), (ii) c.964G>T (p.D322Y), and (iii) c.1385A>T (p.E462V); two nonsense mutations (i) c.709C>T (p.Q237X) and (ii) c.1528C>T (p.R510X), one 4 bp insertion c.1277_1278insTATC (p.Y427IfsX5) and one splice site mutation c.459+5G>A were also identified in six cases. We observe from this study that novel mutations are more frequently observed in Indian patients with Tay–Sachs disease with clustering of ~ 73% of disease causing mutations in exons 5 to 12. This database can be used for a carrier rate screening in the larger population of the country. More »»

2014

Dr. Rajesh kannan, Dr. Mahesh K., Dr. Sheela Nampoothiri, Malfait, F., De Paepe, A., Moorthy, S., and , “Imaging findings in a distinct lethal inherited arteriopathy syndrome associated with a novel mutation in the FBLN4 gene”, European radiology, vol. 24, pp. 1742–1748, 2014.[Abstract]


Objectives We present the imaging findings of a newly identified lethal arteriopathy associated with a novel mutation in the gene encoding fibulin-4, occurring in a distinct community from southern India. Material and methods A total of 31 children from a distinct population subgroup who presented with characteristic arterial dilatation and tortuosity were studied. All children except one belonged to unrelated families from an ethno-religious group (Muslim) from the northern coastal belt of southern India. CT angiography was performed in 30 children and contrast MRA in one. Results Impressive dilatation and elongation of ascending aorta, arch, descending aorta and main pulmonary arteries with characteristic narrowing of aortic isthmus were seen in all patients. Stenosis of arch branches, abdominal visceral branches and pulmonary artery branches was observed in 21 (68 %), 23 (62.5 %) and 20 (65 %) patients respectively. Genetic studies revealed an identical mutation in exon 7 of the FBLN4 gene. On follow-up, 27 of them had died before the age of 3 years and only two children were alive after the age of 4 years. Conclusions FBLN4-associated vasculopathy is a highly lethal disease characterized by severe aneurysmal dilatation of thoracic aorta, its branches and pulmonary arteries with stenoses at typical locations. More »»

2014

V. R. Boggula, Shukla, A., Danda, S., Hariharan, S. V., Dr. Sheela Nampoothiri, Kumar, R., Phadke, S. R., and , “Clinical utility of multiplex ligation-dependent probe amplification technique in identification of aetiology of unexplained mental retardation: a study in 203 Indian patients”, The Indian journal of medical research, vol. 139, p. 66, 2014.[Abstract]


Background & objectives: Developmental delay (DD)/mental retardation also described as intellectual disability (ID), is seen in 1-3 per cent of general population. Diagnosis continues to be a challenge at clinical level. With the advancement of new molecular cytogenetic techniques such as cytogenetic microarray (CMA), multiplex ligation-dependent probe amplification (MLPA) techniques, many microdeletion/microduplication syndromes with DD/ID are now delineated. MLPA technique can probe 40-50 genomic regions in a single reaction and is being used for evaluation of cases with DD/ID. In this study we evaluated the clinical utility of MLPA techniques with different probe sets to identify the aetiology of unexplained mental retardation in patients with ID/DD.
Methods: A total of 203 randomly selected DD/ID cases with/without malformations were studied. MLPA probe sets for subtelomeric regions (P070/P036) and common microdeletions/microduplications (P245-A2) and X-chromosome (P106) were used. Positive cases with MLPA technique were confirmed using either fluorescence in situ hybridization (FISH) or follow up confirmatory MLPA probe sets. 
Results: The overall detection rate was found to be 9.3 per cent (19 out of 203). The detection rates were 6.9 and 7.4 per cent for common microdeletion/microduplication and subtelomeric probe sets, respectively. No abnormality was detected with probe set for X-linked ID. The subtelomeric abnormalities detected included deletions of 1p36.33, 4p, 5p, 9p, 9q, 13q telomeric regions and duplication of 9pter. The deletions/duplications detected in non telomeric regions include regions for Prader Willi/Angelman regions, Williams syndrome, Smith Magenis syndrome and Velocardiofacial syndrome.
Interpretation & conclusions: Our results show that the use of P245-A2 and P070/P036-E1 probes gives good diagnostic yield. Though MLPA cannot probe the whole genome like cytogenetic microarray, due to its ease and relative low cost it is an important technique for evaluation of cases with DD/ID.

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2014

C. Ankleshwaria, Mistri, M., Bavdekar, A., Muranjan, M., Dave, U., Tamhankar, P., Khanna, V., Jasinge, E., Dr. Sheela Nampoothiri, and Kadangot, S. Edayankara, “Novel mutations in the glucocerebrosidase gene of Indian patients with Gaucher disease”, Journal of human genetics, vol. 59, pp. 223–228, 2014.[Abstract]


Gaucher disease (GD) is the most common glycolipid storage disorder resulting from glucocerebrosidase deficiency due to mutations in the GBA gene. Study was performed in 33 unrelated patients with low β-glucosidase activity in leukocytes and/or fibroblasts. The exons and exon–intron boundaries of the GBA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and were looked up in public databases, and in silico analysis was carried for novel mutations. We identified two novel missense mutations G289A (c.866G>C) and I466S (c.1397T>G) in exons 7 and 10, respectively, in two (6.06%) patients that destabilize the protein structure. L444P (c.1448T>C) was the most common mutation identified in 20/33 (60.60%) non-neuronopathic and 1/33 (3.03%) sub-acute neuronopathic form based on clinical presentation at the time of investigation. Other nine rare mutations were: R463C (c.1504C>T), R395C (c.1300C>T), R359Q (c.1193G>A), G355D (c.1181G>A), V352M (c.1171G>A) and S356F (c.1184C>T) found in each patient (18.18%). Compound heterozygous mutation L444P (c.1448T>C)/R496C (c.1603C>T) in exon 10/11 and L444P (c.1448T>C)/R329C (c.1102C>T) were observed in exon 10/8 in one each patient (6.06%). Two patients (6.06%) from Sri Lanka showed E326K (c.1093G>A) mutation in exon 8. We conclude that L444P is the most common mutant allele with exons 8 and 10 as the hot spot region of GBA gene observed in Indian GD patients. More »»