Publications by authors named "Gautham Arunachal"

28 Publications

  • Page 1 of 1

Comparison of The Carrier Frequency of Pathogenic Variants of DMD Gene in an Indian Cohort.

J Neuromuscul Dis 2021 Apr 2. Epub 2021 Apr 2.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India.

Background: Duchenne muscular dystrophy (DMD) is an X-linked disorder caused due to large deletions, duplications,and small pathogenic variants. This article compares the carrier frequency of different pathogenic variants in the DMD gene for the first time in an Indian cohort.

Methods: Ninety-one mothers of genetically confirmed DMD probands are included in this study. Pathogenic variants in the DMD gene in probands were detected by multiplex ligation-dependent probe amplification (MLPA) or next-generation sequencing (NGS). Maternal blood samples were evaluated either by MLPA or Sanger sequencing. The demographic and clinical details for screening of muscle weakness and cardiomyopathy were collected from the confirmed carriers.

Results: Out of 91 probands, large deletions and duplications were identified in 46 and 6 respectively, while 39 had small variants. Among the small variants, substitutions predicted to cause nonsense mutations were the most common (61.5%), followed by frameshift causing small insertion/deletions (25.6%) and splice affecting intronic variants (12.8%). Notably, 19 novel small variants predicted to be disease-causing were identified. Of the 91 mothers, 53 (58.7%) were confirmed to be carriers. Exonic deletions had a significantly lower carrier frequency of 47.8% as compared to small variants (64.1%). The mean age of the carriers at evaluation was 30 years. Among the carriers, two were symptomatic with onset in the 4th decade, manifesting with progressive proximal muscle weakness and dilated cardiomyopathy.

Conclusion: Carrier frequency of small pathogenic variants differs significantly from large deletions. Small pathogenic variants are more commonly inherited, whereas large deletions arise de novo.
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http://dx.doi.org/10.3233/JND-210658DOI Listing
April 2021

Myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK): a cause of progressive myoclonic epilepsy.

Acta Neurol Belg 2021 Mar 16. Epub 2021 Mar 16.

Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, 560029, India.

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http://dx.doi.org/10.1007/s13760-021-01645-xDOI Listing
March 2021

Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.

J Hum Genet 2021 Mar 12. Epub 2021 Mar 12.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India.

Megaconial congenital muscular dystrophy (CMD)(OMIM #602541), related to CHKB mutation, is a rare autosomal recessive disorder. To date, only 35 confirmed patients are recorded. We present a detailed description of the clinical, histopathological, imaging, and genetic findings of five children from four Indian families. The children had moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay mimicking atypical Rett syndrome. In addition, generalized hypotonia was a common initial finding. The progression of muscle weakness was variable, with two patients having a milder phenotype and three having a severe form. Interestingly, the majority did not attain sphincter control. Only patient 1 had classical ichthyotic skin changes. Muscle biopsy in two patients showed a myopathic pattern with characteristic peripherally placed enlarged mitochondria on modified Gomori trichrome stain and electron microscopy. Genetic analysis in these patients identified three novel null mutations in CHKB [c.1027dupA (p.Ser343LysfsTer86);c.224 + 1G > T (5' splice site); c.1123C > T (p.Gln375Ter)] and one reported missense mutation, c.581G > A (p.Arg194Gln), all in the homozygous state. Megaconial CMD, although rare, forms an important group with a complex phenotypic presentation and accounted for 5.5% of our genetically confirmed CMD patients. Atypical Rett syndrome-like presentation may be a clue towards CHKB-related disorder.
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http://dx.doi.org/10.1038/s10038-021-00913-1DOI Listing
March 2021

Recessive VAMP1 mutations associated with severe congenital myasthenic syndromes - A recognizable clinical phenotype.

Eur J Paediatr Neurol 2021 Mar 16;31:54-60. Epub 2021 Feb 16.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India. Electronic address:

Three unrelated girls, all born to consanguineous parents had respiratory distress, severe hypotonia at birth along with prominent fatigable muscle weakness and characteristic myopathic facies. In addition, patient 1 had fatigable ptosis, ophthalmoparesis and profound bulbar weakness and required nasogastric feeding from birth. A feeding gastrostomy was inserted at 9 months of age. She continued to have severe bulbar and limb weakness with dropped head at 5 years of age. Patient 2 and 3 did not have ocular signs at the time of initial presentation during infancy and at 2 years of age respectively. None of the patients attained independent walking. Patient 3, currently aged 16 years continues to be wheelchair bound and has only mild non-progressive bulbar weakness with normal cognitive development. Muscle biopsy in patient 1 and 3 showed predominant myopathic features admixed with small sized (atrophic/hypoplastic) fibres. Next generation sequencing confirmed the presence of a homozygous loss of function VAMP1 mutations in all three patients: A single nucleotide deletion resulting in frameshift: c.66delT (p.Gly23AlafsTer6) in patient 1 and nonsense mutations c.202C>T (pArg68Ter) and c.97C>T (p.Arg33Ter) in patient 2 and 3 respectively. Minimal but definite improvement in muscle power with pyridostigmine was reported in patients 1 and 2. This is the first report of VAMP1 mutations causing CMS from the Indian subcontinent, describing a clinically recognizable severe form of VAMP1-related CMS and highlighting the need for a strong index of suspicion for early genetic diagnosis of potentially treatable CMS phenotypes.
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http://dx.doi.org/10.1016/j.ejpn.2021.02.005DOI Listing
March 2021

Altered REM sleep architecture in patients with Myotonic dystrophy type 1: is related to sleep apnea?

Sleep Med 2021 Mar 1;79:48-54. Epub 2021 Jan 1.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India. Electronic address:

Objective: To determine the sleep architecture and sleep respiratory abnormalities and to correlate with sleep symptoms in patients with Myotonic dystrophy type 1 (DM1).

Methods: We recruited a cohort of genetically confirmed patients with DM1, who attended the Neuromuscular clinic between July 2016 and December 2019. Clinical, sleep and whole night polysomnography data were collected. The analysis of sleep architecture, sleep respiratory parameters and comparison with healthy controls (HC) was performed in our sleep laboratory.

Results: A total of 59 patients with DM1 underwent sleep evaluation. Hypersomnolence in 42 (77.8%), ESS>10 in 23 (39%), and PSQI>5 in 18 (30.5%) were found in patients with DM1. Thirty-one (68.89%) patients with DM1 and 22 (95.65%) HC had more than 4-h of total sleep time (TST). More than 4 h of TST was taken to compare respiratory and sleep architecture parameters. Patients with DM1 had reduced sleep efficiency, reduced N2 sleep, and increase in N1 sleep, wake index, stage shift index, nocturnal sleep-onset REM periods compared to HC. AHI>15 was found in 16 (51.61%) DM1 and in 3 HC (13.64%). AHI had positive correlation with BMI, but not with age, ESS or disease progression (MIRS). All DM1 with AHI>15; 8(80%) and 1(33.33%) in AHI5to15, and AHI<5 groups, respectively had hypersomnolence.

Conclusion: In this first study on Indian cohort, daytime hypersomnolence, poor nocturnal sleep quality, sleep architecture irregularities are identified to be common in patients with DM1. These abnormalities may be explained by sleep-related breathing disorders that are highly prevalent in these patients.
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http://dx.doi.org/10.1016/j.sleep.2020.12.036DOI Listing
March 2021

Whole-exome analyses of congenital muscular dystrophy and congenital myopathy patients from India reveal a wide spectrum of known and novel mutations.

Eur J Neurol 2021 Mar 26;28(3):992-1003. Epub 2020 Nov 26.

National Institute of Biomedical Genomics, Kalyani, India.

Background And Purpose: Congenital muscular dystrophies (CMDs) and congenital myopathies (CMs) are a group of genetically and clinically heterogeneous degenerative primary muscle disorders with onset at birth or during infancy. Due to vast heterogeneity, clinical examination and protein-based analyses often fail to identify the genetic causes of these diseases. The aim of this study was to genetically diagnose a cohort of 36 difficult-to-diagnose CMD and CM cases of Indian origin using next-generation sequencing methods.

Methods: Whole-exome sequencing (WES) was performed to identify pathogenic mutations in previously reported CMD and CM-related genes using variant calling and stringent variant filtration process. Subsequently, in silico homology modelling and molecular dynamics simulations (MDS) studies were undertaken for a number of novel and missense variants.

Results: A total of 33 and 21 rare and deleterious mutations were identified in 28 genes previously reported in CMD and CM based on OMIM, ClinVar and Orphanet, respectively. We could accurately diagnose 54% patients (n = 12/22) in the CMD group and 35% patients (n = 5/14) in the CM group. Furthermore, MDS studies for mutations located in LMNA, LAMA2 and RYR1 suggest that the wild-type proteins are more stable than their mutant counterparts, implying a potential mechanism of pathogenesis.

Conclusion: The WES findings led us to identify reported as well as novel variants for the first time in Indian patients with CMD and CM. This allowed us to achieve an accurate genetic diagnosis, which was difficult using conventional diagnostic tools. Transferring these WES findings to clinical practice will help guide clinical care of the affected patients and inform genetic counselling.
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http://dx.doi.org/10.1111/ene.14616DOI Listing
March 2021

Electroencephalography as a Diagnostic Aid in a Girl with Neuroregression and Stereotypies.

J Neurosci Rural Pract 2020 Apr 2;11(2):359-360. Epub 2020 May 2.

Department of Neurology, National Institute of Mental Health and Neurosciences, Near Diary Circle, Hosur Road, Bengaluru, Karnataka, India.

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http://dx.doi.org/10.1055/s-0040-1709264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195966PMC
April 2020

A Treatable Cause of Intellectual Disability and Autism in a Young Child.

Indian J Pediatr 2020 Oct 24;87(10):850-851. Epub 2020 Mar 24.

Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India.

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http://dx.doi.org/10.1007/s12098-020-03225-yDOI Listing
October 2020

Metabolic Stroke: A Novel Presentation in a Child with Succinic Semialdehyde Dehydrogenase Deficiency.

Ann Indian Acad Neurol 2020 Jan-Feb;23(1):113-117

Department of Medical Genetics, Christian Medical College, Vellore, Tamil Nadu, India.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of gamma-aminobutyric acid metabolism. Children with SSADH deficiency usually manifest with developmental delay, behavioral symptoms, language dysfunction, seizures, hypotonia, extrapyramidal symptoms, and ataxia. Diagnosis of SSADH deficiency is established by an abnormal urine organic acid pattern, including increased excretion of 4-hydroxybutyric acid and the identification of biallelic pathogenic variants in aldehyde dehydrogenase 5 family, member A 1 () gene. Here, we describe a 15-month-old girl with SSADH deficiency presenting with developmental delay, language deficits, and acute-onset right hemiparesis, following recovery from a diarrheal illness. Brain magnetic resonance imaging revealed hyperintense signal changes involving the left globus pallidus in T2-weighted images with restriction of diffusion in the diffusion-weighted images. Increased excretion of 4-hydroxybutyric acid, threo-4,5-dihydroxyhexanoic acid lactone and erythro-4,5-dihydroxyhexanoic acid lactone was detected by urine organic acid analysis and a diagnosis of SSADH deficiency was confirmed by the identification of homozygous pathogenic variant in . Stroke mimic is a novel presentation in our patient with SSADH deficiency. She was initiated on treatment with vigabatrin and has shown developmental gains with the recovery of right hemiparesis. Follow-up neuroimaging shows near complete resolution of signal changes in the left globus pallidus, while there was subtle hyperintensity in the right globus pallidus. The phenotypic spectrum of SSADH deficiency is widely expanding, and this disorder should be considered in the differential diagnosis of children with metabolic stroke.
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http://dx.doi.org/10.4103/aian.AIAN_213_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001443PMC
February 2020

Van der Woude Syndrome: IRF6 Mutations.

Indian J Pediatr 2019 11 29;86(11):1070-1071. Epub 2019 Aug 29.

Department of Clinical Genetics, OT Block 5th Floor, Christian Medical College, Vellore, Tamilnadu, 632004, India.

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http://dx.doi.org/10.1007/s12098-019-03058-4DOI Listing
November 2019

Study of familial aggregation of autoimmune rheumatic diseases in Asian Indian patients with systemic lupus erythematosus.

Rheumatol Int 2019 Dec 1;39(12):2053-2060. Epub 2019 Jul 1.

Department of Clinical Immunology and Rheumatology, Christian Medical College Hospital, Vellore, India.

Systemic lupus erythematosus (SLE) and other autoimmune rheumatic diseases (AIRD) tend to co-aggregate in families, making positive familial history a risk factor. We aimed to estimate familial aggregation of AIRD in SLE patients and to compare between ones having a positive and negative family history of autoimmunity in our cohort. We included families of 157 consecutive SLE patients in a hospital-based, cross-sectional design for a three-generation pedigree study. Clinical and laboratory parameters of these patients were recorded. AIRD was seen in families of 39 SLE patients amounting to a familial prevalence of 24.8% [95% confidence interval (CI) 18.1, 31.6] with a relative risk (λ) of 4.3 for first-degree relatives (FDRs) and 1.1 for second-degree relatives (SDRs). SLE was the commonest AIRD seen in families of 19 patients with a familial prevalence of 12.1% (95% CI 7.0, 17.2) and λ of 78.2 for FDRs and 18.1 for SDRs. AIRD as a whole and SLE alone were seen more commonly with parental consanguinity (p < 0.05). Familial aggregation in SLE patients also showed a relatively higher percentage of affected males and lesser presentation with constitutional features (p < 0.05) than sporadic SLE patients. Rheumatoid arthritis (RA) was the second most common AIRD seen in 16/39 (41%) families with a RR of 3.1 in FDRs of SLE patients. In conclusion, Asian Indian SLE patients seem to have a high familial aggregation of AIRD, which is more pronounced in the background of parental consanguinity. SLE is the commonest AIRD seen amongst FDRs and SDRs of SLE patients, followed by RA, with FDRs being at highest risk.
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http://dx.doi.org/10.1007/s00296-019-04355-zDOI Listing
December 2019

Genomics and Radiogenomics in Inherited Neurometabolic Disorders - A Practical Primer for Pediatricians.

Indian J Pediatr 2019 10 13;86(10):923-938. Epub 2019 Jun 13.

Department of Diagnostic Imaging, Hospital for Sick Children / Medical Imaging, University of Toronto, Toronto, Canada.

Advances in genetics has revolutionised the way we understand, diagnose and manage neurological disorders. Notwithstanding the fact that genetic confirmation has already become standard of care in routine clinical practice, radiological and clinical phenotyping has not diminished in value; in fact it has found an enhanced role in guiding and interpreting genetic test results. Inherited neurometabolic disorders are a prominent group of disorders which are seen commonly in clinical practice and many are potentially treatable. The concept of Radiogenomics is the bridge from phenotype to genotype and the strength of association varies widely across different inherited metabolic diseases. Understanding the strengths and limitations of these correlations forms the basis of success of multidisciplinary approach to diagnose these disorders. In this article authors give a brief overview of the genetic basis of a disease, available genetic tests and the prominent role of radiology in contemplating a diagnostic suspicion and guiding further confirmatory tests.
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http://dx.doi.org/10.1007/s12098-019-02860-4DOI Listing
October 2019

Mutation pattern in 606 Duchenne muscular dystrophy children with a comparison between familial and non-familial forms: a study in an Indian large single-center cohort.

J Neurol 2019 Sep 28;266(9):2177-2185. Epub 2019 May 28.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.

Introduction: Duchenne muscular dystrophy (DMD) is induced by a wide spectrum of mutations such as exon deletions, duplications and small mutations in the dystrophin gene. This is the first study on the mutational spectrum in a cohort of DMD children from India, with an emphasis to compare the mutations in familial and sporadic forms.

Results: Multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS) identified 525 and 70 cases of DMD, respectively, while 11 cases showed absent dystrophin staining with no mutations detected. Families with two or more affected males contributed to 12% of the entire cohort. The mutations comprised of exonic deletions in 492/606 (81.2%), duplications in 33/606 (5.4%) and small mutations (point mutations and INDELs) in 70/606 (11.5%) cases. MLPA identified significantly more larger mutations in sporadic (88.2%) than in familial cases (75.3%). The mutations in NGS were: [nonsense = 40 (57.1%); frameshift = 17 (24.3%); splice variant = 12 (17.1%)]. Nonsense mutations were more common in familial than in sporadic cases: 17.8% vs 10.7%. The familial group reported an earlier onset of disease (2.8 ± 1.7 years) as compared to sporadic cases (3.8 ± 1.6 years).

Conclusion: MLPA could identify mutations in a high percentage of our DMD children. The preponderance of small mutations was noted to be distinctly higher in the familial group. Intriguingly, the familial form of DMD formed a small percentage of the entire cohort. The reasons could be increasing awareness among parents and physicians with early identification of DMD cases, genetic counseling and prenatal testing.
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http://dx.doi.org/10.1007/s00415-019-09380-3DOI Listing
September 2019

Congenital Myasthenic Syndrome: Spectrum of Mutations in an Indian Cohort.

J Clin Neuromuscul Dis 2018 Sep;20(1):14-27

Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, India.

Objectives: To investigate the mutational spectrum and genotype-phenotype correlation in Indian patients with congenital myasthenic syndrome (CMS), using next-generation sequencing of 5 genes.

Methods: CHRNE, COLQ, DOK7, RAPSN, and GFPT1 were sequenced in 25 affected patients.

Results: We found clinically significant variants in 18 patients, of which variants in CHRNE were the most common, and 9 were novel. A common pathogenic COLQ variant was also detected in 4 patients with isolated limb-girdle congenital myasthenia.

Conclusions: Targeted screening of 5 genes is an effective alternate test for CMS, and an affordable one even in a developing country such as India. In addition, we recommend that patients with isolated limb-girdle congenital myasthenia be screened initially for the common COLQ pathogenic variant. This study throws the first light on the genetic landscape of CMSs in India.
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http://dx.doi.org/10.1097/CND.0000000000000222DOI Listing
September 2018

A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation.

Eur J Med Genet 2019 Apr 31;62(4):248-253. Epub 2018 Jul 31.

Department of Neonatology, Christian Medical College, Vellore, India. Electronic address:

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of inborn errors of metabolism with around 100 types described so far. Because of the limited number of reported cases in each type except PMM2-CDG, the complete clinical picture of other types is not known. RFT1-CDG is a rare type, with ten cases reported in the literature. Our patient presented as a floppy neonate with severe respiratory insufficiency and ventilator dependence in the newborn period. He had fetal growth restriction, facial dysmorphism, high arched palate, bilateral cryptorchidism, hypoplastic pons and cerebellum and probable hearing impairment. He succumbed to the illness on day 24 of life. There was a similar history of two previous sibling deaths in the early neonatal period due to respiratory insufficiency and history of multiple neonatal and infant deaths in the extended family. Transferrin iso-electric focusing was normal. Clinical exome sequencing revealed a novel homozygous missense mutation (c.1018 G > A) in RFT1 gene [NM_052859; c.1018G > A; p.G340S; ENST00000296292] and the parents were heterozygous for the same (ClinVar SVC000778540). The pathogenic variants so far reported are all missense variants affecting the luminal loops; whereas the variant in our case is in the trans-membrane helical domain. A strong family history of neonatal deaths and similar presentations in the previous 2 siblings suggests the homogenous phenotype of this mutation. Severe respiratory insuffiency and ventilator dependence shows the lethality of the disease phenotype and incompatibility with survival beyond the neonatal period.
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http://dx.doi.org/10.1016/j.ejmg.2018.07.023DOI Listing
April 2019

Familial interstitial pulmonary fibrosis in two different families in India: A case series.

Lung India 2017 Sep-Oct;34(5):475-479

Department of Pulmonary Medicine, Christian Medical College, Vellore, Tamil Nadu, India.

Introduction: Idiopathic pulmonary fibrosis (IPF), a chronic progressive interstitial lung disease (ILD), Occasionally, IPF occurs in families. Familial interstitial lung disease has been reported worldwide, limited information is available on the disease among Indian patients.

Case Presentation: A 59-year-old woman presented with a 2-year history of progressive dyspnoea. Based on clinical and radiological features, our patient was diagnosed with idiopathic pulmonary fibrosis. Several family members of her first and second generations had died from respiratory failure. Her sister also diagnosed as IPF based on typical High resolution computed tomography (HRCT) finding though she was asymptomatic and came for screening. In addition, another male patient also had similar history and diagnosed as familial IPF based on HRCT and genetic testing in spite of significant occupational exposure. Genetic study revealed SFTPA1 gene was associated with susceptibility to idiopathic pulmonary fibrosis.

Conclusion: Our report illustrates that asymptomatic screening of family member can uncover such a serious disease in patients with familial interstitial fibrosis. Otherwise, clinical, radiological, and histological features are indistinguishable from those of sporadic cases. Furthermore, our work highlights the importance of compiling a thorough family history in individuals presenting with cough and dyspnoea, particularly in younger patients identified with idiopathic pulmonary fibrosis.
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http://dx.doi.org/10.4103/0970-2113.213824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592765PMC
September 2017

Novel mutations and phenotypic associations identified through APC, MUTYH, NTHL1, POLD1, POLE gene analysis in Indian Familial Adenomatous Polyposis cohort.

Sci Rep 2017 05 22;7(1):2214. Epub 2017 May 22.

Sarin Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC)-Tata Memorial Centre, Navi Mumbai, India.

Colo-Rectal Cancer is a common cancer worldwide with 5-10% cases being hereditary. Familial Adenomatous Polyposis (FAP) syndrome is due to germline mutations in the APC or rarely MUTYH gene. NTHL1, POLD1, POLE have been recently reported in previously unexplained FAP cases. Unlike the Caucasian population, FAP phenotype and its genotypic associations have not been widely studied in several geoethnic groups. We report the first FAP cohort from South Asia and the only non-Caucasian cohort with comprehensive analysis of APC, MUTYH, NTHL1, POLD1, POLE genes. In this cohort of 112 individuals from 53 FAP families, we detected germline APC mutations in 60 individuals (45 families) and biallelic MUTYH mutations in 4 individuals (2 families). No NTHL1, POLD1, POLE mutations were identified. Fifteen novel APC mutations and a new Indian APC mutational hotspot at codon 935 were identified. Eight very rare FAP phenotype or phenotypes rarely associated with mutations outside specific APC regions were observed. APC genotype-phenotype association studies in different geo-ethnic groups can enrich the existing knowledge about phenotypic consequences of distinct APC mutations and guide counseling and risk management in different populations. A stepwise cost-effective mutation screening approach is proposed for genetic testing of south Asian FAP patients.
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http://dx.doi.org/10.1038/s41598-017-02319-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440391PMC
May 2017

Menkes disease and response to copper histidine: An Indian case series.

Ann Indian Acad Neurol 2017 Jan-Mar;20(1):62-68

Department of Medical Genetics, Christian Medical College, Vellore, Tamil Nadu, India.

Background: Menkes disease (MD) is an X-linked recessive neurodegenerative disorder caused by mutations in gene. Depending on the residual activity, manifestation may be classical MD, occipital horn syndrome, or distal motor neuropathy. Neurological sparing is expected in female carriers. However, on rare occasions, females may manifest with classical clinical phenotype due to skewed X-chromosome inactivation, X-autosome translocation, and XO genotype. Here, we describe a small series of probands with MD and their response to copper histidine therapy. This series also includes a female with X-13 translocation manifesting neurological symptoms.

Methods: The clinical profile, laboratory and radiological data, and follow-up of four children with MD were collected from the hospital database and are being presented.

Results: All the four children in our series had developmental delay, recurrent respiratory tract infections, hair and skeletal changes, axial hypotonia, tortuous vessels on imaging, low serum copper, ceruloplasmin, and elevated lactate. Fetal hypokinesia and fetal growth retardation were present in two cases. Failure to thrive was present in three children and only one child had epilepsy. Subcutaneous copper histidine was administered to all children. The average time lapse in the initiation of treatment was 20.3 months, and average duration of follow-up was 14.3 months.

Conclusion: We conclude that copper histidine therapy is beneficial in reversing the skin and hair changes, improving appendicular tone, socio-cognitive milestones, and improving weight gain, and immunity. Early diagnosis and management of MD are essential to have a better clinical outcome. More research is needed to explore and devise new strategies in the management of patients with MD.
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http://dx.doi.org/10.4103/0972-2327.199907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341272PMC
March 2017

Molecular Characterization of a Novel Germline VHL Mutation by Extensive In Silico Analysis in an Indian Family with Von Hippel-Lindau Disease.

Genet Res Int 2016 16;2016:9872594. Epub 2016 Mar 16.

Department of Pathology, Christian Medical College, Vellore, Tamil Nadu 632004, India.

Von Hippel-Lindau [VHL] disease, an autosomal dominant hereditary cancer syndrome, is well known for its complex genotype-phenotype correlations. We looked for germline mutations in the VHL gene in an affected multiplex family with Type 1 VHL disease. Real-Time quantitative PCR for deletions and Sanger sequencing of coding regions along with flanking intronic regions were performed in two affected individuals and one related individual. Direct sequencing identified a novel heterozygous single nucleotide base substitution in both the affected members tested, segregating with VHL phenotype in this family. This variant in exon 3, c.473T>A, results in substitution of leucine, a highly conserved acid, to glutamine at position 158 [p.L158Q] and has not been reported thus far as a variant associated with disease causation. Further, this variant was not observed in 50 age and ethnicity matched healthy individuals. Extensive in silico prediction analysis along with molecular dynamics simulation revealed significant deleterious nature of the substitution L158Q on pVHL. The results of this study when collated support the view that the missense variation p.L158Q in the Elongin C binding domain of pVHL may be disease causing.
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http://dx.doi.org/10.1155/2016/9872594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812357PMC
April 2016

A novel de-novo frameshift mutation of the ASXL1 gene in a classic case of Bohring-Opitz syndrome.

Clin Dysmorphol 2016 Jul;25(3):101-5

aDepartment of Clinical Genetics bDepartment of Paediatrics, Christian Medical College, MGR University, Tamil Nadu, India.

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http://dx.doi.org/10.1097/MCD.0000000000000126DOI Listing
July 2016

Hajdu Cheney Syndrome.

J Clin Diagn Res 2016 Feb 1;10(2):OD07-9. Epub 2016 Feb 1.

Professor, Department of Endocrinology, Diabetes & Metabolism, Christian Medical College , Vellore, India .

Hajdu-Cheney Syndrome is a rare genetic disorder characterised by progressive focal bone destruction. It is known to be an autosomal dominant disorder but there have been reports of sporadic cases as well. Although the disease manifestation is found to begin from birth, it is most often not diagnosed until adolescence or adulthood. It could be due to the rarity of the condition and the variation of the disease manifestation at different age groups. We report a case of Hajdu-Cheney Syndrome in a 26-year-old male who presented with severe periodontitis and premature loss of teeth. The other characteristic features included craniofacial dysmorphism, abnormalities of the digits and dental anomalies. Patients with craniofacial dysmorphism along with dental abnormalities should be thoroughly examined for any underlying systemic disorder. A team of specialists may be able to diagnose this condition before the disease is advanced.
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http://dx.doi.org/10.7860/JCDR/2016/15782.7203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800570PMC
February 2016

Beta Propellar Protein-Associated Neurodegeneration: A Rare Cause of Infantile Autistic Regression and Intracranial Calcification.

Neuropediatrics 2016 Apr 9;47(2):123-7. Epub 2016 Feb 9.

Department of Medical Genetics, Christian Medical College, Vellore, Tamil Nadu, India.

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of single gene disorders with distinguished clinical phenotypes and definitive imaging findings. Beta propeller protein-associated neurodegeneration (BPAN) is a subentity of NBIA with X linked dominant inheritance. In this report, we describe a girl with autistic regression, seizures, intracranial calcification, iron accumulation in substantia nigra, and globi pallidi, and diagnosis of BPAN was established based on the identification of previously described disease causing variant in WD repeat domain 45 (WDR45) gene encoding for β propeller protein. This is the first genetically proven case from India. BPAN is an underrecognized disorder and must be considered as a differential diagnosis in children with atypical Rett features and should be enlisted among the causes for autistic regression and intracranial calcification. Pediatricians must be aware of this rare entity for establishing early diagnosis, prognostication, and genetic counseling. Treatment is usually supportive. More research is needed to explore drugs in the management of BPAN that can facilitate the autophagy and promotes cytoprotection.
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http://dx.doi.org/10.1055/s-0035-1571189DOI Listing
April 2016

Harlequin Ichthyosis: Prenatal Diagnosis of a Rare Yet Severe Genetic Dermatosis.

J Clin Diagn Res 2015 Nov 1;9(11):QD04-6. Epub 2015 Nov 1.

Assistant Professor, Department of Medical Genetics, Christian Medical College , Vellore, Tamil Nadu, India .

Harlequin Ichthyosis (HI) is an extremely rare genetic skin disorder. It is the most severe type of ichthyosis. It is characterized by thickened, dry, rough and armor like plates of skin with deep cracks in between. Alternative names for HI include- keratosis diffusafetalis, ichthyosis congenital, icthyosis fetalis, harlequin fetus and icthyosis congenital gravior. It is an autosomal recessive disorder with the majority of affected individuals being homozygous for mutation in the ABCA 12 gene. This condition presents with a wide range of severity and symptoms. Affected neonates usually do not survive beyond first few days of life. We are presenting prenatal diagnosis of a case of this rare condition.
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http://dx.doi.org/10.7860/JCDR/2015/15250.6705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668483PMC
November 2015

Association of Per3 length polymorphism with bipolar I disorder and schizophrenia.

Neuropsychiatr Dis Treat 2014 9;10:2325-30. Epub 2014 Dec 9.

Center for Healthful Behavior Change (CHBC), Division of Health and Behavior, Department of Population Health, NYU Langone Medical Center, Clinical and Translational Research Institute, New York, New York, USA.

Background: Sleep-wake disturbances have frequently been reported in bipolar disorder and schizophrenia, and are considered to be caused by an underlying circadian rhythm disorder. The study presented here was designed to investigate the existence of Per3 polymorphism in bipolar disorder type I (BD-I) and schizophrenic patients in South India.

Methods: Blood samples were collected from 311 BD-I patients, 293 schizophrenia patients, and 346 age- and sex-matched normal controls. Per3 genotyping was performed on DNA by polymerase chain reaction using specific primers.

Results: An increased prevalence of five repeat homozygotes was seen in BD-I patients as compared with healthy controls (odds ratio =1.72 [95% confidence interval: 1.08-2.76, P=0.02]). In BD-I patients, the frequency of the five repeat allele was higher (allele frequency =0.41), and that of the four repeat allele lower (allele frequency =0.36) (χ (2)=4.634; P<0.03) than in the control group. No significant association was observed in the allele frequencies of four and five repeat alleles in schizophrenia patients when compared with controls.

Conclusion: The occurrence of the five repeat allele of Per3 may be a risk factor for BD-I onset in this ethnic group.
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http://dx.doi.org/10.2147/NDT.S73765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267513PMC
December 2014

Epidemiology of comorbid substance use and psychiatric disorders in Asia.

Curr Opin Psychiatry 2012 May;25(3):172-80

National Institute of Mental Health & Neurosciences, Bangalore, India.

Purpose Of Review: Studying comorbidities between substance use disorders (SUDs) and psychiatric disorders in different regions is important from public health and heuristic perspectives. In this study we review recent studies conducted in Asian countries on these comorbidities.

Recent Findings: Comprehensive and methodologically sound studies conducted with focus on comorbidity between SUDs and psychiatric disorders are few and far between in Asian countries. Studies differ widely in their focus and methodological rigor. Some studies from China, Japan and Taiwan report fairly low rates of comorbidity of SUDs, particularly with illicit substances, among individuals with psychiatric disorders. Similar findings exist for rates of psychiatric disorders among those with SUDs. Recent research is lacking in several Asian countries on the issue of comorbidity.

Summary: Interesting regional differences exist in the rates of comorbidity both across the Asian countries and between these countries and the west. Genetic and socio-cultural differences may be responsible for these differences. Methodologically sound, multicenter studies, involving several Asian countries, specifically examining the epidemiology of comorbidity between SUDs and psychiatric disorders, will have the potential to provide useful insights in this regard.
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http://dx.doi.org/10.1097/YCO.0b013e3283523c26DOI Listing
May 2012