The contribution of de novo variants as a cause of intellectual disability (ID) is well established in several cohorts reported from the developed world. However, the genetic landscape as well as the appropriate testing strategies for identification of de novo variants of these disorders remain largely unknown in low-and middle-income countries like India. In this study, we delineate the clinical and genotypic spectrum of 54 families (55 individuals) with syndromic ID harboring rare de novo variants. We also emphasize on the effectiveness of singleton exome sequencing as a valuable tool for diagnosing these disorders in resource limited settings. Overall, 46 distinct disorders were identified encompassing 46 genes with 51 single-nucleotide variants and/or indels and two copy-number variants. Pathogenic variants were identified in CREBBP, TSC2, KMT2D, MECP2, IDS, NIPBL, NSD1, RIT1, SOX10, BRWD3, FOXG1, BCL11A, KDM6B, KDM5C, SETD5, QRICH1, DCX, SMARCD1, ASXL1, ASXL3, AKT3, FBN2, TCF12, WASF1, BRAF, SMARCA4, SMARCA2, TUBG1, KMT2A, CTNNB1, DLG4, MEIS2, GATAD2B, FBXW7, ANKRD11, ARID1B, DYNC1H1, HIVEP2, NEXMIF, ZBTB18, SETD1B, DYRK1A, SRCAP, CASK, L1CAM, and KRAS. Twenty-four of these monogenic disorders have not been previously reported in the Indian population. Notably, 39 out of 53 (74%) disease-causing variants are novel. These variants were identified in the genes mainly encoding transcriptional and chromatin regulators, serine threonine kinases, lysosomal enzymes, molecular motors, synaptic proteins, neuronal migration machinery, adhesion molecules, structural proteins and signaling molecules.

Deleterious, mostly de novo, mutations in the lamin A ( LMNA ) gene cause spatio‐functional nuclear abnormalities that result in several laminopathy‐associated progeroid conditions. In this study, exome sequencing in a sixteen‐year‐old male with manifestations of premature aging led to the identification of a mutation, c.784G>A, in LMNA , resulting in a missense protein variant, p.Glu262Lys (E262K), that aggregates in nucleoplasm. While bioinformatic analyses reveal the instability and pathogenicity of LMNA E262K , local unfolding of the mutation‐harboring helical region drives the structural collapse of LMNA E262K into aggregates. The E262K mutation also disrupts SUMOylation of lysine residues by preventing UBE2I binding to LMNA E262K , thereby reducing LMNA E262K degradation, aggregated LMNA E262K sequesters nuclear chaperones, proteasomal proteins, and DNA repair proteins. Consequently, aggregates of LMNA E262K disrupt nuclear proteostasis and DNA repair response. Thus, we report a structure–function association of mutant LMNA E262K with toxicity, which is consistent with the concept that loss of nuclear proteostasis causes early aging in laminopathies.

Retinoblastoma is an embryonic intraocular tumor arising in the retina of the eye. It is a dangerous tumor that can damage the eye and its surrounding components. Chromosome 13q14.1-14.2 is the cytogenetic location of the RB1 gene. As a result, early identification of Retinoblastoma in children is essential. Over the last few decades, Retinoblastoma treatment has improved with the goal of not only saving life and the eye but also optimizing residual vision. In oncology, machine learning approaches used to predict cancer patient treatment outcomes include data collection and preprocessing, text mining of clinical literature, and constructing prediction models. This paper discusses recent advances in the management of Retinoblastoma, as well as data preparation and model construction for identifying patterns between Retinoblastoma clinical factors and predicting therapy success using machine learning.

As in many other countries, the field of genetic counseling is in its initial stages of development in India, where there are efforts to streamline the profession and to implement graduate‐level training programs. We implemented an elective course on genetic counseling at the undergraduate level in a private university in India to assess students’ interest, to provide early exposure for students interested in pursuing the career, and to aid recruitment. To assess satisfaction with the course and recruitment outcomes, we sent a course evaluation survey to 332 students and received 134 responses. Familiarity with genetic counseling topics increased significantly after completing the course. Of the 42 respondents who reported they were planning to pursue formal genetic counseling training, 21% (n = 9/42) became interested in the profession as a result of taking this course. Survey respondents who were prospective applicants to genetic counseling training programs referred mostly to the websites of the National Society of Genetic Counselors and the American Board of Genetic Counseling for information on genetic counseling and training. Barriers to entry into the field included lack of shadowing opportunities, inadequate coursework, and limited opportunities to interact with practicing genetic counselors. Respondents stated that additional case studies as well as observation of patient interactions would elucidate the role of a genetic counselor and help define the scope of the practice in India and other countries. Overall, genetic counseling education at the undergraduate level is a scalable way to improve understanding of genetic counseling topics, increase professional interest in the field, and support workforce development.

Background & objectives: Subtelomeres are prone to deleterious rearrangements owing to their proximity to unique sequences on the one end and telomeric repetitive sequences, which increase their tendency to recombine, on the other end. These subtelomeric rearrangements resulting in segmental aneusomy are reported to contribute to the aetiology of idiopathic intellectual disability/developmental delay (ID/DD). We undertook this study to estimate the frequency of subtelomeric rearrangements in children with ID/DD. Methods: One hundred and twenty seven children with idiopathic ID/DD were tested for subtelomeric rearrangements using karyotyping and FISH. Blood samples were cultured, harvested, fixed and GTG-banded using the standard protocols. Results: Rearrangements involving the subtelomeres were observed in 7.8 per cent of the tested samples. Detection of rearrangements visible at the resolution of the karyotype constituted 2.3 per cent, while those rearrangements detected only with FISH constituted 5.5 per cent. Five deletions and five unbalanced translocations were detected. Analysis of parental samples wherever possible was informative regarding the inheritance of the rearrangement. Interpretation & conclusions: The frequency of subtelomeric rearrangements observed in this study was within the reported range of 0-35 per cent. All abnormal genotypes were clinically correlated. Further analysis with array technologies presents a future prospect. Our results suggest the need to test individuals with ID/DD for subtelomeric rearrangements using sensitive methods such as FISH.

Isochromosome is a structurally unbalanced chromosome consisting of two short arms or two long arms, which are derived by abnormal centromere division or sister-chromatid exchange. Most autosomal isochromosomes are unusual, while those involving sex chromosomes are common. Kabuki syndrome (KS, OMIM 147920) is a multiple malformation/mental retardation syndrome of unknown etiology. A conventional cytogenetic study on lymphocytes from a 4-year-old girl with physical features suggestive of KS was found to have mosaicism for isochromosome for the long arm of the X. Although most manifestations present in this patient have been described before, this report is a rare association of clinical and cytogenetic findings in this syndrome. A genome-wide analysis and a larger number of patient groups studied could improve our understanding of the genetic basis of KS.

The present study pertains to a 7 month old female infant who showed dysmorphic features and developmental delay. Conventional cytogenetic analysis by GTG banding technique was carried out and this revealed monosomy 21. Interphase FISH and metaphase FISH were employed for better delineation of the observed results. FISH analysis confirmed unbalanced X;21 translocation. This study concludes that FISH technique along with conventional cytogcnetic analysis serves for better understanding and interpretation of complete/ partial autosomal monosomics.