Publications by authors named "Ratna Dua Puri"

53 Publications

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

Neuromuscul Disord 2021 Feb 16. 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
February 2021

Complete Labyrinthine Aplasia: A Unique Sign for Targeted Genetic Testing in Hearing Loss.

J Pediatr Genet 2021 Mar 9;10(1):70-73. Epub 2020 Mar 9.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

Complete labyrinthine aplasia (CLA) is a rare inner ear anomaly. The only identified genetic cause of CLA with severe sensorineural hearing loss is labyrinthine aplasia, microtia, and microdontia (LAMM) syndrome. Here we reported a child who presented with syndromic hearing loss and was diagnosed with LAMM syndrome. Genetic evaluation provided the family with confirmation of the diagnosis, provision of the prognosis, genetic counselling, and prenatal diagnosis. This report highlighted that CLA should be recognized as a unique sign to diagnose LAMM syndrome, to analyze gene mutation, and also demonstrated the utility of genetic testing in patients with suspected LAMM syndrome to provide exact diagnosis and further management.
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http://dx.doi.org/10.1055/s-0040-1708052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853916PMC
March 2021

Mutation and Phenotypic Spectrum of Patients With RASopathies.

Indian Pediatr 2021 Jan;58(1):30-33

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India. Correspondence to: Dr Ratna Dua Puri, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

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.

Conclusion: Noonan syndrome and other RASopathies should be suspected in patients with short stature, cardiac defects, typical facial dysmorphism with or without ectodermal involvement.
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January 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

NGS-based expanded carrier screening for genetic disorders in North Indian population reveals unexpected results - a pilot study.

BMC Med Genet 2020 11 2;21(1):216. Epub 2020 Nov 2.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

Background: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS).

Methods: After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary.

Results: Of the 200 participants, 52 (26%) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West.

Conclusion: A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.
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http://dx.doi.org/10.1186/s12881-020-01153-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607710PMC
November 2020

Biallelic Pathogenic Variants Cause Autosomal Recessive Bilateral Renal Agenesis.

J Am Soc Nephrol 2021 01 5;32(1):223-228. Epub 2020 Oct 5.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are one of the most common malformations identified in the fetal stage. Bilateral renal agenesis (BRA) represents the most severe and fatal form of CAKUT. Only three genes have been confirmed to have a causal role in humans (, , and ).

Methods: Genome sequencing within a diagnostic setting and combined data repository analysis identified a novel gene.

Results: Two patients presented with BRA, detected during the prenatal period, without additional recognizable malformations. They had parental consanguinity and similarly affected, deceased siblings, suggesting autosomal recessive inheritance. Evaluation of homozygous regions in patient 1 identified a novel, nonsense variant in (NM_001348097.1:c.676C>T, p.[Arg226*]). We identified 184 patients in our repository with renal agenesis and analyzed their exome/genome data. Of these 184 samples, 36 were from patients who presented with isolated renal agenesis. Two of them had loss-of-function variants in . The second patient was homozygous for a frameshift variant (NM_001348097.1:c.1294delA, p.[Thr432Profs*13]). The gene encodes a receptor on the Wolffian duct that regulates ureteric bud outgrowth in the development of a functional renal system, and has a putative role in the pathogenesis of Hirschsprung disease.

Conclusions: These findings strongly support the causal role of -inactivating variants for an autosomal recessive, nonsyndromic form of BRA. This knowledge will enable early genetic diagnosis and better genetic counseling for families with BRA.
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http://dx.doi.org/10.1681/ASN.2020040478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894660PMC
January 2021

Hypoxic Ischemic Encephalopathy or Metabolic Etiology-MRI as a Clue to Diagnosis.

Neurol India 2020 Jul-Aug;68(4):941-942

Department of Medical Genetics and Genomics, Institute of Medical Genetics and Genomics, Rajinder Nagar, New Delhi, India.

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http://dx.doi.org/10.4103/0028-3886.293478DOI Listing
August 2020

Mutation and Phenotypic Spectrum of Patients With RASopathies.

Indian Pediatr 2020 Aug 6. Epub 2020 Aug 6.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India. Correspondence to: Dr Ratna Dua Puri, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

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.

Conclusion: Noonan syndrome and other RASopathies should be suspected in patients with short stature, cardiac defects, typical facial dysmorphism with or without ectodermal involvement.
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August 2020

Filaggrin Null-Mutation in Asthma in an Indian Cohort: One Link in a Polygenic Trait.

Authors:
Ratna Dua Puri

Indian J Pediatr 2020 08 10;87(8):583-584. Epub 2020 Jul 10.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110060, India.

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http://dx.doi.org/10.1007/s12098-020-03443-4DOI Listing
August 2020

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

Case Series of Creatine Deficiency Syndrome due to Guanidinoacetate Methyltransferase Deficiency.

Ann Indian Acad Neurol 2020 May-Jun;23(3):347-351. Epub 2020 Jun 10.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

Guanidinoacetate methyltransferase (GAMT) deficiency is the second most common defect in the creatine metabolism pathway resulting in cerebral creatine deficiency syndrome (CCDS). We report three patients from two unrelated families, diagnosed with GAMT deficiency on next-generation sequencing. All the probands had happy predisposition as a predominant manifestation in addition to the reported features of global developmental delay, seizures, and microcephaly. This further expands the phenotype of CCDS. The workup for creatine deficiency disorder should be included in the diagnostic algorithm for children with nonsyndromic intellectual disability, especially in those with a happy demeanor. These cases exemplify the utility of magnetic resonance spectroscopy of the brain in the workup of nonsyndromic intellectual disability to diagnose a potentially treatable disorder. In addition, documentation of low serum creatinine may be supportive. Early diagnosis and treatment is essential for better prognosis.
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http://dx.doi.org/10.4103/aian.AIAN_367_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313580PMC
June 2020

Unique skeletal manifestations in patients with Primrose syndrome.

Eur J Med Genet 2020 Aug 27;63(8):103967. Epub 2020 May 27.

Institute of Medical Genetics and Genomics, New Delhi, India. Electronic address:

Primrose syndrome (OMIM 259050) is a rare disorder characterised by macrocephaly with developmental delay, a recognisable facial phenotype, altered glucose metabolism, and other features such as sensorineural hearing loss, short stature, and calcification of the ear cartilage. It is caused by heterozygous variants in ZBTB20, a member of the POK family of transcription repressors. Recently, this gene was shown to have a role in skeletal development through its action on chondrocyte differentiation by repression of SOX9. We describe five unrelated patients with Primrose syndrome and distinct skeletal features including multiple Wormian bones, platybasia, bitemporal bossing, bathrocephaly, slender bones, epiphyseal and spondylar dysplasia. The radiological abnormalities of the skull and the epiphyseal dysplasia were the most consistent findings. This novel constellation of skeletal features expands the phenotypic spectrum of the disorder.
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http://dx.doi.org/10.1016/j.ejmg.2020.103967DOI Listing
August 2020

Mutation Spectrum of Dystrophinopathies in India: Implications for Therapy.

Indian J Pediatr 2020 Jul 2;87(7):495-504. Epub 2020 May 2.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110060, India.

Background: Dystrophinopathies are common X-linked recessive neuromuscular disorders caused by pathogenic variants in the dystrophin gene (DMD). Analysis of the mutational spectrum in the Indian patients would be useful for confirming the diagnosis, provide genetic counseling, offer reproductive options, and importantly to determine the eligibility for the mutation-specific therapies currently approved/or undergoing trials, such as skipping of specific exons or read-through of stop codon.

Methods: In 1660 patients diagnosed as Duchenne muscular dystrophy (DMD) /Becker muscular dystrophy (BMD) deletion- duplication analysis of all 79 exons was carried out using Multiplex ligation-dependent probe amplification (MLPA) technology. In 63 patients where no mutations were detected by MLPA, the nucleotide sequence of the DMD gene was determined by next gene sequencing. In seven cases where MLPA showed deletion of a single exon, and amplification of the specific exon was successful by polymerase chain reaction (PCR), Sanger sequencing of the concerned region was carried out to detect changes in the sequence.

Results: The mutation spectrum of 1660 patients with DMD/BMD was determined and 1188 (71.6%) patients were identified to have deletions or duplications of one or more exons. Of these, 1090 (65.7%) had true deletions of exons and 98 (5.9%) had duplications of exons. The most frequent change was the deletion of exon 45 (66/1090, 6.1%) and duplication of exon 2 (1/98, 11.2%). Sequencing of dystrophin gene was performed in 70 cases, and variants were identified in 68 patients (97.1% of those analyzed). Stop codon variants were observed in 34 (50%) patients, missense variants in 4 (5.9%), small deletions in 19 (27.9%), small insertions in 6 (8.8%) and slice site variants in 5 (7.4%) patients. Thirty one of 68 variants (45.5%) were novel.

Conclusions: The authors highlight the importance of identifying the type of mutation in patients with DMD. Based on the results, it is estimated that 681 (54.2%) of 1256 patients in this cohort would benefit from the currently ongoing mutation-specific therapies.
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http://dx.doi.org/10.1007/s12098-020-03286-zDOI Listing
July 2020

Robinow Syndrome and Brachydactyly: An Interplay of High-Throughput Sequencing and Deep Phenotyping in a Kindred.

Mol Syndromol 2020 Feb 17;11(1):43-49. Epub 2020 Jan 17.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

We report a family with a spectrum of short stature, craniofacial dysmorphism, and digital anomalies in a father and 2 daughters, with the youngest (proband) displaying a severe phenotype. Clinically, autosomal dominant Robinow syndrome (ADRS) was diagnosed. Whole-exome sequencing identified a heterozygous pathogenic variant in the father and his daughters. The phenotype of short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies related to haploinsufficiency has some facial and digital resemblance to ADRS. Although this variant segregated in the affected members, it failed to explain the severe phenotype of the proband. A reanalysis of the girl's raw data confirmed 2 disorders: a de novo likely pathogenic variant implicated in ADRS and the familial variant. A close interplay of high-throughput sequencing and deep phenotyping unraveled the complexities of the blended phenotype in the proband.
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http://dx.doi.org/10.1159/000505506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109436PMC
February 2020

Sialidosis type II: Expansion of phenotypic spectrum and identification of a common mutation in seven patients.

Mol Genet Metab Rep 2020 Mar 11;22:100561. Epub 2020 Jan 11.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi 110060, India.

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 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 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.
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http://dx.doi.org/10.1016/j.ymgmr.2019.100561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957780PMC
March 2020

Prenatal presentation of a rare genetic disorder: a clinical, autopsy and molecular correlation.

Autops Case Rep 2019 Oct-Dec;9(4):e2019124. Epub 2019 Sep 30.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital. New Delhi, India.

Walker Warburg syndrome (WWS) lies at the severe end of the spectrum of the congenital muscular dystrophies. WWS is a congenital disorder of the O-glycosylation that disrupts in the post-translation modification of dystroglycan proteins. WWS is characterized by the involvement of the central nervous system and rarely by multisystem involvement. Next-generation sequencing discovered that multiple genes are associated with this disorder. is the rarest cause of WWS. We describe a clinical-autopsy report of a molecularly- confirmed WWS case presenting with ventriculomegaly, agenesis of the corpus callosum with a novel phenotype of Dandy-Walker malformation and unilateral multi-cystic kidney. The whole-exome sequencing confirmed a homozygous variant (c.411C>A) in the gene with a premature termination codon. This case emphasizes the importance of detailed postnatal phenotyping through an autopsy in any pregnancy with antenatally identified malformations. Obstetricians, pediatricians as well as fetal medicine experts need to counsel the parents and focus on preserving the appropriate sample for genetic testing. WWS, though rare deserves testing especially in the presence of positive family history. Dandy-Walker malformation is a novel feature and expands the phenotypic spectrum.
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http://dx.doi.org/10.4322/acr.2019.124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771443PMC
September 2019

Clinical and Molecular Disease Spectrum and Outcomes in Patients with Infantile-Onset Pompe Disease.

J Pediatr 2020 01 9;216:44-50.e5. Epub 2019 Oct 9.

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

Objectives: To evaluate the clinical and molecular spectrum, and factors affecting clinical outcome of patients in India diagnosed with infantile-onset Pompe disease (IOPD).

Study Design: In this multicenter, cross-sectional study, we evaluated the records of 77 patients with IOPD to analyze their clinical course, outcomes, and factors influencing the outcomes.

Results: Of the 77 patients with IOPD, phenotype data were available in 59; 46 (78%) had the classic phenotype. Overall, 58 of 77 (75%) and 19 of 77 (25%) patients were symptomatic before and after age 6 months, respectively. Alpha-glucosidase gene variant analysis available for 48 patients (96 alleles) showed missense variants in 49 alleles. Cross-reactive immunologic material (CRIM) status could be determined or predicted in 44 of 48 patients. In total, 32 of 44 patients (72%) were CRIM-positive, and 12 of 44 patients (27%) were CRIM-negative. Thirty-nine cases received enzyme-replacement therapy (ERT), alglucosidase alfa, and 38 patients never received ERT. Median age at initiation of ERT was 6.5 months. Response to ERT was better in babies who had CRIM-positive, non-classic IOPD.

Conclusions: This study highlights the clinical spectrum of IOPD in India and provides an insight on various factors, such as undernutrition, feeding difficulties, and recurrent respiratory infection, as possible factors influencing clinical outcomes in these patients. The study also reiterates the importance of raising awareness among clinicians about the need for early diagnosis and timely treatment of IOPD.
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http://dx.doi.org/10.1016/j.jpeds.2019.08.058DOI Listing
January 2020

Is Molecular Diagnosis Necessary for Children with Duchenne Muscular Dystrophy?

Authors:
Ratna Dua Puri

Indian Pediatr 2019 07;56(7):549-550

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India

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July 2019

Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.

Am J Hum Genet 2019 08 27;105(2):384-394. Epub 2019 Jun 27.

Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698938PMC
August 2019

The fatal fetal tumor: a geneticist's perspective.

J Matern Fetal Neonatal Med 2021 Mar 3;34(6):1006-1008. Epub 2019 Jun 3.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

Epignathus is an extremely rare oral teratoma which leads to high mortality in the early neonatal period. Various theories have been put forward for the genesis of such a tumor, though none is completely convincing. A genetic basis is not well established for the tumor. Microdeletions/duplications, as well as single gene disorders, have been known to cause epignathus, all with additional malformations. Evidence of single gene involvement in an isolated epignathus is lacking. We present a case of a 19-week-fetus with oro-pharyngeal teratoma detected on the level II ultrasound. The couple was counseled regarding the grave prognosis of the fetal condition following which they opted for termination of pregnancy and fetal autopsy. The autopsy revealed fetus-like body attached to the tumor. Genetic testing including a whole genome microarray did not reveal any significant variant. An explanation for the fetus-like body maybe a common origin of the teratoma and the additional fetus-like bodies due to an erroneous process of early embryonic development. Another possibility is of an acardiacus acranius twin masquerading as a fetus-like body. Thus, we conclude that in the absence of an associated malformation, an epignathus is unlikely to have a genetic etiology. This study highlights the importance of performing a fetal autopsy as a part of deep phenotyping to ascertain the etiology, as it identified additional fetal-like body which was not detected on the antenatal ultrasound.
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http://dx.doi.org/10.1080/14767058.2019.1622671DOI Listing
March 2021

Mutation-Proved Clouston Syndrome in a Large Indian Family with a Variant Phenotype.

Indian J Dermatol 2019 Mar-Apr;64(2):143-145

Department of Medical Genetics, Institute of Genomics and Medical Genetics, Sir Ganga Ram Hospital, New Delhi, India.

Hereditary ectodermal dysplasias, a group of disorders affecting skin, hair, nails, and teeth, consist of two main clinical forms - hypohidrotic and hidrotic. Clouston syndrome is a hidrotic ectodermal dysplasia characterized by a triad of generalized hypotrichosis, palmoplantar hyperkeratosis, and nail dystrophy. This paper reports a large Indian family with Clouston syndrome but with the absence of palmoplantar keratoderma, one of the features of the typical triad, thus representing phenotypic heterogeneity, in spite of the presence of a common known mutation in GJB6 gene (p.Gly11Arg).
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http://dx.doi.org/10.4103/ijd.IJD_510_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440177PMC
April 2019

Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.

Genet Med 2019 09 7;21(9):2043-2058. Epub 2019 Mar 7.

Institute of Medical Genetics, University of Zurich, Schlieren, Zurich, Switzerland.

Purpose: Microcephaly is a sign of many genetic conditions but has been rarely systematically evaluated. We therefore comprehensively studied the clinical and genetic landscape of an unselected cohort of patients with microcephaly.

Methods: We performed clinical assessment, high-resolution chromosomal microarray analysis, exome sequencing, and functional studies in 62 patients (58% with primary microcephaly [PM], 27% with secondary microcephaly [SM], and 15% of unknown onset).

Results: We found severity of developmental delay/intellectual disability correlating with severity of microcephaly in PM, but not SM. We detected causative variants in 48.4% of patients and found divergent inheritance and variant pattern for PM (mainly recessive and likely gene-disrupting [LGD]) versus SM (all dominant de novo and evenly LGD or missense). While centrosome-related pathways were solely identified in PM, transcriptional regulation was the most frequently affected pathway in both SM and PM. Unexpectedly, we found causative variants in different mitochondria-related genes accounting for ~5% of patients, which emphasizes their role even in syndromic PM. Additionally, we delineated novel candidate genes involved in centrosome-related pathway (SPAG5, TEDC1), Wnt signaling (VPS26A, ZNRF3), and RNA trafficking (DDX1).

Conclusion: Our findings enable improved evaluation and genetic counseling of PM and SM patients and further elucidate microcephaly pathways.
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http://dx.doi.org/10.1038/s41436-019-0464-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752480PMC
September 2019

Extending the Phenotype and Identification of a Novel Candidate Gene for Immunodeficiency in 5q11 Microdeletion Syndrome.

Mol Syndromol 2019 Jan 14;9(6):312-318. Epub 2018 Dec 14.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

Array CGH has led to the delineation of innumerable microdeletion syndromes. We present a patient with a 7-Mb deletion at 5q11.2 with previously unreported features, such as immunodeficiency, asymmetry of hands and feet, joint laxity, and agenesis of corpus callosum. The clinical features of this patient are compared with 13 patients reported previously. A common critical region (CCR) of 1.4 Mb (54-55.4 Mb) is defined in all cases including the present one. Of the 14 genes present in CCR, is proposed to be the candidate gene for immunodeficiency observed in some of these patients. encodes gp130, a signal transduction protein for various interleukins and cytokines. It is involved in the generation of both T and B lymphocytes as well as the production of acute-phase reactants. Microdeletion 5q11.2 should be considered as a recognisable syndrome based on the common phenotype and the novel features described.
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http://dx.doi.org/10.1159/000494995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381899PMC
January 2019

The first case of antenatal presentation in COG8-congenital disorder of glycosylation with a novel splice site mutation and an extended phenotype.

Am J Med Genet A 2019 03 28;179(3):480-485. Epub 2019 Jan 28.

Institute of Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

Congenital disorders of glycosylation (CDG) are an extremely rapidly growing and phenotypically versatile group of disorders. Conserved oligomeric Golgi (COG) complexes are hetero-octameric proteins involved in retrograde trafficking within the Golgi. Seven of its eight subunits have a causal role in CDG. To date, only three cases of COG8-CDG have been published but none in the antenatal period. We present the first case of antenatally diagnosed COG8-CDG with facial dysmorphism and additional features such as Dandy-Walker malformation and arthrogryposis multiplex congenita, thus expanding the phenotype of this rare disorder. Trio whole exome sequencing revealed a novel homozygous variant in COG8, which creates a new splice site in exon 5 and protein truncation after 12 amino acids downstream to the newly generated splice site. As the mutations of the previous three patients were also identified in exon 5, it is likely to be a potential mutational hotspot in COG8. An association between antenatally increased nuchal translucency and COG8-CDG is also established, which would alert clinicians to its diagnosis early in gestation. It remains to be seen if this observation can be extended to other COG-CDGs.
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http://dx.doi.org/10.1002/ajmg.a.61030DOI Listing
March 2019

Urea cycle disorders in India: clinical course, biochemical and genetic investigations, and prenatal testing.

Orphanet J Rare Dis 2018 10 1;13(1):174. Epub 2018 Oct 1.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

Background: Urea cycle disorders (UCDs) are inherited metabolic disorders that present with hyperammonemia, and cause significant mortality and morbidity in infants and children. These disorders are not well reported in the Indian population, due to lack of a thorough study of the clinical and molecular profile.

Results: We present data from two major metabolic centres in India, including 123 cases of various UCDs. The majority of them (72/123, 58%) presented in the neonatal period (before 30 days of age) with 88% on or before day 7 of life (classical presentation), and had a high mortality (64/72, 88%). Citrullinemia type 1 was the most common UCD, observed in 61/123 patients. Ornithine transcarbamylase (OTC) deficiency was the next most common, seen in 24 cases. Argininosuccinic aciduria was diagnosed in 20 cases. Deficiencies of arginase, N-acetylglutamate synthase, carbamoyl phosphate synthetase, citrin, and lysinuric protein intolerance were also observed. Molecular genetic analysis revealed two common ASS1 mutations: c.470G > A (p.Arg157His) and c.1168G > A (p.Gly390Arg) (36 of 55 tested patients). In addition, few recurrent point mutations in ASL gene, and a deletion of the whole OTC gene were also noted. A total of 24 novel mutations were observed in the various genes studied. We observed a poor clinical outcome with an overall all time mortality of 63% (70/110 cases with a known follow-up), and disability in 70% (28/40) among the survivors. Prenatal diagnosis was performed in 30 pregnancies in 25 families, including one pre-implantation genetic diagnosis.

Conclusions: We report the occurrence of UCDs in India and the spectrum that may be different from the rest of the world. Citrullinemia type 1 was the most common UCD observed in the cohort. Increasing awareness amongst clinicians will improve outcomes through early diagnosis and timely treatment. Genetic diagnosis in the proband will enable prenatal/pre-implantation diagnosis in subsequent pregnancies.
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http://dx.doi.org/10.1186/s13023-018-0908-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167905PMC
October 2018

Fetal valproate syndrome as a phenocopy of Kleefstra syndrome.

Birth Defects Res 2018 09 27;110(15):1205-1209. Epub 2018 Aug 27.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

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http://dx.doi.org/10.1002/bdr2.1379DOI Listing
September 2018

Clinical heterogeneity and molecular profile of triple A syndrome: a study of seven cases.

J Pediatr Endocrinol Metab 2018 Jul;31(7):799-807

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

Background Triple A syndrome is characterized by achalasia, alacrima and adrenal insufficiency with neurological manifestations occurring later in the course of the disease. It occurs due to biallelic mutations in the AAAS gene which codes for the nuclear pore protein ALADIN. A number of other features have been reported over time in this heterogeneous and multisystemic disorder. Unlike other autosomal recessive disorders, triple A syndrome patients show a wide phenotypic variability both among different patients and family members harboring the same mutation(s). A gene-environment interaction has been thought to be a plausible cause. Methods A retrospective analysis of six families and seven patients presenting with triple A syndrome was carried out. The clinical, biochemical and molecular testing data were collected and correlated. The results of treatment and follow-up and genetic counseling of the families were obtained wherever feasible. Results Our cohort consisted mostly of children and displayed a wide phenotypic variability in the presenting symptoms ranging from hypoglycemic seizures at the severe end of the spectrum to insidious hyperpigmentation and delayed development. Neurological and autonomic features were present in a few patients, suggesting requirement of prolonged follow-up for these patients. A significant gap between the onset of symptoms and confirmatory diagnosis was noted, suggesting that a high index of suspicion is required for diagnosing this disorder. Sudden unexplained death was observed in siblings, and early diagnosis and treatment could help in preventing early mortality and improving the quality of life for these patients. Conclusion High index of suspicion for a potentially treatable disorder allows early appropriate intervention.
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http://dx.doi.org/10.1515/jpem-2018-0023DOI Listing
July 2018

Diagnosis and Management of Gaucher Disease in India - Consensus Guidelines of the Gaucher Disease Task Force of the Society for Indian Academy of Medical Genetics and the Indian Academy of Pediatrics.

Indian Pediatr 2018 02;55(2):143-153

Metabolic Liver and Lysosomal Disease Program, Yale University School of Medicine, New Haven, USA.

Justification: Gaucher disease (GD) is amongst the most frequently occurring lysosomal storage disorder in all ethnicities. The clinical manifestations and natural history of GD is highly heterogeneous with extreme geographic and ethnic variations. The literature on GD has paucity of information and optimal management guidelines for Indian patients.

Process: Gaucher Disease Task Force was formed under the auspices of the Society for Indian Academy of Medical Genetics. Invited experts from various specialties formulated guidelines for the management of patients with GD. A writing committee was formed and the draft guidelines were circulated by email to all members for comments and inputs. The guidelines were finalized in December 2016 at the annual meeting of the Indian Academy of Medical Genetics.

Objectives: These guidelines are intended to serve as a standard framework for treating physicians and the health care systems for optimal management of Gaucher disease in India and to define unique needs of this patient population.

Recommendations: Manifestations of GD are protean and a high index of suspicion is essential for timely diagnosis. Patients frequently experience diagnostic delays during which severe irreversible complications occur. Leucocyte acid b-glucosidase activity is mandatory for establishing the diagnosis of Gaucher disease; molecular testing can help identify patients at risk of neuronopathic disease. Enzyme replacement therapy for type 1 and type 3 Gaucher disease is the standard of care. Best outcomes are achieved by early initiation of therapy before onset of irreversible complications. However, in setting of progressive neurological symptoms such as seizures and or/ neuroregression, ERT is not recommended, as it cannot cross the blood brain barrier. The recommendations herein are for diagnosis, for initiation of therapy, therapeutic goals, monitoring and follow up of patients. We highlight that prevention of recurrence of the disease through genetic counseling and prenatal diagnosis is essential in India, due to uniformly severe phenotypes encountered in our population.
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February 2018

Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants.

J Hepatol 2017 12 19;67(6):1253-1264. Epub 2017 Jul 19.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany. Electronic address:

Background & Aims: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity.

Methods: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling.

Results: In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect.

Conclusions: In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype.

Lay Summary: FIC1, BSEP, and MDR3 represent hepatobiliary transport proteins essential for bile formation. Genetic variants in these transporters underlie a broad spectrum of cholestatic liver diseases. To confirm a genetic contribution to the patients' phenotypes, gene sequencing of these three major cholestasis-related genes was performed in 427 patients and revealed 154 different variants of which 25 have not been previously reported in a database. In patients without a disease-causing mutation, common genetic variants were detected in a high number of cases, indicating that these common variants may contribute to cholestasis development.
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http://dx.doi.org/10.1016/j.jhep.2017.07.004DOI Listing
December 2017