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Next generation sequencing based diagnosis has emerged as a promising tool for evaluating critically ill neonates and children. However, there is limited data on its utility in developing countries. We assessed its diagnostic rate and clinical impact on management of pediatric patients with a suspected genetic disorder requiring critical care. The study was conducted at a single tertiary hospital in Northern India. We analyzed 70 children with an illness requiring intensive care and obtained a precise molecular diagnosis in 32 of 70 probands (45.3%) using diverse sequencing techniques such as clinical exome, whole exome, and whole genome. A significant change in clinical outcome was observed in 13 of 32 (40.6%) diagnosed probands with a change in medication in 11 subjects and redirection to palliative care in two subjects. Additional benefits included specific dietary management (three cases), avoidance of a major procedure (one case) and better reproductive counseling. Dramatic therapeutic responses were observed in three cases with SCN1A, SCN2A and KCNQ2-related epileptic encephalopathy. A delayed turn-around for sequencing results was perceived as a major limiting factor in the study, as rapid and ultra-rapid sequencing was not available. Achieving a precise molecular diagnosis has great utility in managing critically ill patients with suspected genetic disorders in developing countries.

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Oculocutaneous albinism is an inherited disorder of melanin biosynthesis, characterized by absent or reduced pigmentation of the skin, hair, and eyes. Molecular alterations of genes that cause non-syndromic albinism in Asian Indians are poorly characterized. This information would be useful for developing therapies for this disorder. We analyzed 164 persons with non-syndromic albinism, belonging to unrelated families from all parts of India, for molecular changes in the causative genes. Subjects with white hair, white skin, and red iris had their tyrosinase gene sequenced and were also tested by MLPA for deletions/duplications. Subjects with negative results or with darker skin, golden/brown or darker hair had sequencing of TYR, P, TYRP1, SLC45A2 and GPR143 genes. Pathogenic variants in TYR (OCA1) were observed in 139 (84.7%) patients, in the P gene (OCA2) in 20 (12.2%), in TYRP1 (OCA3) in two (1.2%), in SLC45A2 (OCA 4) in one (0.61%), and in GPR143 (X-linked ocular albinism) in two (1.2%) patients. Of 278 alleles with variants in TYR, 179 (64.3%) alleles had (p.R278*) alteration, suggesting the possibility of therapy with a stop codon readthrough molecule. We report 20 patients with 13 disease associated variants in the P gene and 18 novel pathogenic variants in TYR, P, TYRP1, SLC45A2 and GPR143 genes. The data are compared with those reported from India, Pakistan and rest of the world. The therapeutic options in albinism are briefly described, opening this field for future therapies.

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OBJECTIVES: To determine the diagnostic yield of next generation sequencing (NGS) in patients with moderate/severe/profound intellectual disability (ID) unexplained by conventional tests and to assess the impact of definitive diagnosis on the clinical management and genetic counselling of these families. METHODS: This was a ambi-directional study conducted at Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi. The study comprised 227 patients (prospective cohort - 126, retrospective cohort - 101) in whom NGS based tests were performed. RESULTS: The mean age of study cohort was 4.5 ± 4.4 y (2.5 mo to 37.3 y). The male: female ratio was 1.6:1. The overall diagnostic yield of NGS was 53.3% (121/227) with causative variants identified in 84 known ID genes. Autosomal recessive intellectual disability (ARID) (23.3%, 53/227) was the most common followed by autosomal dominant intellectual disability (ADID) (20.7%, 47/227) and X-linked intellectual disability (XLID) (9.2%, 21/227). The diagnostic yield was notably higher for ID plus associated condition group (55.6% vs. 20%) (p = 0.0075, Fisher's exact test) compared to isolated ID group. The impact of diagnosis on active or long-term management was observed in 17/121 (14%) and on reproductive outcomes in 26/121 (21.4%) families. CONCLUSIONS: There is paucity of data on molecular genetic spectrum of ID from India. The current study identifies extensive genetic heterogeneity and the impact of NGS in patients with ID unexplained by standard genetic tests. The study identified ARID as the most common cause of ID with additional implications for reproductive outcomes. It reiterates the importance of phenotype in genetic testing.

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Desbuquois dysplasia (DBQD) is an uncommon, autosomal recessive disorder with multiple joint dislocations. It is caused by pathogenic variants in CANT1 (calcium-activated nucleotidase 1) [NM_001159773.2]. This study adds to the scant data of nine reported antenatal phenotypes of DBQD. The present paper describes two unrelated consanguineous families with antenatal features of lethal skeletal dysplasia. The defining radiological changes were identified in only one patient who presented in the late second and third trimesters. Solo exome sequencing was performed and two previously reported homozygous variants c.896C>T (p.Pro299Leu) in patient 1 and c.902_906dup (p.Ser303fs*20) in patient 2 were identified. This study highlights the fetal presentations in DBQD and adds to its phenotypic spectrum. A complete clinical workup, including fetal autopsy and radiographs is essential to confirm the diagnosis of lethal skeletal dysplasia. Molecular diagnosis remains the diagnostic modality to define the causative variant. A definitive diagnosis is essential to inform management and offer reproductive care.

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Larsen's syndrome is characterized by dislocation of multiple large joints, digital anomalies, craniofacial dysmorphism, and short stature. In this paper, we describe a case of a 5-month-old boy with a triad of cardinal features in association with other signs. The diagnosis was confirmed by exome sequencing, which led to the identification of a novel missense variant NM_001457.4:c.4928C > G (p.Ala1643Gly) in the FLNB gene. We describe the role of protein modelling for the establishment of pathogenicity of this variant. We also outline the challenges in genetic diagnosis due to variable expressivity of the variant and discuss the clinicogenetic profile of previously reported patients with Larsen's syndrome in India.

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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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Reform of the abortion laws in favour of the well-being of pregnant women is one aspect of the removal of gender discrimination. The Medical Termination of Pregnancy Act (MTP Act) 1971, was a breakthrough legislation in this regard, as it reduced the number of unsafe illegal abortions. With advancements in ultrasonography and genetic technologies, many foetal malformations and genetic disorders were being diagnosed after 20 weeks of gestation. The fact that termination of pregnancy was not legally permitted beyond 20 weeks of gestation caused great distress to such women, and highlighted the need to increase the upper limit of termination of pregnancy. Concurrently, there has been greater awareness around the world on the rights of women to take decisions regarding their own bodies. The MTP Bill, 2020, has come as a breath of fresh air extending the term limit for legal abortions to 24 weeks for certain categories of women, and removing the limit for abortion in the presence of a significant foetal abnormality. The amendments were recently approved by Parliament and the President of India, and have become law as of March 25, 2021. This paper presents the amendments made and their implications for obstetric, ultrasonographic and foetal medical practice. It also presents a critique of the various Acts and suggests further amendments that would enhance the value of the Act.

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Autosomal dominant leukodystrophy is an adult onset neurodegenerative disorder presenting with progressive symptoms of ataxia and autonomic dysfunction in fourth or fifth decade in life. It has clinical similarity with multiple sclerosis, but shows characteristic magnetic resonance imaging findings of diffuse bilaterally symmetrical leukodystrophy which can distinguish this disorder. It is a rare disorder with no known treatment till date, and has never been described from the Indian subcontinent. We present an Indian family with autosomal dominant adult-onset demyelinating leukodystrophy with multiple members affected over four generations, and demonstrate a cheap and accurate molecular method of real-time polymerase chain reaction to detect the LMNB1 gene duplication, which is the genetic basis of this devastating disorder.

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To examine the impact of the COVID-19 pandemic, we interviewed 26 patients with lysosomal storage disorders receiving enzyme replacement therapy. 20 (77 %) had significant interruption in their treatment, with an average of 8 (range 2-28) missed doses. Alternate methods of delivering uninterrupted care including home therapy were used. Vulnerable patients with chronic genetic disorders require organization for their multidisciplinary needs of care.

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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 ±â€¯9.7 years and 15.8 ±â€¯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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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 FGF3 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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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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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 (ITGA8, GREB1L, and FGF20). 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 GFRA1 (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 GFRA1. The second patient was homozygous for a frameshift variant (NM_001348097.1:c.1294delA, p.[Thr432Profs*13]). The GFRA1 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 GFRA1-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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Hypophosphatemic rickets is one of the major causes of refractory rickets exhibiting genetic heterogeneity. Most cases are X-linked due to PHEX gene mutations. However recently, autosomal dominant (AD) forms have been described, due to mutations in FGF23. The authors present a 13-year-old girl who had hypophosphatemic rickets due to R179W mutation in FGF23 gene, being the first case in India with this mutation. She presented with bone pains, short stature and osteopenic bones, symptoms appearing after onset of menarche. This presentation is different from that seen in younger children with rickets. Burosumab, an anti-FGF23 antibody is an effective novel therapy for FGF23-related rickets but it is not available in India. High doses of calcitriol and phosphate were required to alleviate the symptoms and signs. The authors aim to alert pediatricians to keep in mind this treatable disorder to prevent diagnostic delays and improve treatment outcome.

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With the advent of next generation sequencing technology there has been a spurt of papers on genetics in epilepsy in children. Genetic testing has now become an essential part of clinical practice in epilepsy. It helps in reaching an etiological diagnosis, providing prognostic information, guiding therapy precisely indicated for the patient and avoiding drugs that may worsen the seizures. Once the pathogenic variant has been found, this enables determining and counseling the risk of recurrence to the patient and other relatives at risk. It also makes available different reproductive options such as prenatal diagnosis or pre-implantation diagnosis. The authors describe the benefits, the clinical situations that require genetic testing, the types of genetic tests that are available, and how to choose the appropriate test and their likely yields. Genetic counseling, both pre- and post-test that should be provided is described briefly. Two useful tables are included that depict the therapy for variants in different epilepsy genes.

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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 GLA 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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Incidence of colorectal cancer (CRC) is lower in India than in other parts of the world. Approximately 5% to 10% of CRC is inherited. Hereditary non-polyposis colorectal cancer (HNPCC) syndrome and familial adenomatous polyposis (FAP) syndrome are the two known familial cancer syndromes of gastrointestinal tract, which occur due to inherited genetic predisposition. Not much is known about the molecular profile of families with inherited CRC syndromes seen in Indian population. At our institute, we have been providing genetic testing and counseling service to all the families referred to us with suspicion of inherited cancer predisposition syndrome. We analyzed 36 suspected families at our clinic. Personal and family history of cancer was obtained from the proband and appropriate genetic testing was performed in 19 patients (13 with HNPCC, 5 with FAP, and 1 with Cowden syndrome). We present here our experience and spectrum of pathogenic variants observed in this patient cohort and review on published studies describing molecular profile of Indian patients with CRC syndromes.

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