Introduction Alpha-mannosidosis [Online Mendelian Inheritance in man (OMIM) 248500] is an ultra-o... more Introduction Alpha-mannosidosis [Online Mendelian Inheritance in man (OMIM) 248500] is an ultra-orphan lysosomal storage disorder with a prevalence between 1 per 300 000 and 1 per 500 000 live births (Malm et al., 2001). This autosomal recessive disorder, due to biallelic variations in the MAN2B1 gene results in deficiency of the enzyme, acid alpha-mannosidase that is involved in the degradation of N-linked oligosaccharides (Paciotti et al., 2017). The key clinical features include intellectual disability, impaired hearing, coarse facies, recurrent infections and skeletal manifestations. Ataxia and psychiatric manifestations are common in adult patients (Guffon et al., 2019). Ocular features include strabismus, corneal and lenticular opacities (Malm et al., 2001) with few reports of abnormal fundal changes. We describe two patients with alpha-mannosidosis from an extended consanguineous family in India with the same homozygous pathogenic variant in MAN2B1 gene. This case report adds to the scant literature on the natural history and progression of alpha-mannosidosis with advancing age. It describes the variable phenotype within two affected members of one family including presence of retinal dystrophy in the adult patient. Delayed diagnosis, progressive neurologic phenotype and survival outcomes become especially relevant with the availability of enzyme replacement therapy (ERT). This case report comes at a time where gaps in prevalent data of this disorder make evaluation of long-term efficacy of ERT challenging.
Biochemical analysis of the Gaucher Disease patients. The plasma chitotriosidase enzyme activity ... more Biochemical analysis of the Gaucher Disease patients. The plasma chitotriosidase enzyme activity and β-Glucosidase enzyme activity were checked using the standard protocol. (DOCX 17 kb)
ClinVar Accession ID of the variants generated in the given study. The variants identified throug... more ClinVar Accession ID of the variants generated in the given study. The variants identified through Sanger sequencing are reported in NCBI ClinVar database. The file provides accession ID and the links to an individual variant. (DOC 29 kb)
Population screening of the c.1448T>C (Leu444Pro) variant. The screening identified two carrie... more Population screening of the c.1448T>C (Leu444Pro) variant. The screening identified two carriers of Leu444Pro out of 1200 population. This gives the carrier frequency of 1:600. Sanger sequencing confirmed the results. (DOC 236 kb)
In silico analysis of the functional effect of the variants identified in the adult patients with... more In silico analysis of the functional effect of the variants identified in the adult patients with type 1 GD. The in silico tools predicting the effect of DNA variants, coding non-synonymous variants, amino acid substitution, and non-coding variants were employed to predict the functional effect of the variants identified in the given study. (DOC 37 kb)
Background Gaucher disease is a rare pan-ethnic disorder which occurs due to an increased accumul... more Background Gaucher disease is a rare pan-ethnic disorder which occurs due to an increased accumulation of undegraded glycolipid glucocerebroside inside the cells' lysosomes. A beta-Glucosidase (GBA) gene defect results in glucocerebrosidase enzyme deficiency. Though the disease is mainly diagnosed in childhood, the adult manifestation is often missed or identified late due to the failure to recognize the heterogeneous clinical presentation. The present study includes seven unrelated Indian adult patients (age range: 20–40 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality. Methods The biochemical investigation implicated measuring plasma chitotriosidase enzyme activity followed by confirmatory test of β-Glucosidase enzyme activity from the leukocytes. The molecular characterization involved patients' initial screening for the common Gaucher mutation (Leu444Pro). Later, all patients were subjected to whole GBA gene coding region study usi...
To examine the impact of the COVID-19 pandemic, we interviewed 26 patients with lysosomal storage... more To examine the impact of the COVID-19 pandemic, we interviewed 26 patients with lysosomal storage disorders receiving enzyme replacement therapy. 20 (77 %) had significant interruption in their treatment, with an average of 8 (range 2–28) missed doses. Alternate methods of delivering uninterrupted care including home therapy were used. Vulnerable patients with chronic genetic disorders require organization for their multidisciplinary needs of care.
Mucolipidosis type II or inclusion cell disease (I-cell) disease is a rare autosomal recessive ly... more Mucolipidosis type II or inclusion cell disease (I-cell) disease is a rare autosomal recessive lysosomal storage disorder caused by deficiency of N-actelyglucosamine-1phosphotransferase alpha/beta. The disease manifests in utero with short, bent long bones and periosteal cloaking evident at birth. We describe the clinical features in three neonates and allude to the key skeletal and biochemical manifestations to suspect mucolipidosis II, and further confirm the diagnosis by appropriate enzyme testing. As some of these features are transient, early identification and suspicion are important to diagnose mucolipidosis II in the neonatal period.
Objective: To examine the common and specific clinical features, mutation spectrum and genotype-p... more Objective: To examine the common and specific clinical features, mutation spectrum and genotype-phenotype correlation in Noonan syndrome and related RASopathies. Participants: Records of 30 patients with clinical diagnosis of Noonan syndrome and related RASopathies presenting over a six-year period at a Tertiary care Medical Genetics centre were reviewed. Detailed clinical phenotype evaluation and genetic testing (PTPN11 sequencing or next generation sequencing) was done. The genetic results were used to classify the patients. Results: Noonan syndrome was confirmed in 22 patients, 5 had cardiofaciocutaneous syndrome and 3 had Noonan syndrome like disorder with loose anagen hair. The molecular diagnosis was confirmed in 27 patients. Mutations in PTPN11 gene were confirmed in 57.8 % patients. Developmental delay, cardiac defects, ectodermal abnormalities and coarse face was the predominant phenotype. Noonan syndrome like disorder with loose anagen hair was clinically identifiable by the sparse, slow growing hair and caused by one recurrent SHOC2, c.4A>G mutation. Conclusions: Noonan syndrome and other RASopathies should be suspected in patients with short stature, cardiac defects, typical facial dysmorphism with or without ectodermal involvement.
The term baby presented with respiratory distress with X-ray pictures consistent as hyaline membr... more The term baby presented with respiratory distress with X-ray pictures consistent as hyaline membrane disease (HMD). Baby was ventilated and treated with surfactant. Because of the persistence of high ventilation needs with X-ray pictures consistent with HMD with a transient response to surfactant every time, the possibility of an inherited disorder of surfactant metabolism was kept. Whole-exome sequencing revealed a novel homozygous missense mutation in the gene for ATP binding cassette transporter protein A3. The baby died after 100 days of ventilation.
Introduction:Gaucher's disease is an inherited, autosomal recessive storage disease of glucocereb... more Introduction:Gaucher's disease is an inherited, autosomal recessive storage disease of glucocerebroside due to a deficiency of glucocerebrosidase enzymes. It has an estimated global incidence of 1: 40,000 to 1:60,000 live births.We present this to highlight the importance of bone marrow examination as an initial diagnostic modality providing an early pointer towards storage disorders, thus reducing the diagnostic delay and helping in early treatment initiation. Method:(Case) We present a 3 year old Hindu boy born out of a non consanguineous marriage(1 st child) referred to special OPD(PHO) with complaints of pallor, recurrent infections and abdominal distension. He had hepatosplenomegaly and rest of the systems was within normal limit. His routine Peripheral blood examination showed a leucoerthroblastic picture with a reticulocyte count of 1.8%. His glucocerebrosidase enzyme assay done from a private lab previously was inconclusive. A bone marrow examination was finally done and aspirate and biopsy revealed sheets of PAS positive gaucher cells. Imprint was not very informative. Result:(Diagnosis) The genetic tests done in a outsourced lab using PCR with Gene ID 2629, revealed homozygous pLeu483 Pro pathogenic missense mutation which confirmed gauchers. Conclusion:Our case highlights the importance of a meticulous bone marrow examination as a screening of storage disorders. Enzyme assays may be inconclusive in case of prior transfusion or if not performed in standard laboratories. However enzymatic study and genetic examination remain the gold standards for diagnosis of gauchers.
Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of ... more Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N‐acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross‐Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up‐to‐date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty‐five patients representing the known clinical spectrum of Farber disease (living patients aged 1–28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease‐causing variants.
Obstetrics & Gynecology International Journal, 2019
Objectives: The supernumerary marker chromosomes (SMCs) are extra structurally abnormal chromosom... more Objectives: The supernumerary marker chromosomes (SMCs) are extra structurally abnormal chromosomes that cannot be unambiguously identified or characterised by conventional karyotyping. Their clinical phenotypes are variable and are dependent on their size, gene content, inheritance and level of mosaicism. In the past, fluorescence in situ hybridization (FISH) and related techniques were used to identify the chromosome origin, but the molecular makeup was still unknown. Chromosome microarray analysis (CMA) can detect the exact genomic breakpoints and gene content of the SMC. This can be correlated with the phenotype for better genetic counselling Methods: In the last 5 years, out of 20,000 samples referred for various reasons for karyotyping, we found 18 SMCs (0.09%) as unexpected results, nine were prenatal samples and nine were postnatal. All eighteen samples were subjected to CMA to characterize the SMCs. FISH was done for identification or validation, wherever possible. Results: Out of 18 SMCs, 14 were successfully characterized: eight (57.14%) were acrocentric chromosomes [seven der(15) and one der(22)], five (35.71%) were nonacrocentric chromosomes [der(9) , der(11), der(12), two der(18)] and one (7.14%) was a complex, novel SMC originating from the maternal translocation t(10;13). The remaining four were very small and heterochromatic with normal array reports. Seven had SMC-related known syndromes such as 15q11q13 duplication syndrome (n=2), Cat Eye syndrome, Trisomy 9p syndrome, i(12)p Pallister Killian syndrome and the rare Trisomy 18p syndrome(n=2). Conclusion: The results, their molecular relevance and pathological significance for genetic counselling were discussed case by case individually. The study emphasizes the usefulness of CMA in identification and characterization of the additional genetic material of the SMC which can be correlated with the phenotypes of the postnatal patient for future management and also the clinical significance conveyed to the parents when the SMC is found in the prenatal samples.
Sialidosis, an autosomal recessive disorder, is characterized by progressive lysosomal storage of... more Sialidosis, an autosomal recessive disorder, is characterized by progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. It occurs as a result of biallelic mutations in the NEU1 gene. Sialidosis is traditionally classified as a milder, late-onset type I and a severe early-onset type II disease. The presence of a cherry-red spot is a well-established ophthalmological clue to the disorder. We present a clinical-radiological report of seven unrelated patients with molecularly confirmed sialidosis type II. To the best of our knowledge, This is the largest reported series of patients with Sialidosis type II. A novel, previously unreported ophthalmic phenotype of bulls-eye maculopathy, is described. All seven phenotypically heterogeneous patients had the same pathogenic variant (c.679G > A; p.Gly227Arg) at a homozygous level in the NEU1 gene. We propose that this is a common mutation in north Indians for this rare disorder. We also observed an overlap of symptoms and a continuum of phenotypes in type I and II Sialidosis.
Sengers syndrome is an autosomal recessive mitochondrial disease comprising a tetrad of congenita... more Sengers syndrome is an autosomal recessive mitochondrial disease comprising a tetrad of congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the AGK gene cause Senger syndrome. We describe two unrelated Asian Indian families with two novel mutations, c.909 G>A (p.Trp303Ter) and c.982G>T (p.E328Ter), in the AGK gene. Similar nonsense mutations have previously been reported with a severe phenotype and early infantile death, while this patient is doing well at 3 years, suggesting a mild phenotype. The second child tested positive for two previously reported mutations, c.841C>T (p.Arg281Ter) and c.424-3C>G. The presence of a splice site mutation typically predicts a milder phenotype with one exception reported to date. The second patient we report died at 9 months of age adding to the one previously reported exception. Both these cases add onto the scant literature of genotype phenotype correlation in Sengers syndrome. We emphasize the importance of diagnosis of this clinically recognizable syndrome to counsel families of recurrence risks and option of prenatal diagnosis.
Tay-Sachs disease (TSD) (OMIM) is a neurodegenerative lysosomal storage disorder caused due to mu... more Tay-Sachs disease (TSD) (OMIM) is a neurodegenerative lysosomal storage disorder caused due to mutations in the HEXA gene. To date, nearly 190 mutations have been reported in HEXA gene. Here, we have characterized 34 enzymatically confirmed TSD families to investigate the presence of novel as well as known variants in HEXA gene. Overall study detected 25 variants belonging to 31 affected TSD patients and 3 carrier couples confirmed by enzyme study. Of these 17 patients harbors 15 novel variants, including seven missense variants [p.V206L, p.Y213H, p.R252C, p.F257S, p.C328G, p.G454R, and p.P475R], four nonsense variant [p.S9X, p.E91X, p.W420X, and p.W482X], two splice site variants [c.347-1G>A and c.460-1G>A], and two small deletion [c.1349delC (p.A450VfsX3) and c.52delG (p.G18Dfs*82)]. While remaining 17 patients harbors 10 previously reported variants that includes six missense variants [p.M1T, p.R170Q, p.D322Y, p.D322N, p.E462V, and p.R499C], one nonsense variant [p.Q106X], two splice site variants [c.1073+1G>A and c.459+4A>G] and one 4 bp insertion [c.1278insTATC (p.Y427IfsX5)]. In conclusion, Indian infantile TSD patients provide newer insight into the molecular heterogeneity of the TSD. Combining present study and our earlier studies, we have observed that 67% genotypes found in Indian TSD patients are novel, which are associated with severe infantile phenotypes, while rest 33% genotypes found in our cohort were previously reported in various populations. In addition, higher frequency of the p.E462V and c.1278insTATC mutations in the present study further support and suggest the prevalence of p.E462V mutation in the Indian population.
Introduction Alpha-mannosidosis [Online Mendelian Inheritance in man (OMIM) 248500] is an ultra-o... more Introduction Alpha-mannosidosis [Online Mendelian Inheritance in man (OMIM) 248500] is an ultra-orphan lysosomal storage disorder with a prevalence between 1 per 300 000 and 1 per 500 000 live births (Malm et al., 2001). This autosomal recessive disorder, due to biallelic variations in the MAN2B1 gene results in deficiency of the enzyme, acid alpha-mannosidase that is involved in the degradation of N-linked oligosaccharides (Paciotti et al., 2017). The key clinical features include intellectual disability, impaired hearing, coarse facies, recurrent infections and skeletal manifestations. Ataxia and psychiatric manifestations are common in adult patients (Guffon et al., 2019). Ocular features include strabismus, corneal and lenticular opacities (Malm et al., 2001) with few reports of abnormal fundal changes. We describe two patients with alpha-mannosidosis from an extended consanguineous family in India with the same homozygous pathogenic variant in MAN2B1 gene. This case report adds to the scant literature on the natural history and progression of alpha-mannosidosis with advancing age. It describes the variable phenotype within two affected members of one family including presence of retinal dystrophy in the adult patient. Delayed diagnosis, progressive neurologic phenotype and survival outcomes become especially relevant with the availability of enzyme replacement therapy (ERT). This case report comes at a time where gaps in prevalent data of this disorder make evaluation of long-term efficacy of ERT challenging.
Biochemical analysis of the Gaucher Disease patients. The plasma chitotriosidase enzyme activity ... more Biochemical analysis of the Gaucher Disease patients. The plasma chitotriosidase enzyme activity and β-Glucosidase enzyme activity were checked using the standard protocol. (DOCX 17 kb)
ClinVar Accession ID of the variants generated in the given study. The variants identified throug... more ClinVar Accession ID of the variants generated in the given study. The variants identified through Sanger sequencing are reported in NCBI ClinVar database. The file provides accession ID and the links to an individual variant. (DOC 29 kb)
Population screening of the c.1448T>C (Leu444Pro) variant. The screening identified two carrie... more Population screening of the c.1448T>C (Leu444Pro) variant. The screening identified two carriers of Leu444Pro out of 1200 population. This gives the carrier frequency of 1:600. Sanger sequencing confirmed the results. (DOC 236 kb)
In silico analysis of the functional effect of the variants identified in the adult patients with... more In silico analysis of the functional effect of the variants identified in the adult patients with type 1 GD. The in silico tools predicting the effect of DNA variants, coding non-synonymous variants, amino acid substitution, and non-coding variants were employed to predict the functional effect of the variants identified in the given study. (DOC 37 kb)
Background Gaucher disease is a rare pan-ethnic disorder which occurs due to an increased accumul... more Background Gaucher disease is a rare pan-ethnic disorder which occurs due to an increased accumulation of undegraded glycolipid glucocerebroside inside the cells' lysosomes. A beta-Glucosidase (GBA) gene defect results in glucocerebrosidase enzyme deficiency. Though the disease is mainly diagnosed in childhood, the adult manifestation is often missed or identified late due to the failure to recognize the heterogeneous clinical presentation. The present study includes seven unrelated Indian adult patients (age range: 20–40 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality. Methods The biochemical investigation implicated measuring plasma chitotriosidase enzyme activity followed by confirmatory test of β-Glucosidase enzyme activity from the leukocytes. The molecular characterization involved patients' initial screening for the common Gaucher mutation (Leu444Pro). Later, all patients were subjected to whole GBA gene coding region study usi...
To examine the impact of the COVID-19 pandemic, we interviewed 26 patients with lysosomal storage... more To examine the impact of the COVID-19 pandemic, we interviewed 26 patients with lysosomal storage disorders receiving enzyme replacement therapy. 20 (77 %) had significant interruption in their treatment, with an average of 8 (range 2–28) missed doses. Alternate methods of delivering uninterrupted care including home therapy were used. Vulnerable patients with chronic genetic disorders require organization for their multidisciplinary needs of care.
Mucolipidosis type II or inclusion cell disease (I-cell) disease is a rare autosomal recessive ly... more Mucolipidosis type II or inclusion cell disease (I-cell) disease is a rare autosomal recessive lysosomal storage disorder caused by deficiency of N-actelyglucosamine-1phosphotransferase alpha/beta. The disease manifests in utero with short, bent long bones and periosteal cloaking evident at birth. We describe the clinical features in three neonates and allude to the key skeletal and biochemical manifestations to suspect mucolipidosis II, and further confirm the diagnosis by appropriate enzyme testing. As some of these features are transient, early identification and suspicion are important to diagnose mucolipidosis II in the neonatal period.
Objective: To examine the common and specific clinical features, mutation spectrum and genotype-p... more Objective: To examine the common and specific clinical features, mutation spectrum and genotype-phenotype correlation in Noonan syndrome and related RASopathies. Participants: Records of 30 patients with clinical diagnosis of Noonan syndrome and related RASopathies presenting over a six-year period at a Tertiary care Medical Genetics centre were reviewed. Detailed clinical phenotype evaluation and genetic testing (PTPN11 sequencing or next generation sequencing) was done. The genetic results were used to classify the patients. Results: Noonan syndrome was confirmed in 22 patients, 5 had cardiofaciocutaneous syndrome and 3 had Noonan syndrome like disorder with loose anagen hair. The molecular diagnosis was confirmed in 27 patients. Mutations in PTPN11 gene were confirmed in 57.8 % patients. Developmental delay, cardiac defects, ectodermal abnormalities and coarse face was the predominant phenotype. Noonan syndrome like disorder with loose anagen hair was clinically identifiable by the sparse, slow growing hair and caused by one recurrent SHOC2, c.4A>G mutation. Conclusions: Noonan syndrome and other RASopathies should be suspected in patients with short stature, cardiac defects, typical facial dysmorphism with or without ectodermal involvement.
The term baby presented with respiratory distress with X-ray pictures consistent as hyaline membr... more The term baby presented with respiratory distress with X-ray pictures consistent as hyaline membrane disease (HMD). Baby was ventilated and treated with surfactant. Because of the persistence of high ventilation needs with X-ray pictures consistent with HMD with a transient response to surfactant every time, the possibility of an inherited disorder of surfactant metabolism was kept. Whole-exome sequencing revealed a novel homozygous missense mutation in the gene for ATP binding cassette transporter protein A3. The baby died after 100 days of ventilation.
Introduction:Gaucher's disease is an inherited, autosomal recessive storage disease of glucocereb... more Introduction:Gaucher's disease is an inherited, autosomal recessive storage disease of glucocerebroside due to a deficiency of glucocerebrosidase enzymes. It has an estimated global incidence of 1: 40,000 to 1:60,000 live births.We present this to highlight the importance of bone marrow examination as an initial diagnostic modality providing an early pointer towards storage disorders, thus reducing the diagnostic delay and helping in early treatment initiation. Method:(Case) We present a 3 year old Hindu boy born out of a non consanguineous marriage(1 st child) referred to special OPD(PHO) with complaints of pallor, recurrent infections and abdominal distension. He had hepatosplenomegaly and rest of the systems was within normal limit. His routine Peripheral blood examination showed a leucoerthroblastic picture with a reticulocyte count of 1.8%. His glucocerebrosidase enzyme assay done from a private lab previously was inconclusive. A bone marrow examination was finally done and aspirate and biopsy revealed sheets of PAS positive gaucher cells. Imprint was not very informative. Result:(Diagnosis) The genetic tests done in a outsourced lab using PCR with Gene ID 2629, revealed homozygous pLeu483 Pro pathogenic missense mutation which confirmed gauchers. Conclusion:Our case highlights the importance of a meticulous bone marrow examination as a screening of storage disorders. Enzyme assays may be inconclusive in case of prior transfusion or if not performed in standard laboratories. However enzymatic study and genetic examination remain the gold standards for diagnosis of gauchers.
Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of ... more Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N‐acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross‐Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up‐to‐date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty‐five patients representing the known clinical spectrum of Farber disease (living patients aged 1–28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease‐causing variants.
Obstetrics & Gynecology International Journal, 2019
Objectives: The supernumerary marker chromosomes (SMCs) are extra structurally abnormal chromosom... more Objectives: The supernumerary marker chromosomes (SMCs) are extra structurally abnormal chromosomes that cannot be unambiguously identified or characterised by conventional karyotyping. Their clinical phenotypes are variable and are dependent on their size, gene content, inheritance and level of mosaicism. In the past, fluorescence in situ hybridization (FISH) and related techniques were used to identify the chromosome origin, but the molecular makeup was still unknown. Chromosome microarray analysis (CMA) can detect the exact genomic breakpoints and gene content of the SMC. This can be correlated with the phenotype for better genetic counselling Methods: In the last 5 years, out of 20,000 samples referred for various reasons for karyotyping, we found 18 SMCs (0.09%) as unexpected results, nine were prenatal samples and nine were postnatal. All eighteen samples were subjected to CMA to characterize the SMCs. FISH was done for identification or validation, wherever possible. Results: Out of 18 SMCs, 14 were successfully characterized: eight (57.14%) were acrocentric chromosomes [seven der(15) and one der(22)], five (35.71%) were nonacrocentric chromosomes [der(9) , der(11), der(12), two der(18)] and one (7.14%) was a complex, novel SMC originating from the maternal translocation t(10;13). The remaining four were very small and heterochromatic with normal array reports. Seven had SMC-related known syndromes such as 15q11q13 duplication syndrome (n=2), Cat Eye syndrome, Trisomy 9p syndrome, i(12)p Pallister Killian syndrome and the rare Trisomy 18p syndrome(n=2). Conclusion: The results, their molecular relevance and pathological significance for genetic counselling were discussed case by case individually. The study emphasizes the usefulness of CMA in identification and characterization of the additional genetic material of the SMC which can be correlated with the phenotypes of the postnatal patient for future management and also the clinical significance conveyed to the parents when the SMC is found in the prenatal samples.
Sialidosis, an autosomal recessive disorder, is characterized by progressive lysosomal storage of... more Sialidosis, an autosomal recessive disorder, is characterized by progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. It occurs as a result of biallelic mutations in the NEU1 gene. Sialidosis is traditionally classified as a milder, late-onset type I and a severe early-onset type II disease. The presence of a cherry-red spot is a well-established ophthalmological clue to the disorder. We present a clinical-radiological report of seven unrelated patients with molecularly confirmed sialidosis type II. To the best of our knowledge, This is the largest reported series of patients with Sialidosis type II. A novel, previously unreported ophthalmic phenotype of bulls-eye maculopathy, is described. All seven phenotypically heterogeneous patients had the same pathogenic variant (c.679G > A; p.Gly227Arg) at a homozygous level in the NEU1 gene. We propose that this is a common mutation in north Indians for this rare disorder. We also observed an overlap of symptoms and a continuum of phenotypes in type I and II Sialidosis.
Sengers syndrome is an autosomal recessive mitochondrial disease comprising a tetrad of congenita... more Sengers syndrome is an autosomal recessive mitochondrial disease comprising a tetrad of congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the AGK gene cause Senger syndrome. We describe two unrelated Asian Indian families with two novel mutations, c.909 G>A (p.Trp303Ter) and c.982G>T (p.E328Ter), in the AGK gene. Similar nonsense mutations have previously been reported with a severe phenotype and early infantile death, while this patient is doing well at 3 years, suggesting a mild phenotype. The second child tested positive for two previously reported mutations, c.841C>T (p.Arg281Ter) and c.424-3C>G. The presence of a splice site mutation typically predicts a milder phenotype with one exception reported to date. The second patient we report died at 9 months of age adding to the one previously reported exception. Both these cases add onto the scant literature of genotype phenotype correlation in Sengers syndrome. We emphasize the importance of diagnosis of this clinically recognizable syndrome to counsel families of recurrence risks and option of prenatal diagnosis.
Tay-Sachs disease (TSD) (OMIM) is a neurodegenerative lysosomal storage disorder caused due to mu... more Tay-Sachs disease (TSD) (OMIM) is a neurodegenerative lysosomal storage disorder caused due to mutations in the HEXA gene. To date, nearly 190 mutations have been reported in HEXA gene. Here, we have characterized 34 enzymatically confirmed TSD families to investigate the presence of novel as well as known variants in HEXA gene. Overall study detected 25 variants belonging to 31 affected TSD patients and 3 carrier couples confirmed by enzyme study. Of these 17 patients harbors 15 novel variants, including seven missense variants [p.V206L, p.Y213H, p.R252C, p.F257S, p.C328G, p.G454R, and p.P475R], four nonsense variant [p.S9X, p.E91X, p.W420X, and p.W482X], two splice site variants [c.347-1G>A and c.460-1G>A], and two small deletion [c.1349delC (p.A450VfsX3) and c.52delG (p.G18Dfs*82)]. While remaining 17 patients harbors 10 previously reported variants that includes six missense variants [p.M1T, p.R170Q, p.D322Y, p.D322N, p.E462V, and p.R499C], one nonsense variant [p.Q106X], two splice site variants [c.1073+1G>A and c.459+4A>G] and one 4 bp insertion [c.1278insTATC (p.Y427IfsX5)]. In conclusion, Indian infantile TSD patients provide newer insight into the molecular heterogeneity of the TSD. Combining present study and our earlier studies, we have observed that 67% genotypes found in Indian TSD patients are novel, which are associated with severe infantile phenotypes, while rest 33% genotypes found in our cohort were previously reported in various populations. In addition, higher frequency of the p.E462V and c.1278insTATC mutations in the present study further support and suggest the prevalence of p.E462V mutation in the Indian population.
Uploads
Papers by Ratna Puri