Qualification: 
DCH, MBBS
Email: 
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 Publication Type Title

2017

Journal Article

K. Yokote, Chanprasert, S., Lee, L., Eirich, K., Takemoto, M., Watanabe, A., Koizumi, N., Lessel, D., Mori, T., Hisama, F. M., Ladd, P. D., Angle, B., Baris, H., Cefle, K., Palanduz, S., Ozturk, S., Chateau, A., Deguchi, K., Easwar, T. K. M., Federico, A., Fox, A., Grebe, T. A., Hay, B., Dr. Sheela Nampoothiri, Seiter, K., Streeten, E., Piña-Aguilar, R. E., Poke, G., Poot, M., Posmyk, R., Martin, G. M., Kubisch, C., Schindler, D., and Oshima, J., “WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects.”, Hum Mutat, vol. 38, no. 1, pp. 7-15, 2017.[Abstract]


Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

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2017

Journal Article

K. G. Gopakumar, Thankamony, P., Dr. Sheela Nampoothiri, Bali, D., Raj, J., Vasudevan, J. A., and Nair, R. K., “Wolman Disease: A Mimic of Infant Leukemia.”, J Pediatr Hematol Oncol, 2017.[Abstract]


BACKGROUND: Infant leukemia most commonly present with pallor and hepatosplenomegaly. The possibility of other differential diagnosis also has to be kept in mind during evaluation, as identifying the precise etiology for this clinical presentation is crucial for management.

OBSERVATION: An infant, was referred to us with suspected infant leukemia and was subsequently diagnosed to have lysosomal acid lipase deficiency/Wolman disease with a novel 5 bp deletion "c.1180_1184del" in the last exon (exon 10) of the lipase A (LIPA) gene.

CONCLUSIONS: Hepatosplenomegaly and pallor resulting from nutritional deficiency or bone marrow involvement in Wolman disease can mimic infant leukemia.

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2016

Journal Article

R. Gupta, Gupta, N., Dr. Sheela Nampoothiri, Mandal, K., Kishore, Y., Sharma, P., Kabra, M., and Phadke, S. R., “Smith-Magenis Syndrome: Face Speaks.”, Indian J Pediatr, vol. 83, no. 6, pp. 589-93, 2016.[Abstract]


<p>Smith-Magenis syndrome is a well delineated microdeletion syndrome with characteristic facial and behavioral phenotype. With the availability of the multi-targeted molecular cytogenetic techniques like Multiplex Ligation Probe Amplification and cytogenetic microarray, the cases are diagnosed even without clinical suspicion. Here, the authors present clinical features of nine Indian cases of Smith-Magenis syndrome. Characteristic facial phenotype including tented upper lip, broad forehead, midface hypoplasia, short philtrum and upslant of palpebral fissure is obvious in the photographs. The behavioral variations were seen in some of the cases but were not the presenting features. The characteristic facial phenotype can be an important clinical guide to the diagnosis.</p>

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2016

Journal Article

J. Urquhart, Roberts, R., de Silva, D., Shalev, S., Chervinsky, E., Dr. Sheela Nampoothiri, Sznajer, Y., Revencu, N., Gunasekera, R., Suri, M., Ellingford, J., Williams, S., Bhaskar, S., and Clayton-Smith, J., “Exploring the genetic basis of 3MC syndrome: Findings in 12 further families.”, Am J Med Genet A, vol. 170A, no. 5, pp. 1216-24, 2016.[Abstract]


<p>The 3MC syndromes are a group of rare autosomal recessive disorders where the main clinical features are cleft lip and palate, hypertelorism, highly arched eyebrows, caudal appendage, postnatal growth deficiency, and genitourinary tract anomalies. Ophthalmological abnormalities, most notably anterior chamber defects may also be seen. We describe the clinical and molecular findings in 13 individuals with suspected 3MC syndrome from 12 previously unreported families. The exclusion of the MASP1 and COLEC11 Loci in two individuals from different consanguineous families and the absence of mutations in four further individuals sequenced for both genes raises the possibility that that there is further genetic heterogeneity of 3MC syndrome.</p>

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2016

Journal Article

Dr. Sheela Nampoothiri, Fernández-Rebollo, E., Yesodharan, D., Gardella, T. J., Rush, E. T., Langman, C. B., and Jüppner, H., “Jansen Metaphyseal Chondrodysplasia due to Heterozygous H223R-PTH1R Mutations With or Without Overt Hypercalcemia.”, J Clin Endocrinol Metab, vol. 101, no. 11, pp. 4283-4289, 2016.[Abstract]


CONTEXT: Jansen's metaphyseal chondrodysplasia (JMC) is a rare skeletal dysplasia characterized by abnormal endochondral bone formation and typically severe hypercalcemia despite normal/low levels of PTH. Five different heterozygous activating PTH/PTHrP receptor (PTH1R) mutations that change one of three different amino acid residues are known to cause JMC. OBJECTIVES: Establishing the diagnosis of JMC during infancy or early childhood can be challenging, especially in the absence of family history and/or overt hypercalcemia. We therefore sought to provide radiographic findings supporting this diagnosis early in life. PATIENTS AND METHODS: Three patients, a mother and her two sons, had radiographic evidence for JMC. However, obvious hypercalcemia and suppressed PTH levels were encountered only in both affected children. Sanger sequencing and endonuclease (SphI) digestion of PCR-amplified genomic DNA were performed to search for the H223R-PTH1R mutation. RESULTS: The heterozygous H223R mutation was identified in all three affected individuals. Surprisingly, however, the now 38-year-old mother was never overtly hypercalcemic and was therefore not diagnosed until her sons were found to be affected by JMC at the ages of 28 months and 40 days, respectively. The presented radiographic findings at different ages will help diagnose other infants/toddlers suspected of having JMC. CONCLUSION: The H223R mutation is typically associated with profound hypercalcemia despite low/normal PTH levels. However, the findings presented herein show that overt hypercalcemia is not always encountered in JMC, even if caused by this relatively frequent mutation, which is similar to observations with other PTH1R mutations that show less constitutive activity. More »»

2016

Journal Article

L. Devi Padmanabhan and Dr. Sheela Nampoothiri, “Prenatal detection of congenital high airway obstruction syndrome with encephalocele.”, Indian J Radiol Imaging, vol. 26, no. 1, pp. 70-2, 2016.[Abstract]


<p>Congenital high airway obstruction syndrome (CHAOS) causes secondary morphological changes which can be detected on ultrasound. Here we report a case of congenital high airway obstruction with an occipital encephalocele detected at 23 weeks of gestation.</p>

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2016

Journal Article

L. Devi Padmanabhan, Hamza, Z. V., Thampi, M. Venugopala, and Dr. Sheela Nampoothiri, “Prenatal diagnosis of amniotic band syndrome.”, Indian J Radiol Imaging, vol. 26, no. 1, pp. 63-6, 2016.[Abstract]


<p>Amniotic band can cause a broad spectrum of anomalies ranging from simple band constrictions to major craniofacial and visceral defects. It can cause significant neonatal morbidity. Accurate diagnosis will help in the management of the present pregnancy and in counseling with regard to future pregnancies. Here we report three cases of amniotic band syndrome detected in the prenatal period.</p>

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2016

Journal Article

S. Mohan, Dr. Sheela Nampoothiri, Yesodharan, D., Venkatesan, V., Koshy, T., Paul, S. F. D., and Perumal, V., “Reciprocal Microduplication of the Williams-Beuren Syndrome Chromosome Region in a 9-Year-Old Omani Boy.”, Lab Med, vol. 47, no. 2, pp. 171-5, 2016.[Abstract]


<p><b>BACKGROUND: </b>Microdeletions of the 7q11.23 Williams-Beuren syndrome chromosome region (WBSCR) are reported with a frequency of 1 in 10,000, whereas microduplications of the region, although expected to occur at the same frequency, are not widely reported.</p><p><b>METHOD: </b>We evaluated a 9-year old Omani boy for idiopathic intellectual disability using genetic methods, including multiplex ligation-dependent probe amplification (MLPA), for detection of microdeletions (P064-B3).</p><p><b>RESULTS: </b>MLPA analysis revealed that the boy has a rare microduplication of the WBSCR. Prominent clinical features include global developmental delay with pronounced speech delay, dysmorphic facies, and autistic features.</p><p><b>CONCLUSION: </b>Microduplications, in general, are reported at a lesser frequency, perhaps owing to their milder phenotype. Complete genetic assessment in children with idiopathic intellectual disability would help in identifying rare conditions such as duplication of the WBSCR.</p>

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2016

Journal Article

L. Bonafé, Kariminejad, A., Li, J., Royer-Bertrand, B., Garcia, V., Mahdavi, S., Bozorgmehr, B., Lachman, R. L., Mittaz-Crettol, L., Campos-Xavier, B., Dr. Sheela Nampoothiri, Unger, S., Rivolta, C., Levade, T., and Superti-Furga, A., “Brief Report: Peripheral Osteolysis in Adults Linked to ASAH1 (Acid Ceramidase) Mutations: A New Presentation of Farber's Disease.”, Arthritis Rheumatol, vol. 68, no. 9, pp. 2323-7, 2016.[Abstract]


<p><b>OBJECTIVE: </b>To establish a diagnosis and provide counseling and treatment for 3 adult patients from one family presenting with peripheral osteolysis.</p><p><b>METHODS: </b>Following clinical and radiographic assessment, exome sequencing, targeted gene resequencing, and determination of enzyme activity in cultured fibroblasts were performed.</p><p><b>RESULTS: </b>The proband (age 40 years) had a history of episodic fever and pain in childhood that subsided around puberty. He and 2 of his older sisters (ages 58 and 60 years, respectively) showed adult-onset progressive shortening of fingers and toes with redundancy of the overlying skin. Radiographs showed severe osteolysis of the distal radius and ulna, carpal bones, metacarpal bones, and phalanges. Sequencing of the known genes for recessively inherited osteolysis, MMP2 and MMP14, failed to show pathogenic mutations. Exome sequencing revealed compound heterozygosity for mutations c.505T>C (p.Trp169Arg) and c.760A>G (p.Arg254Gly) in ASAH1, the gene coding for acid ceramidase. Sanger sequencing confirmed correct segregation in the family, and enzyme activity in fibroblast cultures from the patients was reduced to ∼8% of that in controls, confirming a diagnosis of Farber's disease.</p><p><b>CONCLUSION: </b>Our findings indicate that hypomorphic mutations in ASAH1 may result in an osteoarticular phenotype with a juvenile phase resembling rheumatoid arthritis that evolves to osteolysis as the final stage in the absence of neurologic signs. This observation delineates a novel type of recessively inherited peripheral osteolysis and illustrates the long-term skeletal manifestations of acid ceramidase deficiency (Farber's disease) in what appear to be the oldest affected individuals known so far.</p>

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2016

Journal Article

K. Kouz, Lissewski, C., Spranger, S., Mitter, D., Riess, A., Lopez-Gonzalez, V., Lüttgen, S., Aydin, H., von Deimling, F., Evers, C., Hahn, A., Hempel, M., Issa, U., Kahlert, A. - K., Lieb, A., Villavicencio-Lorini, P., Ballesta-Martinez, M. Juliana, Dr. Sheela Nampoothiri, Ovens-Raeder, A., Puchmajerová, A., Satanovskij, R., Seidel, H., Unkelbach, S., Zabel, B., Kutsche, K., and Zenker, M., “Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation.”, Genet Med, vol. 18, no. 12, pp. 1226-1234, 2016.[Abstract]


PURPOSE: Noonan syndrome (NS) is an autosomal-dominant disorder characterized by craniofacial dysmorphism, growth retardation, cardiac abnormalities, and learning difficulties. It belongs to the RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase (MAPK) pathway. RIT1 was recently reported as a disease gene for NS, but the number of published cases is still limited

METHODS: </strong>We sequenced RIT1 in 310 mutation-negative individuals with a suspected RASopathy and prospectively in individuals who underwent genetic testing for NS. Using a standardized form, we recorded clinical features of all RIT1 mutation-positive patients. Clinical and genotype data from 36 individuals with RIT1 mutation reported previously were reviewed.

RESULTS:Eleven different RIT1 missense mutations, three of which were novel, were identified in 33 subjects from 28 families; codons 57, 82, and 95 represent mutation hotspots. In relation to NS of other genetic etiologies, prenatal abnormalities, cardiovascular disease, and lymphatic abnormalities were common in individuals with RIT1 mutation, whereas short stature, intellectual problems, pectus anomalies, and ectodermal findings were less frequent.

CONCLUSION: RIT1 is one of the major genes for NS. The RIT1-associated phenotype differs gradually from other NS subtypes, with a high prevalence of cardiovascular manifestations, especially hypertrophic cardiomyopathy, and lymphatic problems.Genet Med 18 12, 1226-1234.

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2015

Journal Article

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

Journal Article

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 »»

2014

Journal Article

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

Journal Article

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

Journal Article

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 »»
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