Publications by authors named "Neerja Gupta"

161 Publications

Combined Methylmalonic Aciduria and Homocystinuria Presenting as Pulmonary Hypertension.

Indian J Pediatr 2021 Sep 12. Epub 2021 Sep 12.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

Combined methylmalonic aciduria and homocystinuria, cblC type, (MAHCC) is a rare autosomal recessive metabolic disorder of remethylation caused due to mutations in the MMACHC (metabolism of cobalamin associated C) gene with predominant neurological involvement. Microvascular, renal, and cardiovascular complications are also known to occur. However, the disease presenting primarily with a cardiovascular phenotype without any neurological involvement is a rare entity. We report a case of developmentally normal 23-mo-old female child, who presented with pulmonary arterial hypertension (PAH) and succumbed to cardiac failure. Extensive workup for PAH was inconclusive. Posthumous trio whole-exome sequencing revealed pathogenic compound heterozygous variants in the MMACHC. Diagnosis of MAHCC should be considered as a differential diagnosis for unexplained PAH in children. An elevated plasma homocysteine level can serve as a simple screening modality for this disorder. Accurate diagnosis has paramount therapeutic implications, as management with hydroxocobalamin and betaine may lead to partial or complete remission of PAH in these patients.
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http://dx.doi.org/10.1007/s12098-021-03938-8DOI Listing
September 2021

Cerebral Venous Sinus Thrombosis in a Child with Lesch-Nyhan Syndrome.

Neurol India 2021 Jul-Aug;69(4):1021-1023

Child Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Lesch-Nyhan syndrome is a rare neurometabolic condition characterized by progressive choreoathetosis, intellectual disability, and peculiar manifestations like self-mutilation. Occasional case reports in adults have suggested an association between Lesch-Nyhan syndrome and hypercoagulability; however, no such report of either a venous or arterial stroke in children with Lesch-Nyhan Syndrome exists in literature. We present a 3-year-old boy with global developmental delay, dystonic posturing, choreoathetoid movements, and self-mutilation involving fingers and lips. He had acute worsening of sensorium, recurrent seizures, and opisthotonous posturing. A diagnosis of Lesch-Nyhan Syndrome was confirmed by extremely low hypoxanthine-guanine phosphoribosyltransferase enzyme levels. In view of an acute neurological deterioration, magnetic resonance imaging brain and magnetic resonance venogram were done that showed sagittal and left transverse venous sinus thrombosis. This case is the first case report of cerebral venous sinus thrombosis in a child with Lesch-Nyhan Syndrome. It further strengthens the association between hypercoagulability and Lesch-Nyhan syndrome.
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http://dx.doi.org/10.4103/0028-3886.325342DOI Listing
September 2021

Physical Growth and Its Determinants in Indian Children with Down Syndrome, from 3 Months to 5 Years of Age.

Indian J Pediatr 2021 Aug 19. Epub 2021 Aug 19.

Departments of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

Objective: To compare the growth of Indian children with Down syndrome (DS), with typically developing Indian children. The effect of comorbidities on their physical growth was also evaluated, so that factors affecting growth can be identified early and timely interventions be planned.

Methods: A cross-sectional study was conducted at the All India Institute of Medical Sciences, New Delhi from June 2015 to June 2017. Children with karyotype-proven DS within age group of 3 mo to 5 y were enrolled as study subjects. Children with DS having mosaic karyotype were excluded. Anthropometry and associated comorbidities were assessed.

Results: Hundred and eight children with DS were enrolled, mean WHO z scores were-WAZ: -2.31 (SD 1.44), HAZ: -2.51 (SD 1.47), BAZ: -1.07 (SD 1.8), and HCZ: -2.79 (SD 1.21). Congenital heart disease (in 44.5% children), hypothyroidism (in 27.7%), and anemia (in 50%) were the common comorbidities. Growth parameters of children with and without any comorbidity were significantly different, mean WHO z scores were WAZ -2.61 vs. -1.09 (p = 0.005), HAZ -2.43 vs. -2.41 (p = 0.3), BAZ -1.49 vs. -0.38 (p = 0.001), and HCZ -3.13 vs. -2.33 (p = 0.001).

Conclusion: Growth of Indian children with DS is significantly less compared to normally growing children. Weight was affected maximum during infancy, length was more affected as the age progressed, head circumference was affected similarly in all age groups, whereas BMI showed almost progressive increase with age. Children with severe heart disease had significantly lower BMI whereas children with treated hypothyroidism had better growth. There is a need for a large longitudinal study on Indian children with DS to construct Indian DS-specific growth charts.
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http://dx.doi.org/10.1007/s12098-021-03864-9DOI Listing
August 2021

Utility of fetal whole exome sequencing in the etiological evaluation and outcome of nonimmune hydrops fetalis.

Prenat Diagn 2021 Oct 2;41(11):1414-1424. Epub 2021 Aug 2.

Department of Pediatrics, Division of Genetics, All India Institute of Medical Sciences, New Delhi, India.

Introduction: Nonimmune hydrops fetalis (NIHF) has varied etiology. We assessed the etiological spectrum and evaluated the utility of fetal whole exome sequencing (fWES) for the diagnosis of NIHF.

Methods: In this prospective cohort study, we evaluated antenatally diagnosed fetuses with NIHF between July 2018 and December 2019 according to the routine diagnostic algorithm. Fetuses that remained undiagnosed after routine NIHF workup were subjected to fetal chromosomal microarray and/or WES. Pregnancies were followed up for clinical outcomes.

Results: Of the 45 fetuses, consanguinity and recurrent hydrops fetalis were observed in 13.3% (6/45) and 28.8% (13/45), respectively. Overall, an etiological diagnosis was possible in 75.5% (34/45) of fetuses, while the cause remained unknown in 24.4% (11/45). A genetic etiology was identified in 46.6% (21/45): aneuploidy and monogenic disorders in 28.8% (13/45) and 17.8% (8/45), respectively. fWES on 19 fetuses detected disease-causing variants in 42.1% (8/19). Nine novel variants were detected in RAPSN, ASCC1, NEB, PKD1L1, GUSB, and PIEZO1. Only 8.8% (4/45) of the cohort survived without morbidity.

Conclusions: This study describes the etiological spectrum and the disease-causing variants in an Indian cohort of hydropic fetuses.
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http://dx.doi.org/10.1002/pd.6022DOI Listing
October 2021

Functional characterization of novel variants in SMPD1 in Indian patients with acid sphingomyelinase deficiency.

Hum Mutat 2021 Oct 3;42(10):1336-1350. Epub 2021 Aug 3.

Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.

Pathogenic variations in SMPD1 lead to acid sphingomyelinase deficiency (ASMD), that is, Niemann-Pick disease (NPD) type A and B (NPA, NPB), which is a recessive lysosomal storage disease. The knowledge of variant spectrum in Indian patients is crucial for early and accurate NPD diagnosis and genetic counseling of families. In this study, we recruited 40 unrelated pediatric patients manifesting symptoms of ASMD and subnormal ASM enzyme activity. Variations in SMPD1 were studied using Sanger sequencing for all exons, followed by interpretation of variants based on American College of Medical Genetics and Genomics & Association for Molecular Pathology (ACMG/AMP) criteria. We identified 18 previously unreported variants and 21 known variants, including missense, nonsense, deletions, duplications, and splice site variations with disease-causing potential. Eight missense variants were functionally characterized using in silico molecular dynamic simulation and in vitro transient transfection in HEK293T cells, followed by ASM enzyme assay, immunoblot, and immunofluorescence studies. All the variants showed reduced ASM activity in transfected cells confirming their disease-causing potential. The study provides data for efficient prenatal diagnosis and genetic counseling of families with NPD type A and B.
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http://dx.doi.org/10.1002/humu.24263DOI Listing
October 2021

A patient with POLA1 splice variant expands the yet evolving phenotype of Van Esch O'Driscoll syndrome.

Eur J Med Genet 2021 Aug 10;64(8):104261. Epub 2021 Jun 10.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029 , India. Electronic address:

Van Esch-O'Driscoll syndrome (VEODS) is a rare cause of syndromic X-linked intellectual disability characterised by short stature, microcephaly, variable degree of intellectual disability, and hypogonadotropic hypogonadism. To date, heterozygous hypomorphic variants in the gene encoding the DNA Polymerase α subunit, POLA1, have been observed in nine patients from five unrelated families with VEODS. We report a three-year-old child with VEODS having borderline intellectual disability due to a novel splice site variant causing exon 6 skipping and reduced POLA1 expression.
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http://dx.doi.org/10.1016/j.ejmg.2021.104261DOI Listing
August 2021

Phenotypic and genotypic spectrum of CTSK variants in a cohort of twenty-five Indian patients with pycnodysostosis.

Eur J Med Genet 2021 Jul 1;64(7):104235. Epub 2021 May 1.

Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. Electronic address:

Background: Pycnodysostosis is an autosomal recessive skeletal dysplasia with easily recognizable clinical features and marked molecular heterogeneity. In this study, we explored the clinical and molecular spectrum of 25 Indian patients with pycnodysostosis from 20 families.

Methods: Clinical information was collected on a predesigned clinical proforma. Sanger method was employed to sequence all the exons and exon/intron boundaries of the CTSK gene. Novel variants were systematically assessed by prediction softwares and protein modelling. The pathogenicity of variant was established based on ACMG-AMP criteria. An attempt was also made to establish a genotype-phenotype correlation and devise a diagnostic scoring system based on clinical and radiological findings.

Results: Consanguinity and positive family history were present in 65% (13/20) and 45% (9/20) of the families respectively. Short stature and fractures were the predominant presenting complaints and was evident in 96% (24/25) and 32% (8/25) of affected individuals respectively. Gestalt facial phenotype and acro-osteolysis were present in 76% (19/25) and 82.6% (19/23) of the individuals respectively. Hepatosplenomegaly was present in 15% (3/20) of the individuals with one of them having severe anaemia. Causative sequence variations were identified in all of them. A total of 19 variants were identified from 20 families amongst which 10 were novel. Homozygous variants were identified in 90% (18/20) families. Amongst the novel variants, there was a considerable proportion (40%) of frameshift variants (4/10). No significant genotype-phenotype correlation was noted. Scoring based on clinical and radiological findings led to the proposal that a minimum of 2 scores in each category is required in addition to high bone density to diagnose pycnodysostosis with certainty.

Conclusion: This study delineated the genotypic and phenotypic characterisation of Indian patients with pycnodysostosis with identification of 10 novel variants. We also attempted to develop a clinically useful diagnostic scoring system which requires further validation.
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http://dx.doi.org/10.1016/j.ejmg.2021.104235DOI Listing
July 2021

Late onset Pompe Disease in India - Beyond the Caucasian phenotype.

Neuromuscul Disord 2021 05 16;31(5):431-441. Epub 2021 Feb 16.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.

We evaluated the clinical histories, motor and pulmonary functions, cardiac phenotypes and GAA genotypes of an Indian cohort of twenty patients with late onset Pompe disease (LOPD) in this multi-centre study. A mean age at onset of symptoms and diagnosis of 9.9 ± 9.7 years and 15.8 ± 12.1 years respectively was identified. All patients had lower extremity limb-girdle muscle weakness. Seven required ventilatory support and seven used mobility assists. Of the four who used both assists, two received ventilatory support prior to wheelchair use. Cardiac involvement was seen in eight patients with various combinations of left ventricular hypertrophy, tricuspid regurgitation, cardiomyopathy, dilated ventricles with biventricular dysfunction and aortic regurgitation. Amongst 20 biochemically diagnosed patients (low residual GAA enzyme activity) GAA genotypes of 19 patients identified homozygous variants in eight and compound heterozygous in 11: 27 missense, 3 nonsense, 2 initiator codon, 3 splice site and one deletion. Nine variants in 7 patients were novel. The leaky Caucasian, splice site LOPD variant, c.-32-13T>G mutation was absent. This first study from India provides an insight into a more severe LOPD phenotype with earlier disease onset at 9.9 years compared to 33.3 years in Caucasian patients, and cardiac involvement more than previously reported. The need for improvement in awareness and diagnosis of LOPD in India is highlighted.
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http://dx.doi.org/10.1016/j.nmd.2021.02.013DOI Listing
May 2021

Spine radiograph in dysplasias: A pictorial essay.

Indian J Radiol Imaging 2020 Oct-Dec;30(4):436-447. Epub 2021 Jan 13.

Department of Radiodiagnosis, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.

Spine radiograph is an essential component of a skeletal survey. It provides important diagnostic clues to various types of skeletal dysplasia. In some conditions, a spine radiograph alone may be diagnostic and characteristic; but mostly, it yields more value as a part of the complete skeletal survey. In this article we will discuss about a few common lethal and non-lethal skeletal dysplasias and their characteristic imaging findings; primarily focusing on the spine radiograph.
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http://dx.doi.org/10.4103/ijri.IJRI_395_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954163PMC
January 2021

Hydrops fetalis in PKD1L1-related heterotaxy: Report of two foetuses and expanding the phenotypic and molecular spectrum.

Ann Hum Genet 2021 05 2;85(3-4):138-145. Epub 2021 Mar 2.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

Abnormalities in the normal left-right axis asymmetry range from situs inversus totalis to situs ambiguous or heterotaxy. More than 80 genes have been described to have a role in the establishment of the normal situs of the internal organs. Pathogenic variants in the PKD1L1 gene have recently been described in heterotaxy and congenital heart disease. Till date, 11 families have been described with PKD1L1-related heterotaxy. We describe the first Indian family with two affected foetuses with PKD1L1-related nonimmune hydrops, congenital heart disease, situs inversus, and heterotaxy, with biallelic variants in the compound heterozygous state.
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http://dx.doi.org/10.1111/ahg.12417DOI Listing
May 2021

A Novel Homozygous HAX1 Mutation in a Child With Cyclic Neutropenia: A Case Report and Review.

J Pediatr Hematol Oncol 2021 Feb 25. Epub 2021 Feb 25.

Department of Pediatrics, Division of Pediatric Pulmonology Department of Pediatrics, Division of Pediatric Oncology Department of Pediatrics, Division of Genetics Laboratory Oncology Unit, Dr B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.

Background: Cyclic neutropenia is a rare genetic disorder causing the arrest of neutrophil function and is characterized by periodic neutropenia and recurrent infections. Patients with cyclic neutropenia with autosomal dominant, sporadic, and X-linked may have mutations in the ELANE gene, and autosomal recessive cases have homozygous/compound heterozygous variants in the HAX1 gene primarily.

Observation: The authors describe a novel variant in the HAX1 gene, which was detected by next-generation sequencing in an 8-year-old male child who presented with recurrent infections and neutropenia.

Conclusion: The patient extends the clinical variability associated with HAX1 variants and highlights the importance of genetic investigations in patients with suspected cyclic neutropenia.
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http://dx.doi.org/10.1097/MPH.0000000000002110DOI Listing
February 2021

A data set of variants derived from 1455 clinical and research exomes is efficient in variant prioritization for early-onset monogenic disorders in Indians.

Hum Mutat 2021 Apr 1;42(4):e15-e61. Epub 2021 Mar 1.

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

Given the genomic uniqueness, a local data set is most desired for Indians, who are underrepresented in existing public databases. We hypothesize patients with rare monogenic disorders and their family members can provide a reliable source of common variants in the population. Exome sequencing (ES) data from families with rare Mendelian disorders was aggregated from five centers in India. The dataset was refined by excluding related individuals and removing the disease-causing variants (refined cohort). The efficiency of these data sets was assessed in a new set of 50 exomes against gnomAD and GenomeAsia. Our original cohort comprised 1455 individuals from 1203 families. The refined cohort had 836 unrelated individuals that retained 1,251,064 variants with 181,125 population-specific and 489,618 common variants. The allele frequencies from our cohort helped to define 97,609 rare variants in gnomAD and 44,520 rare variants in GenomeAsia as common variants in our population. Our variant dataset provided an additional 1.7% and 0.1% efficiency for prioritizing heterozygous and homozygous variants respectively for rare monogenic disorders. We observed additional 19 genes/human knockouts. We list carrier frequency for 142 recessive disorders. This is a large and useful resource of exonic variants for Indians. Despite limitations, datasets from patients are efficient tools for variant prioritization in a resource-limited setting.
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http://dx.doi.org/10.1002/humu.24172DOI Listing
April 2021

Lipoprotein Lipase Deficiency: Diet is the Key!

Indian J Pediatr 2021 02 12;88(2):111-112. Epub 2021 Jan 12.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

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http://dx.doi.org/10.1007/s12098-020-03640-1DOI Listing
February 2021

Association of Sleep Apnea With Development and Behavior in Down Syndrome: A Prospective Clinical and Polysomnographic Study.

Pediatr Neurol 2021 03 19;116:7-13. Epub 2020 Nov 19.

Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. Electronic address:

Background: The prevalence of sleep-disordered breathing is high in children with Down syndrome. Although the association between sleep-disordered breathing and developmental delay and behavioral abnormalities are proven among typically developing children, there are few such studies of children with Down syndrome. This study assesses the relationship between the severity of sleep apnea and development and behavioral abnormalities in individuals with Down syndrome.

Methods: In a cross-sectional prospective study, 53 children with Down syndrome were assessed for sleep-disordered breathing by overnight polysomnography. Behavior was assessed using Child Behavior Checklist (CBCL) and developmental quotient (DQ) using Developmental Profile 3. The association between various domains of behavior and development with the Apnea-Hypopnea Index (AHI) was assessed using Spearman rank correlation. Multiple linear regression assessed the independent effects of various factors on development and behavior.

Results: Of 53 subjects (three to 11.8 years), 51 (96%) were found to have obstructive sleep apnea (OSA). In both three to five year and six to 12 year age groups, there was a statistically significant positive correlation between the CBCL scores and the AHI (rho = 0.77 and 0.83, respectively). There was a statistically significant negative correlation between the DQ and the AHI (rho = -0.62). In multiple linear regression, AHI was the only independent variable that was associated with CBCL and DQ.

Conclusions: This study provides robust evidence that OSA can negatively influence the development and behavior in children with Down syndrome as in typically developing children. Moreover, with increasing severity of OSA, children with Down syndrome have more behavioral abnormalities, especially attention deficit and hyperactivity, and also have poorer development scores.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.10.007DOI Listing
March 2021

Fabry disease in India: A multicenter study of the clinical and mutation spectrum in 54 patients.

JIMD Rep 2020 Nov 15;56(1):82-94. Epub 2020 Aug 15.

Lysosomal Disorders Unit, Institute of Immunity and Transplantation Royal Free London NHS Foundation Trust London UK.

Fabry disease (FD) is a treatable X linked lysosomal storage disorder with a wide phenotypic spectrum. There is a scarcity of published data on the burden of FD in India. This study evaluates the clinical and molecular spectrum of Indian patients with FD. In this multicentric study involving 10 tertiary referral centers in India, we analyzed the clinical course and genotype of 54 patients from 37 families. Family screening identified 19 new patients (35%) from 12 index cases. Then, 33 gene variants were identified in 49/54 (90.7%) which included 11 novel and 22 known pathogenic variants. Of the 54 patients in our cohort, 40 patients had "classical" and 10 patients had a "nonclassical" presentation. The symptoms and signs included kidney dysfunction in 38/54 (70.3%), neuropathic pain in 34/54 (62.9%), left ventricular hypertrophy in 22/49 (44.8%) and stroke in 5/54 (9.2%). Female heterozygotes were 10/54 (18.5%) of whom 2 were index cases. There was a significant delay in reaching the diagnosis of 11.7 years. Enzyme replacement therapy was initiated in 28/54 (51.8%) patients with significant improvement of neuropathic pain and gastrointestinal symptoms. This study highlights the clinical presentation and mutational spectrum of FD in India and suggests that family screening and screening of high-risk groups (hypertrophic cardiomyopathy, idiopathic chronic renal failure and cryptogenic stroke) could be the most cost-effective strategies for early identification of FD.
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http://dx.doi.org/10.1002/jmd2.12156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653245PMC
November 2020

The impact of COVID-19 pandemic on the diagnosis and management of inborn errors of metabolism: A global perspective.

Mol Genet Metab 2020 11 25;131(3):285-288. Epub 2020 Sep 25.

Translational Metabolic laboratory, Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands.

Quantitative estimates for the global impact of COVID-19 on the diagnosis and management of patients with inborn errors of metabolism (IEM) are lacking. We collected relevant data from 16 specialized medical centers treating IEM patients in Europe, Asia and Africa. The median decline of reported IEM related services in March 1st-May 31st 2020 compared to the same period in 2019 were as high as 60-80% with a profound impact on patient management and care for this vulnerable patient group. More representative data along with outcome data and guidelines for managing IEM disorders under such extraordinary circumstances are needed.
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http://dx.doi.org/10.1016/j.ymgme.2020.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518833PMC
November 2020

Rubinstein-Taybi syndrome in diverse populations.

Am J Med Genet A 2020 12 27;182(12):2939-2950. Epub 2020 Sep 27.

Kapi'olani Medical Center and University of Hawai'i, Honolulu, Hawaii, USA.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.
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http://dx.doi.org/10.1002/ajmg.a.61888DOI Listing
December 2020

Stippled keratoderma and nail dystrophy associated with hyperkeratotic pustular lesions in a 2-year-old boy.

Pediatr Dermatol 2020 Sep;37(5):e64-e66

Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India.

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http://dx.doi.org/10.1111/pde.14313DOI Listing
September 2020

Clinical application of a novel next generation sequencing assay for CYP21A2 gene in 310 cases of 21- hydroxylase congenital adrenal hyperplasia from India.

Endocrine 2021 01 18;71(1):189-198. Epub 2020 Sep 18.

Consultant Pediatrician and Deputy Director, Hirabai Cowasji Jehangir medical research Institute, Jehangir Hospital, Pune, Maharashtra, India.

Purpose: Accurate diagnosis is required for management of Congenital adrenal hyperplasia (CAH). The conventional method for detection of mutations in the CYP21A2 gene is targeted capillary sequencing which is labor intensive and has limited multiplexing capability. Next generation sequencing (NGS) provides data with high sequence coverage and depth. Our objective was to develop an accurate NGS-based assay to characterize the mutation spectrum in CYP21A2 gene in Indian patients suspected to have 21-OH CAH.

Methods: Cases with 21-OH CAH from 12 endocrine units across India were studied. DNA was extracted from proband's and parent's(subset) blood. Locus-specific long-range PCR and gel electrophoresis of amplicons was followed by NGS where no visible 30 kb homozygous/whole gene deletion was observed. Orthogonal confirmation was performed by capillary sequencing (ABI 3500) and Multiplex Ligation-dependent Probe Amplification (MLPA, MRC-Holland). PCR products were purified and individual libraries were pooled and sequenced (Illumina).

Results: Of the 310 CAH cases, biallelic mutations (pathogenic/ likely pathogenic variants involving both CYP21A2 gene copies) were detected in 256 (82.6%), heterozygous mutations in 13 (4.2 %), and none in 41 (13.2%). Most common mutation was c.293-13A/C>G (29.03%), followed by 30 kb deletion (18.24%). Thirty samples tested orthogonally (by capillary sequencing or MLPA) showed 100% concordance with NGS assay. Nine novel variants were identified.

Conclusions: We have developed and validated a comprehensive NGS-based assay for detection of variants in CYP21A2 gene in patients with 21-OH CAH. We describe CYP21A2 mutation spectrum and novel variants in a large cohort of Indian patients with CAH.
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http://dx.doi.org/10.1007/s12020-020-02494-zDOI Listing
January 2021

Report of an Indian Family with Sengers Syndrome.

Indian J Pediatr 2021 01 27;88(1):92. Epub 2020 Aug 27.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

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http://dx.doi.org/10.1007/s12098-020-03471-0DOI Listing
January 2021

Identification and characterization of 30 novel pathogenic variations in 69 unrelated Indian patients with Mucolipidosis Type II and Type III.

J Hum Genet 2020 Nov 10;65(11):971-984. Epub 2020 Jul 10.

Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.

Mucolipidosis (ML) (OMIM 607840 & 607838) is a rare autosomal recessive inherited disorder that occurs due to the deficiency of golgi enzyme uridine diphosphate (UDP)- N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) responsible for tagging mannose-6-phosphate for proper trafficking of lysosomal enzymes to lysosomes. Variants in GlcNAc-phosphotransferase (GNPTAB (α, β subunits) and GNPTG (γ subunits) are known to result in impaired targeting of lysosomal enzymes leading to Mucolipidosis (ML) Type II or Type III. We analyzed 69 Indian families of MLII/III for clinical features and molecular spectrum and performed in silico analysis for novel variants. We identified 38 pathogenic variants in GNPTAB and 5 pathogenic variants in GNPTG genes including missense, frame shift, deletion, duplication and splice site variations. A total of 26 novel variants were identified in GNPTAB and 4 in GNPTG gene. In silico studies using mutation prediction software like SIFT, Polyphen2 and protein structure analysis further confirmed the pathogenic nature of the novel sequence variants detected in our study. Except for a common variant c.3503_3504delTC in early onset MLII, we could not establish any other significant genotype and phenotype correlation. This is one of the largest studies reported till date on Mucolipidosis II/III in order to identify mutation spectrum and any recurrent mutations specific to the Indian ethnic population. The mutational spectrum information in Indian patients will be useful in better genetic counselling, carrier detection and prenatal diagnosis for patients with ML II/III.
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http://dx.doi.org/10.1038/s10038-020-0797-8DOI Listing
November 2020

Methylene Tetrahydrofolate Reductase Deficiency.

Indian J Pediatr 2020 Nov 26;87(11):951-953. Epub 2020 May 26.

Department of Pediatrics, Division of Genetics, All India Institute of Medical Sciences, New Delhi, 110029, India.

5,10-Methylene-tetrahydrofolate reductase (MTHFR) deficiency is a rare, autosomal recessive, metabolic disorder of folate metabolism, which affects homocysteine remethylation. Elevated homocysteine with normal or low methionine level is the key to diagnosis. Early recognition and treatment with betaine, has been shown to improve the survival and neurological outcomes. The authors report five Indian patients from three unrelated families, with MTHFR deficiency to emphasize the importance of early recognition and initiation of specific treatment.
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http://dx.doi.org/10.1007/s12098-020-03290-3DOI Listing
November 2020

Bi-allelic loss-of-function novel variants in LTBP3-related skeletal dysplasia: Report of first patient from India.

Am J Med Genet A 2020 08 20;182(8):1944-1946. Epub 2020 May 20.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Dental anomalies and short stature (DASS) has been recently identified as a distinct entity, associated with bi-allelic hypomorphic variants in LTBP3 gene. Only 20 individuals from nine families have been previously reported, with a consistent phenotype of short stature, brachyolmia, and amelogenesis imperfecta. We report the first case from India, with novel radiographic and molecular findings in LTBP3 gene, thereby expanding the phenotypic spectrum of DASS.
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http://dx.doi.org/10.1002/ajmg.a.61629DOI Listing
August 2020

Duchenne Muscular Dystrophy- Where Genetic Testing is Inevitable and Vital!

Indian J Pediatr 2020 07 16;87(7):487-488. Epub 2020 May 16.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

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http://dx.doi.org/10.1007/s12098-020-03324-wDOI Listing
July 2020

Identification of a Novel 19-bp Deletion Mutation in Using Exome Sequencing in Two Siblings with Autosomal Recessive Cutis Laxa Type 1C.

J Pediatr Genet 2020 Jun 22;9(2):125-131. Epub 2019 Oct 22.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), New Delhi, India.

Autosomal recessive type I cutis laxa is genetically heterogeneous. Biallelic mutations in latent transforming growth factor β-binding protein 4 (LTBP4; MIM*604710) lead to type 1C cutis laxa due to nonsense, frameshift, single base pair indels, or duplication mutations. In this report, we describe the first Indian family with cutis laxa as a result of a novel 19 base pair homozygous deletion leading to premature termination of short isoform LTBP-4S.
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http://dx.doi.org/10.1055/s-0039-1698806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183407PMC
June 2020

Spectrum of amyloglucosidase mutations in Asian Indian patients with Glycogen storage disease type III.

Am J Med Genet A 2020 05 28;182(5):1190-1200. Epub 2020 Mar 28.

Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Glycogen storage disease type III (GSD III) is a rare autosomal recessive inborn error of glycogen degradation pathway due to deficiency or reduced activity of glycogen debranching enzyme (GDE) that results in accumulation of abnormal glycogen in the liver, muscle, and heart. The cardinal hallmarks are hepatomegaly, fasting hypoglycemia, seizures, growth retardation, progressive skeletal myopathy, and cardiomyopathy in few. To date, 258 mutations in amyloglucosidase (AGL) gene have been identified worldwide. However, the mutation spectrum in the Asian Indian region is yet to be well characterized. We investigated 24 patients of Asian origin from 21 unrelated families with a provisional diagnosis of GSD III based on clinical and biochemical criteria. Molecular diagnosis was assessed by bidirectional sequencing and the impact of novel missense variants on the tertiary (three-dimensional) structure of GDE was evaluated by molecular modeling approach. Eighteen different pathogenic variants were identified, out of which 78% were novel. Novel variants included five nonsense, three small duplications and two small deletions, a splice site variant, and three missense variants. Variations in Exons 4, 14, 19, 24, 27, and 33 accounted for 61% of the total pathogenic variants identified and Allele p.Gly798Alafs*3 showed a high allele frequency of 11%. Molecular modeling study of novel pathogenic missense variants indicated the probable underlying molecular mechanism of adverse impact of variations on the structure and catalytic function of human GDE. Our study is the first large study on GSD III from the Asian subcontinent, which further expands the mutation spectrum of AGL.
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http://dx.doi.org/10.1002/ajmg.a.61547DOI Listing
May 2020

Use of Sentinel Lymph Node Biopsy and Early Physiotherapy to Reduce Incidence of Lymphedema After Breast Cancer Surgery: an Institutional Experience.

Indian J Surg Oncol 2020 Mar 7;11(1):15-18. Epub 2020 Jan 7.

4Dept of Physiotherapy Max Healthcare, Flat 124, Samrat Apartment, Vasundhara Enclave, New Delhi, 110096 India.

Newer advances in breast cancer management have led to increased disease free survival and overall survival. It is important to prevent debilitating complications after axillary lymph node dissection (ALND) to be able to successfully translate this survival benefit to quality of life benefit. By reducing disruption of lymphatic channels, sentinel lymph node biopsy (SLNB) decreases incidence of lymphedema (LE). Initiating early physiotherapy regimens, too, improves arm symptoms. In this review, we analyze the incidence of LE at our center and compare it with western literature. Retrospective analysis of all post-surgery breast cancer 18 patients, who followed up routinely with our oncophysiotherapist, was carried out. Incidence of LE in patients undergoing SLNB or ALND was followed up for a mean period of 17.5 months. Only 3.6%, i.e., 6 patients out of 166 developed LE. Amongst 166, 80 had only SLNB; the rest had ALND (either upfront or post-positive SLNB). None of the SLNB only cohort patients developed LE. SLNB in clinically node negative axilla, followed by initiation of arm physiotherapy early in post-operative period, may reduce LE incidence in breast cancer patients.
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http://dx.doi.org/10.1007/s13193-019-01030-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064678PMC
March 2020

Mevalonate Kinase Deficiency as Cause of Periodic Fever in Two Siblings.

Indian Pediatr 2020 02;57(2):180-181

Shimane University School of Medicine 89-1 En-ya-cho, Izumo Shimane, Japan.

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease caused by mutations in MVK. We report two siblings with MKD, presenting with recurrent febrile illnesses, detected to have compound heterozygous variants in MVK. MKD mimics common pediatric conditions and should be considered as a differential diagnosis.
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February 2020
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