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Objectives: To establish a technique for mutation identification and prenatal screening in confirmed cases of Canavan disease.Method: Mutations in ASPA gene were identified by sequencing. Six exons of ASPA gene were amplified using intronic primers flanking the exons and then sequenced on ABI 3500Dx automated unit. This technique was used to identify mutations in three cases of Canavan disease. Prenatal diagnosis was performed in two families.Results: Two reported mutations c.162 C > A (p.Asn54Lys) and c.859 G > A (p.Ala287Thr) were identified in two different cases of Canavan disease. Third case was compound heterozygous for two novel mutations (c.728 T > G, p.Ile243Ser; c.902 T > C, p.Leu301Pro). Prenatal diagnosis was performed in three pregnancies in two families, two affected fetuses and one unaffected fetus were identified.Conclusions: Molecular characterization of Canavan disease helps identify the cause at genetic level, thus confirming diagnosis and enabling identification of carriers in the family. Though enzyme assay and NAA measurement allows diagnosis and prenatal diagnosis of Canavan diasease, molecular methods have the advantage of bringing accuracy in prenatal testing with an earlier result. This is the first case report of mutation studies in Canavan disease from Indian subcontinent. [ABSTRACT FROM AUTHOR]

A fifteen-month-old boy, born to consanguineously married couple, presented with asymptomatic hepatomegaly. Investigations revealed mildly deranged liver functions, necroinflammatory changes and cirrhosis on liver biopsy, a markedly raised alpha feto protein and tyrosine levels in plasma and a generalized aminoaciduria. His diagnosis of hereditary tyrosinemia was established on findings of raised serum and urine succinylacetone and a deficient activity of fumaryl acetoacetate hydroxylase enzyme. Prenatal diagnosis of hereditary tyrosinemia was performed in a subsequent pregnancy in this family from India. [ABSTRACT FROM AUTHOR]

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., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

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., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Beckwith-Wiedemann syndrome (BWS; MIM# 130650) is a well-characterized pediatric overgrowth disorder. In approximately 5% of the cases, it is caused by pathogenic variants in the CDKN1C (cyclin-dependent kinase inhibitor 1C). CDKN1C gene encodes for a protein p57 (KIP2) that acts as an inhibitor of cyclin-dependent kinases (CDK) that are expressed in the G and S-phase of the cell cycle, thus regulating cellular proliferation. Variants in CDKN1C gene lead to loss of inhibitory function of CDK and thus impair the inhibition of growth, resulting in BWS phenotype. We describe here a 2.5-year-old boy with a maternally inherited variant c.182G > T, p.Trp61Cys in the CDKN1C gene causing BWS. The natural history of the disorder is described along with the gradual change in the facial features. An insight into the genotype-phenotype correlation and disorders to be considered in the differential diagnosis is provided. We describe a common overgrowth syndrome with its rare genetic mechanism and highlight the salient features that help in making a diagnosis and managing patients., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Background: Pathogenic variants in the transmembrane sulfate transporter protein SLC26A2 are associated with different phenotypes of inherited chondrodysplasias. As limited data is published from India, in this study we sought to elucidate the molecular basis of inherited chondrodysplasias in an Indian cohort., Methods: Molecular screening of 32 fetuses with antenatally diagnosed lethal skeletal dysplasia was performed by next generation sequencing and Sanger sequencing. The genotype-protein phenotype characterization was done using computational biology techniques like homology modelling, stability and pathogenicity predictions., Results: We identified five rare autosomal recessive SLC26A2 [NM_000112.4] variants, including three homozygous c.796dupA(p.Thr266Asnfs*12), c.1724delA(p.Lys575Serfs*10), and c.1375_1377dup(p.Val459dup) and two heterozygous variants (c.532C > T(p.Arg178*)) and (c.1382C > T(p.Ala461Val)) in compound heterozygous form in a total of four foetuses. Genotype-protein phenotype annotations highlighted that the clinically severe achondrogenesis 1B causative c.796dupA(p.Thr266Asnfs*12) and c.1724delA(p.Lys575Serfs*10)variants impact SLC26A2 protein structure by deletion of the protein core and transmembrane STAS domains, respectively. In clinically moderate atelosteogenesis type 2 phenotype, the c.1382C > T(p.Ala461Val) variant is predicted to distort alpha helix conformation and alter the bonding properties and free energy dynamics of transmembrane domains and the c.532C > T(p.Arg178*) variant results in loss of both core transmembrane and STAS domains of the SLC26A2 protein. The c.1375_1377dup(p.Val459dup) variant identified in clinically milder atelosteogenesis type II-diastrophic dysplasia spectrum lethal phenotype is predicted to decrease the Qualitative Model Energy Analysis (QMean), which affects major geometrical aspects of the SLC26A2 protein structure., Conclusion: We expand the spectrum of SLC26A2 related lethal chondrodysplasia and report three novel variants correlating clinical severity and protein phenotype within the lethal spectrum of this rare dysplasia. We demonstrate the relevance of structural characterization to aid novel variant reclassification to provide better prenatal management and reproductive options to families with lethal antenatal skeletal disorder., Competing Interests: Declaration of competing interest There was no conflict of interest for any author., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

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., (© 2022 Wiley Periodicals LLC.)

Objective: To define the spectrum of genetic disorders in patients with short stature visiting the genetic out-patient department in a tertiary care hospital., Methods: A chart review was done for 455 individuals (10 months-16 yrs) with short stature, who were evaluated at the genetic clinic from 1 January, 2017 upto 31 October, 2018. 226 patients who needed detailed evaluation, the spectrum of genetic diagnosis is presented., Results: Proportionate short stature was identified in 63% individuals (n=142) of which 93 (65%) were recognizable syndromes such as Turner syndrome, and William syndrome, and RASopathies. In clinically undefined syndromes (39, 27%), a diagnosis could be made by karyotype (n=3/10), chromosomal microarray (6/12) and exome sequencing (1/6). In the 84 children in the disproportionate short stature group (37%), lysosomal storage disorders (LSDs) (45%, n=38) were identified by enzyme analysis in 86.8% and skeletal dysplasias (44%, n=37) identified by skeletal survey in 89% cases., Conclusions: In undefined syndromic short stature, chromosomal microarray may be the first investigation of choice if phenotyping is not suggestive of a specific genetic syndrome. Exome sequencing can be useful in identifying newer genes among idiopathic and familial short stature cohorts.

Aim: To study genetic variants in patients of familial dilated cardiomyopathy., Methodology: Patients with reduced ejection fraction of less than 45% and dilated left ventricle are considered to have dilated cardiomyopathy. Clinical history was taken and possible secondary causes of dilated cardiomyopathy were excluded. Family history of ≥2 affected relatives or sudden cardiac death in a relative with age less than 35 years were included. Such patients blood sample were sent for next generation sequencing and analysed for presence of genetic variants., Results: As part of pilot study 20 patients (44% were female and 66% were male) were included. There was presence of 16 different pathogenic variants in 14 patients. Two patients had more than one variants in them. Most common of which were sarcomeric mutations constituting 32%. Titin followed by Filamin, Lamin and Desmosomal where the most commonly repeated mutations., Discussion: In our patients of familial dilated cardiomyopathy, 70% were detected to have pathogenic variants in them. Most common variations were seen on Titin gene. Thus those with familial dilated cardiomyopathy should be considered for next generation sequencing. First degree relatives of those with pathogenic variants should be screened using cascade testing for earlier detection and disease monitoring in them., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Rare diseases affect > 400 million people globally with a disproportionate burden falling on children, resulting in high morbidity and mortality rates. Affected individuals in some under-resourced countries have limited access to expert care or treatments; moreover, they suffer long diagnostic journeys during which debilitating and life-threatening complications occur. Lysosomal storage disorders (LSD) are prototype rare diseases due, in the main, to inherited deficiencies of lysosomal enzymes/transporters that affect up to 1 in 5000 newborns. Recognizing the need to provide treatment access to people with LSDs everywhere, a collaborative partnership was pioneered and set up 30 years ago. Partnering with local authorities, non-government organizations across six continents, local as well as international experts, a robust, sustainable Humanitarian Program emerged that now represents the most enduring charitable access program for LSD treatment. Here we present the history, process, lasting beneficial effect of the program to develop healthcare systems and infrastructures, and the lessons learned from addressing major unmet needs for LSDs., (© 2022. The Author(s).)

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.

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., (© 2020. Dr. K C Chaudhuri Foundation.)

Background & Aims: Lysosomal storage disorders (LSDs) remain a significant cause of morbidity in the Indian population and treatment is largely out of reach for most patients. Although data on enzymatic and molecular diagnosis of Gaucher disease (GD) and Fabry disease (FD) in Indian patients are available, the present study intended to establish the pathogenic levels of Lyso GL-1 and Lyso GL-3 in patients of GD and FD respectively as diagnostic aids., Materials and Methods: From 2017 to 2019, ninety confirmed Gaucher cases (by enzymatic and molecular analysis) were tested for chitotriosidase (fluorometrically) and Lyso GL-1 (LC-MS/MS) and ten confirmed Fabry cases were analyzed for Lyso GL-3 (LC-MS/MS)., Results: Lyso GL-1 (median: 685.5 ng/mL, cut-off: 14) and Lyso GL-3 (median: 75.6 ng/mL, cut-off: 3.5) were found to be elevated in all enzymatically deficient patients of GD and FD respectively, however, no specific trend was observed between the levels of these biomarkers and the pathogenic variant(s) present in the patients of these disorders., Conclusions: This is the first report on Lyso GL-1 and Lyso GL-3 levels in Indian patients of GD and FD respectively. These results will be useful for early diagnosis to improve management of these LSDs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest Access to ERT (alglucosidase alfa) is provided under the Indian Charitable Access Program (INCAP) of Sanofi Genzyme for patients of authors RDP, NG, SN, SJ, MK, MM, MB and ICV. The association is purely academic, and no financial compensation is provided. The authors are also committee members of the INCAP and/or CAP programs. The authors declare no other conflicts of interest. PSK is a member of the IMAB (India Medical Advisory Board) and an advisor within the INCAP. PSK has received research/grant support from Sanofi Genzyme, Valerion Therapeutics, and Amicus Therapeutics. PSK has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics and Asklepios Biopharmaceutical, Inc. (AskBio). PSK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Amicus Therapeutics, and Baebies. PSK has equity in Asklepios Biopharmaceutical, Inc. (AskBio), which is developing gene therapy for Pompe disease., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (© 2021 Wiley Periodicals LLC.)

Background: Karyotyping has been the gold standard for prenatal chromosome analysis. The resolution should be higher by chromosome microarray analysis (CMA). The challenge lies in recognizing benign and pathogenic or clinically significant copy number variations (pCNV) and variations of unknown significance (VOUS). The aim was to evaluate the diagnostic yield and clinical utility of CMA, to stratify the CMA results in various prenatal referral groups and to accumulate Indian data of pCNVs and VOUS for further interpretation to assist defined genetic counseling., Methods: Karyotyping and CMA were performed on consecutive referrals of 370 prenatal samples of amniotic fluid ( n  = 274) and chorionic villi ( n  = 96) from Indian pregnant women with high maternal age ( n  = 23), biochemical screen positive ( n  = 61), previous child abnormal ( n  = 59), abnormal fetal ultrasound ( n  = 205) and heterozygous parents ( n  = 22)., Results and Conclusion: The overall diagnostic yield of abnormal results was 5.40% by karyotyping and 9.18% by CMA. The highest percentage of pCNVs were found in the group with abnormal fetal ultrasound (5.40%) as compared to other groups, such as women with high maternal age (0.81%), biochemical screen positive (0.54%), previous abnormal offspring (0.81%) or heterozygous parents group (1.62%). Therefore, all women with abnormal fetal ultrasound must undergo CMA test for genotype-phenotype correlation. CMA detects known and rare deletion/duplication syndromes and characterizes marker chromosomes. Accumulation of CNV data will form an Indian Repository and also help to resolve the uncertainty of VOUS. Pretest and posttest genetic counseling is essential to convey benefits and limitations of CMA and help the patients to take informed decisions., Competing Interests: Conflict of interestThe authors declare that there is no conflict of interests., (© Federation of Obstetric & Gynecological Societies of India 2021.)

Objectives: Diagnosis of lysosomal storage disorders (LSDs) remains challenging due to wide clinical, biochemical and molecular heterogeneity. The study applies a combined biochemical and genetic approach to diagnose symptomatic Indian patients of Pompe, Fabry, Gaucher and Hurler disease to generate a comprehensive dataset of pathogenic variants for these disorders., Design & Methods: Symptomatic patients were biochemically diagnosed by fluorometric methods and molecular confirmation was carried out by gene sequencing. Genetic variants were analyzed according to the ACMG/AMP 2015 variant interpretation guidelines., Results: Amongst the 2181 suspected patients, 285 (13%) were biochemically diagnosed. Of these, 22.5% (64/285) diagnosed with Pompe disease harboured c.1933G>A, c.1A>G, c.1927G>A and c.2783G>C as common and 10 novel pathogenic variants while 7.4% (21/285) patients diagnosed with Fabry disease carried c.851T>C, c.902G>A, c.905A>C and c.1212_1234del as frequent disease-causing variants along with 7 novel pathogenic variants. As many as 48.4% (138/285) patients were diagnosed with Gaucher disease and had c.1448T>C as the most common pathogenic variant followed by c.1342G>C and c.754T>C with 7 previously unreported disease-causing variants and in the 21.7% (62/285) diagnosed cases of Hurler disease, c.1469T>C, c.754delC c.568_581del and c.1898C>T were identified as the most common causative variants along with 21 novel pathogenic variants., Conclusion: This comprehensive data set of disease-causing frequent and novel pathogenic variants reported for the first time in such a large patient cohort for each of these four LSDs from the Indian sub-continent, along with their biochemical and clinical spectrum will contribute towards providing definitive diagnosis and treatment, identifying carrier status, as well as in counselling prenatal cases to reduce the morbidity and mortality associated with these disorders., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

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.

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.

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.

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., (Copyright © 2021 by the American Society of Nephrology.)

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)