Publications by authors named "Shubha Phadke"

244 Publications

Deciphering the molecular landscape of microcephaly in 87 Indian families by exome sequencing.

Eur J Med Genet 2022 May 11:104520. Epub 2022 May 11.

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

Microcephaly is a frequent feature of neurodevelopmental disorders (NDDs). Our study presents the heterogeneous spectrum of genetic disorders in patients with microcephaly either in isolated form or in association with other neurological and extra-neural abnormalities. We present data of 91 patients from 87 unrelated families referred to our clinic during 2016-2020 and provide a comprehensive clinical and genetic landscape in the studied cohort. Molecular diagnosis using exome sequencing was made in 45 families giving a yield of 51.7%. In 9 additional families probable causative variants were detected. We identified disease causing variations in 49 genes that are involved in different functional pathways Among these, 36 had an autosomal recessive pattern, 8 had an autosomal dominant pattern (all inherited de novo), and 5 had an X-linked pattern. In 41 probands where sequence variations in autosomal recessive genes were identified 31 were homozygotes (including 16 from non-consanguineous families). The study added 28 novel pathogenic/likely pathogenic variations. The study also calls attention to phenotypic variability and expansion in spectrum as well as uncovers genes where microcephaly is not reported previously or is a rare finding. We here report phenotypes associated with the genes for ultra-rare NDDs with microcephaly namely ATRIP, MINPP1, PNPLA8, AIMP2, ANKLE2, NCAPD2 and TRIT1.
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http://dx.doi.org/10.1016/j.ejmg.2022.104520DOI Listing
May 2022

COASY related pontocerebellar hypoplasia type 12: A common Indian mutation with expansion of the phenotypic spectrum.

Am J Med Genet A 2022 May 2. Epub 2022 May 2.

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

Pontocerebellar hypoplasia (PCH) type 12 is a rare, perinatal lethal neurodegenerative genetic disorder caused by biallelic mutations in the COASY gene. Herein, we describe the clinical and neuroradiological profile of nine affected fetuses/neonates from five families identified with a common COASY: c.1486-3C>G biallelic variant. Four of the five families were identified after data reanalysis of unresolved, severe PCH like phenotype and the fifth family through collaboration. The common antenatal phenotype was cerebellar hypoplasia. Microcephaly, arthrogryposis, and intrauterine growth restriction were the shared postnatal findings. The neurological manifestations included seizures, poor sucking, and spasticity. Novel findings of corpus callosum agenesis, simplified gyral pattern, normal sized pons, optic neuropathy, and a small thorax are reported in this series. The allele frequency of the COASY: c.1486-3C>G variant was 0.62% in the available Asian Indian database. We describe this as a possible common Indian origin variant. To the best of our knowledge, this is the largest PCH12 series reported.
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http://dx.doi.org/10.1002/ajmg.a.62768DOI Listing
May 2022

Clinical, radiological and molecular studies in 24 individuals with Dyggve-Melchior-Clausen dysplasia and Smith-McCort dysplasia from India.

J Med Genet 2022 Apr 27. Epub 2022 Apr 27.

Department of Clinical Genetics, Centre for Human Genetics, Bangalore, Karnataka, India.

Background: Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in SMC differentiates the two. DMC and SMC1 are allelic and caused by homozygous or compound heterozygous variants in . SMC2 is caused by variations in . Both and are important in intravesicular transport and function in the Golgi apparatus.

Methods: Detailed clinical phenotyping and skeletal radiography followed by molecular testing were performed in all affected individuals. Next-generation sequencing and Sanger sequencing were used to confirm and variants. Sanger sequencing of familial variants was done in all parents.

Results: 24 affected individuals from seven centres are described. 18 had DMC and 6 had SMC2. Parental consanguinity was present in 15 of 19 (79%). Height <3 SD and gait abnormalities were seen in 20 and 14 individuals, respectively. The characteristic radiological findings of lacy iliac crests and double-humped vertebral bodies were seen in 96% and 88% of the affected. Radiological findings became attenuated with age. 23 individuals harboured biallelic variants in either or . Fourteen different variants were identified, out of which 10 were novel. The most frequently occurring variants in this group were c.719 C>A (3), c.1488_1489del (2), c.1484dup (2) and c.1563+2T>C (2) in DYM and c.400C>T (2) and c.186del (2) in . The majority of these have not been reported previously.

Conclusion: This large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare 'Golgipathies'.
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http://dx.doi.org/10.1136/jmedgenet-2021-108098DOI Listing
April 2022

How Experts Make a Call: Copy Number Variation Analysis in Unusual/Rare Case Scenarios.

Neurol India 2022 Jan-Feb;70(1):148-154

Department of Pediatrics, Genetic Metabolic Unit, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Background: Cytogenetic microarray (CMA) has brought a revolution in the field of cytogenetics by improving resolution by 500 times that of traditional karyotyping. Analysis and interpretation of whole genome copy number variations (CNVs) is quite a challenging task for clinicians. Some software packages and databases are available which are based on algorithm. However, there is no clear rule to decide the pathogenicity.

Objective: To formulate a step-wise approach to evaluate the interpretation of a CNV and to help the clinicians to interpret the CNV reported by a laboratory with help of four representative cases of different phenotypes.

Methods And Material: CMA was done using AffymetrixCytoscan 750K array in four cases from different families. Analysis was done based on the proposed approach.

Results: The prediction of the effect of these CNVs depends on multiple factors and can change over time as the databases are expanded. CMA in four cases from different families revealed, a rare co-occurrence of 22q13.3 duplication and 22q13.3 deletion in a proband, a deletion along with mosaicism on 10q21.2 and 10p15.3, respectively, in the second case. Third case resulted in one variant of unknown significance of 1.2 Kb deletion on 10q11.22 and the fourth case showed a benign CNV. All CNVs were analyzed based on the proposed approach and helped in subsequent management and counselling of the families. The results indicate the effectiveness of a principled, feature-based, statistical framework for uncharacterized CNV interpretation, which future studies can expand upon to construct more reliable classifiers.
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http://dx.doi.org/10.4103/0028-3886.338651DOI Listing
March 2022

Autosomal recessive spinocerebellar ataxia-20 due to a novel SNX14 variant in an Indian girl.

Am J Med Genet A 2022 Jun 23;188(6):1909-1914. Epub 2022 Feb 23.

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

Autosomal recessive spinocerebellar ataxia-20 is a rare disorder having distinctive coarse facies in addition to intellectual disability and cerebellar ataxia, with less than 35 cases reported worldwide. It is caused by biallelic variants in the SNX14 gene and is classified under the group of autophagy disorders. We report a 9-year-old girl who presented with classic clinical features of autosomal recessive spinocerebellar ataxia-20 and cerebellar atrophy on magnetic resonance imaging of brain. Trio exome sequencing with Sanger confirmation revealed a novel splice site variant, c.140 + 3A > T in the SNX14 gene. The variant pathogenicity established by mRNA expression study showed a significant reduction in the expression levels of SNX14 gene in proband and her parents on comparison to the control. The electron microscopy of the skin fibroblasts of proband depicted numerous cytoplasmic vacuoles with variable degrees of dense staining material. In addition, we have briefly reviewed and compared the phenotypic features of published cases of autosomal recessive spinocerebellar ataxia-20 in the literature. Coarse facies, intellectual disability with severe speech delay, hypotonia, and cerebellar atrophy were universal findings in the published cases. This is the second reported case from the Indian subcontinent.
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http://dx.doi.org/10.1002/ajmg.a.62701DOI Listing
June 2022

Congenital Hyperinsulinemia of Infancy: Role of Molecular Testing in Management and Genetic Counseling.

Indian J Pediatr 2022 Apr 19;89(4):395-398. Epub 2022 Feb 19.

Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226014, India.

Congenital hyperinsulinemia (CHI) is a genetically and clinically heterogenous disorder. In addition to the standard care of management of the proband, genetic counseling regarding the risk of recurrence in the future siblings is an important part in the management of the disorder. The counseling needs identification of accurate etiology and is challenging due to the complexity of the molecular mechanisms of CHI. This case highlights the importance of molecular testing which not only helped in planning the management of the proband with CHI but also helped in providing genetic counseling for which the family had consulted the medical genetics department.
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http://dx.doi.org/10.1007/s12098-021-04014-xDOI Listing
April 2022

Genotype-phenotype spectrum of 130 unrelated Indian families with Mucopolysaccharidosis type II.

Eur J Med Genet 2022 Mar 8;65(3):104447. Epub 2022 Feb 8.

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

MPS II is an X linked recessive lysosomal storage disorder with multi-system involvement and marked molecular heterogeneity. In this study, we explored the clinical and molecular spectrum of 144 Indian patients with MPS II from 130 unrelated families. Clinical information was collected on a predesigned clinical proforma. Sanger method was employed to sequence all the exons and exon/intron boundaries of the IDS gene. In cases where causative variation was not detected by Sanger sequencing, MLPA and RFLP were performed to identify large deletions/duplications and complex rearrangements. Cytogenetic microarray was done in one patient to see the breakpoints and extent of deletion. In one patient with no detectable likely pathogenic or pathogenic variation, whole-genome sequencing was also performed. Novel variants were systematically assessed by in silico prediction software and protein modelling. The pathogenicity of variants was established based on ACMG criteria. An attempt was also made to establish a genotype-phenotype correlation. Positive family history was present in 31% (41/130) of patients. Developmental delay and intellectual disability were the main reasons for referral. Macrocephaly, coarse facies and dysostosis were present in almost all patients. Hepatosplenomegaly, joint contractures and short stature were the characteristic features, seen in 87% (101/116), 67.8% (74/109) and 41.4% (41/99) patients respectively. Attenuated phenotype was seen in 32.6% (47/144) patients, while severe phenotype was seen in 63% (91/144) patients. The detection rate for likely pathogenic or pathogenic variants in our cohort is 95.5% (107/112) by Sanger sequencing, MLPA and RFLP. We also found two variants of unknown significance, one each by Sanger sequencing and WGS. Total of 71 variants were identified by Sanger sequencing and 29 of these variants were found to be novel. Amongst the novel variants, there was a considerable proportion (51%) of frameshift variants (15/29). Almost half of the causative variants were located in exon 3,8 and 9. A significant genotype-phenotype correlation was also noted for both known and novel variants. This information about the genotype spectrum and phenotype will be helpful for diagnostic and prognostic purposes.
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http://dx.doi.org/10.1016/j.ejmg.2022.104447DOI Listing
March 2022

Monosomy 1p36: Report of a cohort of 13 Asian Indian patients.

Am J Med Genet A 2022 04 6;188(4):1317-1322. Epub 2022 Jan 6.

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

Monosomy 1p36 is one of the common microdeletion syndromes with a recognizable facial phenotype. Failure to thrive, developmental delay, congenital heart disease, and other abnormalities are common in these patients. This is the first study on Asian Indian patients with monosomy 1p36, documenting the phenotypic characteristics of 13 patients, indicating phenotypic similarities in a diverse population and broadening the clinical spectrum.
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http://dx.doi.org/10.1002/ajmg.a.62630DOI Listing
April 2022

Kallmann Syndrome and X-linked Ichthyosis Caused by Translocation Between Chromosomes X and Y: A Case Report.

J Reprod Infertil 2021 Oct-Dec;22(4):302-306

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

Background: Xp22.3 region is characterized by low frequency of interspersed repeats and low GC content. Several clinically important genes including ANOS1 (KAL1) reside in this region. This gene was first identified due to translocation between chromosomes X and Y in a patient with Kallmann syndrome.

Case Presentation: A 20 year old male presented with complaints of delayed secondary sexual characteristics, impaired sense of smell, and poor scholastic performance. On examination, he had short stature (151 ; <3rd centile). His sexual maturity corresponded to Tanner stage 3. Stretched penile length was 3.6 (<3rd centile). Right testis was undescended with low left testicular volume (12 ). There was mild ichthyosis over abdomen and back. He had hyposmia, hoarse voice, and synkinesia. Investigations were suggestive of hypogonadotrophic hypogonadism. Karyotype revealed an extra chromosomal material on p arm of chromosome X (46,Xp+,Y). On cytogenetic microarray, deletion of 8.3 on Xp22.33 region and duplication of 12.8 on Yq11.22 region were identified. The breakpoint on X chromosome resulted in deletion of exons 7-14 of ANOS1 gene and complete STS, NLGN4X, ARSL (ARSE), SHOX, and VCX genes.

Conclusion: Patients diagnosed with Kallmann syndrome should receive careful clinical evaluation to detect presence of a contiguous gene syndrome.
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http://dx.doi.org/10.18502/jri.v22i4.7657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669406PMC
August 2020

Ectodysplasin pathogenic variants affecting the furin-cleavage site and unusual clinical features define X-linked hypohidrotic ectodermal dysplasia in India.

Am J Med Genet A 2022 03 4;188(3):788-805. Epub 2021 Dec 4.

Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.

Hypohidrotic ectodermal dysplasia (HED) is a rare genetic disorder caused by mutational inactivation of a developmental pathway responsible for generation of tissues of ectodermal origin. The X-linked form accounts for the majority of HED cases and is caused by Ectodysplasin (EDA) pathogenic variants. We performed a combined analysis of 29 X-linked hypohidrotic ectodermal dysplasia (XLHED) families (including 12 from our previous studies). In addition to the classical triad of symptoms including loss (or reduction) of ectodermal structures, such as hair, teeth, and sweat glands, we detected additional HED-related clinical features including facial dysmorphism and hyperpigmentation in several patients. Interestingly, global developmental delay was identified as an unusual clinical symptom in many patients. More importantly, we identified 22 causal pathogenic variants that included 15 missense, four small in-dels, and one nonsense, splice site, and large deletion each. Interestingly, we detected 12 unique (India-specific) pathogenic variants. Of the 29 XLHED families analyzed, 11 (38%) harbored pathogenic variant localized to the furin cleavage site. A comparison with HGMD revealed significant differences in the frequency of missense pathogenic variants; involvement of specific exons and/or protein domains and transition/transversion ratios. A significantly higher proportion of missense pathogenic variants (33%) localized to the EDA furin cleavage when compared to HGMD (7%), of which p.R155C, p.R156C, and p.R156H were detected in three families each. Therefore, the first comprehensive analysis of XLHED from India has revealed several unique features including unusual clinical symptoms and high frequency of furin cleavage site pathogenic variants.
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http://dx.doi.org/10.1002/ajmg.a.62579DOI Listing
March 2022

Variable neurological phenotypes of homocystinuria caused by biallelic methylenetetrahydrofolate reductase variants.

Clin Dysmorphol 2022 Apr;31(2):59-65

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

Inherited methylenetetrahydrofolate reductase (MTHFR) deficiency is associated with a wide spectrum of disorders including homocystinuria. This study aims to describe the neurological phenotypes and molecular profiles of patients with homocystinuria caused by biallelic variants in MTHFR. We report six subjects with MTHFR deficiency who presented with variable neurological phenotypes which could be viewed as a continuous spectrum. Fatal infantile encephalopathy was observed in one family, whereas another patient presented at 27 years with acute leukoencephalopathy and recovered within 3 months. Intermediate forms presenting as complicated hereditary spastic paraparesis of variable severity were observed in four subjects. Clinical and molecular information of the 207 cases reported in literature were also retrieved and analyzed. We categorized all subjects into three categories - severe, intermediate and mild forms according to the clinical presentation. In addition, a total of 286 disease-causing variations reported to date were analyzed. These included seven disease-causing variants reported in this study of which one is novel. Some genotype-phenotype correlation could be seen which corroborated with previous observations. However, inter- and intrafamilial variability was also noted. Treatment with betaine, B12 and folic acid was started in four subjects with variable outcomes.
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http://dx.doi.org/10.1097/MCD.0000000000000407DOI Listing
April 2022

Pseudoachondroplasia: Phenotype and genotype in 11 Indian patients.

Am J Med Genet A 2022 03 9;188(3):751-759. Epub 2021 Nov 9.

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

Pseudoachondroplasia (PSACH) is an autosomal dominant disorder characterized by rhizomelic short-limbed skeletal dysplasia. The primary clinical and radiographic features include disproportionate dwarfism, joint laxity and hyperextensibility, exaggerated lumbar lordosis, and late ossification of the epiphyses. Identification of disease-causing variants in heterozygous state in COMP establishes the molecular diagnosis of PSACH. We examined 11 families with clinical features suggestive of PSACH. In nine families, we used Sanger sequencing of exons 8-19 of COMP (NM_000095.2) and in two families exome sequencing was used for confirming the diagnosis. We identified 10 de novo variants, including five known variants (c.925G>A, c.976G>A, c.1201G>T, c.1417_1419del, and c.1511G>A) and five variants (c.874T>C, c.1201G>C, c.1309G>A, c.1416_1421delCGACAA, and c.1445A>T) which are not reported outside Indian ethnicity. We hereby report the largest series of individuals with molecular diagnosis of PSACH from India and reiterate the well-known genotype-phenotype corelation in PSACH.
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http://dx.doi.org/10.1002/ajmg.a.62566DOI Listing
March 2022

Novel pathogenic variants in an Indian cohort with epidermolysis bullosa: Expanding the genotypic spectrum.

Eur J Med Genet 2021 Dec 29;64(12):104345. Epub 2021 Sep 29.

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

Background: Epidermolysis bullosa (EB) is a genodermatosis characterized by skin fragility and blisters with variable severity. Patients with Dystrophic EB (DEB) or Junctional EB (JEB) mainly present to clinic due to greater functional impairment. Pathogenic sequence variations in COL7A1 are implicated in DEB.

Objective: We have tried to decipher the molecular spectrum and genotype phenotype correlation of 21 Indian patients with EB.

Methods: Next generation sequencing (NGS) was performed to determine the pathogenic variants. Sanger sequencing was also done for validation of the variants in eleven individuals.

Results: Pathogenic variants were detected in 20 individuals (diagnostic yield of 95%). Majority of them (90%) had sequence variation in COL7A1 while two had pathogenic variants in ITGB4 and KRT14 respectively. Out of the 18 patients confirmed to have DEB, 3 had Dominant DEB (DDEB) whereas 15 patients had Recessive DEB (RDEB). Amongst 23 sequence variations identified, 12 were found to be novel (3 were missense, 5 were premature termination codon variants while 4 were splice-site changes).

Conclusion: Genotype phenotype correlation was noted with milder manifestations in those with dominant inheritance types. Exact molecular diagnosis can be ascertained by NGS in majority of cases.
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http://dx.doi.org/10.1016/j.ejmg.2021.104345DOI Listing
December 2021

Molecular analysis of severe hemophilia B in Indian families: Identification of mutational hotspot and novel variants.

Int J Lab Hematol 2022 Feb 29;44(1):186-192. Epub 2021 Sep 29.

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

Introduction: Hemophilia B is associated with molecular heterogeneity, with more than 1200 unique variants in the F9 gene. We hereby describe the mutational spectrum of severe hemophilia B patients presenting in a tertiary-care center in India.

Method: DNA was extracted from peripheral blood samples of 35 diagnosed severe hemophilia B patients belonging to 32 families, and were subjected to Sanger sequencing. Determination of the effect of novel variants on the protein structure and correlation between genotype and phenotype was attempted using in-silico tools.

Results: Twenty-seven different mutations were detected in 30 probands, including 20 known and 7 novel variants. Also, we found one suspected case of whole gene deletion. The serine peptidase domain harbored most of the variants (48.1%). Inhibitory antibodies were found in two patients.

Conclusions: This study provides a comprehensive mutational spectrum and mutation screening strategy by Sanger sequencing of F9 gene in severe hemophilia B patients, in a resource-constraint setting.
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http://dx.doi.org/10.1111/ijlh.13715DOI Listing
February 2022

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

Hum Mutat 2021 10 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

Homozygous Missense Variation in Causes Prenatal-Onset Severe Neurodegeneration.

Mol Syndromol 2021 Jun 19;12(3):174-178. Epub 2021 Mar 19.

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.

The patatin-like protein family plays an important role in various biological functions including lipid homeostasis, cellular growth, and signaling. Conserved across species, the patatin domain is shared by all 9 members of the PNPLA family without redundancy in the coding sequences. The defective function of , , and are known to cause mitochondrial-related neurodegeneration. Recently, has been associated with mitochondrial myopathy and poor weight gain with lactic acidosis in 3 unrelated families. Using whole-exome sequencing, we identified a homozygous novel missense variation c.1874A>G in the patatin domain of . The patient had prenatal-onset severe and progressive neurodegeneration with mortality in infancy.
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http://dx.doi.org/10.1159/000513524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215966PMC
June 2021

Partial Trisomy of Chromosome 8q and Partial Monosomy of Chromosome 6p with Robinow Syndrome-Like Phenotype.

Indian J Pediatr 2021 08 22;88(8):813-818. Epub 2021 May 22.

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Uttar Pradesh, 226014, Lucknow, India.

Genetic disorders can be monogenic or chromosomal. Deletions, duplications, and cryptic imbalances due to rearrangements of the telomeres are seen in a number of patients with psychomotor and language delay. Here, the authors report a case of 1-y-old boy born to nonconsanguineous couple who was evaluated for global developmental delay with phenotypic resemblance to a monogenic disorder namely Robinow syndrome. Cytogenetic microarray showed a double segment imbalance involving chromosome 6p25.3p25.2 and chromosome 8q23.3q24.3. Robinow syndrome also known as fetal face syndrome is a rare disorder with characteristic facial phenotype resembling fetal face with macrocephaly, low-set ears, broad great toes, gum hypertrophy, micropenis, and rhizomelia. Facial features include hypertelorism, wide mouth and short nose with upturned tip. It can have dominant or recessive mode of inheritance. The chromosomal abnormality in this case may provide clue to some novel gene for Robinow syndrome etiology.
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http://dx.doi.org/10.1007/s12098-021-03763-zDOI 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

Genetic heterogeneity of disorders with overgrowth and intellectual disability: Experience from a center in North India.

Am J Med Genet A 2021 08 4;185(8):2345-2355. Epub 2021 May 4.

Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.

Overgrowth, defined as height and/or OFC ≥ +2SD, characterizes a subset of patients with syndromic intellectual disability (ID). Many of the disorders with overgrowth and ID (OGID) are rare and the full phenotypic and genotypic spectra have not been unraveled. This study was undertaken to characterize the phenotypic and genotypic profile of patients with OGID. Patients with OGID were ascertained from the cohort of patients who underwent cytogenetic microarray (CMA) and/or exome sequencing (ES) at our center over a period of 6 years. Thirty-one subjects (six females) formed the study group with ages between 3.5 months and 13 years. CMA identified pathogenic deletions in two patients. In another 11 patients, a disease causing variant was detected by ES. The spectrum of disorders encompassed aberrations in genes involved in the two main pathways associated with OGID. These were genes involved in epigenetic regulation like NSD1, NFIX, FOXP1, and those in the PI3K-AKT pathway like PTEN, AKT3, TSC2, PPP2R5D. Five novel pathogenic variants were added by this study. NSD1-related Sotos syndrome was the most common disorder, seen in five patients. A causative variant was identified in 61.5% of patients who underwent only ES compared to the low yield of 11.1% in the CMA group. The molecular etiology could be confirmed in 13 subjects with OGID giving a diagnostic yield of 42%. The major burden was formed by autosomal dominant monogenic disorders. Hence, ES maybe a better first-tier genomic test rather than CMA in OGID.
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http://dx.doi.org/10.1002/ajmg.a.62241DOI Listing
August 2021

Clinical and Mutation Spectra of Cockayne Syndrome in India.

Neurol India 2021 Mar-Apr;69(2):362-366

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute, Lucknow, Uttar Pradesh, India.

Background: Cockayne syndrome is an autosomal recessive disorder caused by biallelic mutations in ERCC6 or ERCC8 genes.

Aims: To study the clinical and mutation spectrum of Cockayne syndrome.

Setting And Design: Medical Genetics Outpatient Department of Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow. This was a prospective study from 2007 to 2015.

Materials And Methods: Clinical details were recorded, and sequencing of ERCC6 and ERCC8 were performed.

Results And Conclusions: Of the six families, one family had a homozygous mutation in ERCC8 and the other five families had homozygous mutations in ERCC6. Novel variants in ERCC6 were identified in four families. Phenotypic features may vary from severe to mild, and a strong clinical suspicion is needed for diagnosis during infancy or early childhood. Hence, molecular diagnosis is needed for confirmation of diagnosis in a child with a suspicion of Cockayne syndrome. Prenatal diagnosis can be provided only if molecular diagnosis is established in the proband.
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http://dx.doi.org/10.4103/0028-3886.314579DOI Listing
June 2021

Spectrum of Systemic Auto-Inflammatory Diseases in India: A Multi-Centric Experience.

Front Immunol 2021 19;12:630691. Epub 2021 Mar 19.

Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation. To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India. Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed. Data on 107 patients with SAID were collated-of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficiency of Adenosine Deaminase 2 ( (six patients; five families); STING-associated vasculopathy infantile-onset (SAVI) (three patients, one family); Spondyloenchondro-dysplasia with Immune Dysregulation (SPENCD) (two patients). Diseases affecting inflammasomes include Mevalonate Kinase Deficiency (eight patients); Cryopyrin-Associated Periodic Syndromes (CAPS) (seven patients); NLR Family, Pyrin domain-containing 12 NLRP12) (two patients); Familial Mediterranean fever (FMF) (two patients); Autoinflammation and PLCG-associated antibody deficiency and immune dysregulation (APLAID) (two patients). TNF receptor-associated periodic syndrome (TRAPS) (three patients); A20 haploinsufficiency (four patients); Deficiency of Interleukin 1 Receptor Antagonist (DIRA) (two patients) were categorized as non-inflammasome related conditions. There were significant delays in diagnosis Corticosteroids and other immunosuppressive agents were used for treatment as anti-IL-1 drugs and other biological agents were and still are not available in India. Eight (16.3%) patients had so far succumbed to their illness. This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available.
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http://dx.doi.org/10.3389/fimmu.2021.630691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017183PMC
September 2021

Monogenic Lupus with IgA Nephropathy Caused by Spondyloenchondrodysplasia with Immune Dysregulation.

Indian J Pediatr 2021 08 13;88(8):819-823. Epub 2021 Mar 13.

Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.

Monogenic disorders causing systemic lupus erythematosus represent a small subset of cases. Type-1 interferonopathies, like spondyloenchondrodysplasia with immune dysregulation constitute an important functional category of monogenic lupus. Apart from autoimmune disorders, neurological and skeletal abnormalities are additional manifestations observed in this disorder. A young female presented with seizures due to acute hemorrhagic stroke secondary to malignant hypertension. On evaluating the cause for hypertension, there was evidence of glomerulonephritis and multiple autoantibodies positivity including dsDNA. A diagnosis of lupus was made based on clinical and laboratory findings. Kidney biopsy revealed mesangial proliferative glomerulonephritis with predominant IgA deposits favouring IgA nephropathy. Additional features in the form of short stature with vertebral abnormalities and bilateral basal ganglia calcification led to evaluation of Type-1 interferonopathies. Sanger sequencing identified a novel compound heterozygous variants c.550C>T (p.Q184*) in exon 3 and c.740T>G (p.L247R) in exon 4 of ACP5 gene. Parents were found to be carriers of the variants in ACP5 gene. Management included antihypertensive agents and symptomatic therapy. On follow-up, there was complete resolution of glomerulonephritis and normalization of blood pressure. This case report documents the classic phenotype comprising autoimmune, skeletal, and neurological abnormalities in spondyloenchondrodysplasia with immune dysregulation with a novel variant on Sanger sequencing in an Indian patient. This report also highlights the rare coexistence of IgA nephropathy in monogenic lupus.
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http://dx.doi.org/10.1007/s12098-020-03636-xDOI Listing
August 2021

Homozygosity stretches around homozygous mutations in autosomal recessive disorders: patients from nonconsanguineous Indian families.

J Genet 2021 ;100

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226 014, India.

India has a large heterogeneous population with its unique social and genetic characteristics. Tradition of marriage between specific caste groups have produced unique characteristics to the mutation spectrum of genetic disorders and may be a higher prevalence of autosomal recessive (AR) disorders in some communities. We observed that in many nonconsanguineous families with rare autosomal disorders, maternally and paternally inherited mutations are same, indicating common ancestor. In this era of genomic techniques, finding homozygous regions have become easy. It was seen that the patients with AR disorders, who were homozygous for the disease causing pathogenic / likely pathogenic variations, have large stretches (0.6-188 Mb) of homozygosity around the causative sequence variations. SNP microarray data of patients from consanguineous and nonconsanguineous families also showed that even patients from nonconsanguineous families had 3-49 Mb size regions of homozygosity. Long stretches of homozygosity around homozygous rare pathogenic variants in nonconsanguineous families with rare AR disorders supports the notion that these couples may have a common ancestor for more than six generations and the system of marriages between same groups. Hence, using the strategy of homozygosity by descent even in nonconsanguineous families can be fruitful in identifying the novel pathogenic variations and novel genes.
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July 2021

Twins with PEX7 related intellectual disability and cataract: Highlighting phenotypes of peroxisome biogenesis disorder 9B.

Am J Med Genet A 2021 05 14;185(5):1504-1508. Epub 2021 Feb 14.

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.

Peroxisome biogenesis disorders (PBDs) are a group of autosomal recessive disorders caused due to impaired peroxisome assembly affecting the formation of functional peroxisomes. PBDs are caused by a mutation in PEX gene family resulting in disease manifestation with extreme variability ranging from the onset of profound neurologic symptoms in newborns to progressive degenerative disease in adults. Disease causing variations in PEX7 is known to cause severe rhizomelic chondrodysplasia punctata type 1 and PBD 9B, an allelic disorder resulting in a milder phenotype, often indistinguishable from that of classic Refsum disease. This case report highlights the variability of PEX7 related phenotypes and suggests that other than RCDP1 and late onset phenotype similar to Refsum disease, some cases present with cataract and neurodevelopmetal abnormalities during childhood without chondrodysplasia or rhizomelia. This report also underlines the importance of considering PBD 9B in children presenting with neurodevelopmental abnormalities especially if they have congenital cataract.
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http://dx.doi.org/10.1002/ajmg.a.62110DOI Listing
May 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 04 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

Clinical and molecular characterization of four patients with Robinow syndrome from different families.

Am J Med Genet A 2021 04 26;185(4):1105-1112. Epub 2021 Jan 26.

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

Robinow syndrome (RS) is a rare heterogeneous disorder characterized by short stature, short-limbs, craniofacial, oro-dental abnormalities, vertebral segmentation defects, and frequently genital hypoplasia. Both autosomal dominant and recessive patterns of inheritance are observed with many causative genes. Here, we present the phenotypes and genotypes of four children with RS from different Indian families. Sequence variants were identified in genes ROR2, DVL1, and DVL3. Our results expand the mutational spectrum of RS and we also highlight the radiological changes in the radius and ulna in patients with ROR2 sequence variants which are primarily characteristic for ROR2 related RS but have been reported in WNT5A related RS.
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http://dx.doi.org/10.1002/ajmg.a.62082DOI Listing
April 2021

Novel FOXP1 pathogenic variants in two Indian subjects with syndromic intellectual disability.

Am J Med Genet A 2021 04 11;185(4):1324-1327. Epub 2021 Jan 11.

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.

We describe two unrelated Indian boys with Mental retardation with language impairment with or without autistic features (OMIM#613670). Novel pathogenic variants c. 593_599 delins AGAAG and c.1556T>C in FOXP1 were identified in Patients 1 and 2, respectively by exome sequencing. The patients shared the cardinal features of significant language impairment, prominent forehead, downslanted palpebral fissures, frontal upsweep of hair, and behavioral abnormalities. Camptodactyly (with pterygia in Patient 2) was an additional feature noted in our study. The phenotype was consistent with previous reports of patients with monogenic defects in FOXP1. The facial features overlap with Sotos syndrome. However, presence of frontal upsweep of hair is a good pointer toward FOXP1 related syndromic intellectual disability.
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http://dx.doi.org/10.1002/ajmg.a.62083DOI Listing
April 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

Desbuquois dysplasia Kim variant: a rare case report syndrome.

Clin Dysmorphol 2021 Jan;30(1):62-65

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

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http://dx.doi.org/10.1097/MCD.0000000000000356DOI Listing
January 2021

Carrier frequency of SMN1-related spinal muscular atrophy in north Indian population: The need for population based screening program.

Am J Med Genet A 2021 01 14;185(1):274-277. Epub 2020 Oct 14.

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.

Chromosome 5q related Spinal muscular atrophy (SMA) is an autosomal recessive, progressive, neuromuscular disorder most commonly caused by homozygous deletion of exon 7 or exon 7 and 8 of SMN1 gene. Being the leading genetic cause of infant mortality, studies of its prevalence and incidence are necessary. Carrier testing for the common pathogenic variant for SMA is offered to the couples visiting our tertiary care hospital in North India. Subjects were tested for SMA carrier status by Multiplex Ligation-dependent Probe amplification (MLPA) technique for deletion of exons 7 and 8 of SMN1 gene. The retrospective data of individuals tested for SMA carrier status in last 4 years (2016-2019) was evaluated. Six hundred and six individuals without family history of SMA or carrier of SMA who were subjected to MLPA based screening for SMA carrier status were included in the study. The carrier frequency of SMN1 deletion (deletion of exon 7 and/or exon 8) was found to be 1 in 38 (16 out of 606). The catchment area of our medical genetics clinic covering the state of Uttar Pradesh (16.5% of Indian population according to censusindia.gov.in, 2011) and neighboring states, showing SMA carrier frequency of 1:38 in a cohort with no prior positive family history has important significance for policy making.
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http://dx.doi.org/10.1002/ajmg.a.61918DOI Listing
January 2021
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