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BACKGROUND: One of the complications of chronic transfusions in thalassemia is the development of red cell alloimmunization. AIMS: The aim of the study was to determine the frequency, specificity of red cell alloantibodies, and factors influencing alloimmunization in multiply transfused thalassemia patients. MATERIALS AND METHODS: The study was carried out prospectively on beta-thalassemia patients over 10 months. Plasma samples were used for antibody screening and identification using the column agglutination technique. Patients' clinical, laboratory, and transfusion details were obtained from hospital information system and patient files. STATISTICAL ANALYSIS: Continuous variables were reported as median and quartile, whereas categorical variables were provided as numbers and proportions. P < 0.05 was considered statistically significant. RESULTS: Out of 255 patients, 17 (6.6%) patients developed alloantibodies. Alloimmunized patients had significantly higher median ages at their first transfusions (1 year vs. 0.5 years; P = 0.042) than nonalloimmunized patients. Alloimmunized patients had significantly higher conjugated bilirubin (P = 0.016) and serum ferritin (P = 0.007). The majority of alloantibodies had specificity toward K antigen, followed by E, C, D, JKa, and JKb antigens. Alloimmunized patients received more units per year than nonalloimmunized patients (median, 30 vs. 24 units; P < 0.001). The average transfusion interval time between two successive transfusions showed a significant difference (P < 0.001). CONCLUSIONS: The prevalence of alloimmunization in thalassemia patients in North India is relatively low. Since most of the alloantibodies belong to Rh and Kell blood group system, extended phenotype-matched blood for Rh and Kell will be helpful in further preventing or decreasing the development of alloantibodies in multiply transfused thalassemia patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Koolen‐de Vries syndrome is a recurrent microdeletion syndrome caused due to deletion of around 400–600 kb region at 17q21.31. The deleted region contains various genes including KANSL1 and individuals with KANSL1 sequence variations and similar phenotypic manifestations have also been described. It is characterized by typical facial features, variable degree of intellectual disability, seizures, and behavioral problems. Here, we describe the phenotypic features of two patients and to the best of our knowledge, this is the first case report of Koolen‐de Vries syndrome from India. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The phenotypic spectrum of Type 2 collagenopathies ranges from lethal achondrogenesis Type 2 to milder osteoarthritis with mild chondrodysplasia. All of them are monoallelic except for the two recent reports showing that biallelic variants in COL2A1 can cause spondyloepiphyseal dysplasia congenita in two children. Here we report two additional families with homozygous variants, c.4135C>T (p.Arg1379Cys) and c.3190C>T (p.Arg1133Cys) in COL2A1 resulting in two distinct skeletal dysplasia phenotypes of intermediate severity. Though all six patients from four families exhibit a spondylo‐epimetaphyseal dysplasia, they demonstrate a wide variation in severity of short stature and involvement of epiphyses, metaphyses, and vertebrae. We hypothesize that the variants are likely to be hypomorphic, given the underlying mechanisms of disease causation for known heterozygous variants in COL2A1. With this report, we provide further evidence to the existence of autosomal recessive Type 2 collagenopathy. [ABSTRACT FROM AUTHOR]

Renpenning syndrome is one of the well‐characterized causes of X‐linked intellectual disability and is associated with microcephaly and various visceral malformations. Face is considered characteristic but the dysmorphism is subtle. Here we report an Indian adult with a very lean habitus, progressive atrophy of the upper back muscles, microcephaly, loss of cervical lordosis, and upper thoracic scoliosis. Using whole‐exome sequencing, a hemizygous deletion was identified in PQBP1 that leads to a frameshift and premature termination of translation. The loss of normal curvatures of cervical and upper thoracic spine due to muscular atrophy is a characteristic feature, though it may be age dependent. [ABSTRACT FROM AUTHOR]

Objective: To compile the socio-demographic profile and estimate the economic burden of transfusion dependent thalassemia.Methods: This cross-sectional descriptive study was conducted at a tertiary care hospital in north India. Transfusion dependent thalassemia patients on regular blood transfusion for at least a year were selected. Thalassemia diagnosis was based on HPLC and/or mutation analysis results. Clinical and laboratory parameters were collected from electronic health records. Information regarding socio-economic profile and costs incurred, including indirect costs were collected by interviewing patients' guardians. The data was analyzed as a whole cohort and also in subgroups based on age.Results: The data of 261 patients with a median age of 127 mo was collected. The median age at diagnosis was 9.8 mo. The total treatment expenses of a patient per year ranged from US$ 629 (INR 41,514) to US$ 2300 (INR 151,800), in the different age groups, at an average of US$ 1135 (INR 74,948). More than half (53%) of this was spent on medications. On an average, 38.8% of the family income was spent on the treatment of a thalassemia patient annually. Only 19 of 262 cases had an average pre-BT Hb ≥ 9 g/dl and serum ferritin ≤1500 ng/dl.Conclusions: The treatment for transfusion dependent thalassemia is costly and mostly borne by the families in India. This study provides a realistic magnitude of this burden and will be useful in planning a thalassemia management program at the state or national level. [ABSTRACT FROM AUTHOR]