Comparative yield of molecular diagnostic algorithms for autism spectrum disorder diagnosis in India: evidence supporting whole exome sequencing as first tier test.

BACKGROUND: Autism spectrum disorder (ASD) affects 1 in 100 children globally with a rapidly increasing prevalence. To the best of our knowledge, no data exists on the genetic architecture of ASD in India. This study aimed to identify the genetic architecture of ASD in India and to assess the use of whole exome sequencing (WES) as a first-tier test instead of chromosomal microarray (CMA) for genetic diagnosis. METHODS: Between 2020 and 2022, 101 patient-parent trios of Indian origin diagnosed with ASD according to the Diagnostic and Statistical Manual, 5th edition, were recruited. All probands underwent a sequential genetic testing pathway consisting of karyotyping, Fragile-X testing (in male probands only), CMA and WES. Candidate variant validation and parental segregation analysis was performed using orthogonal methods. RESULTS: Of 101 trios, no probands were identified with a gross chromosomal anomaly or Fragile-X. Three (2.9%) and 30 (29.7%) trios received a confirmed genetic diagnosis from CMA and WES, respectively. Amongst diagnosis from WES, SNVs were detected in 27 cases (90%) and CNVs in 3 cases (10%), including the 3 CNVs detected from CMA. Segregation analysis showed 66.6% (n = 3 for CNVs and n = 17 for SNVs) and 16.6% (n = 5) of the cases had de novo and recessive variants respectively, which is in concordance with the distribution of variant types and mode of inheritance observed in ASD patients of non-Hispanic white/ European ethnicity. MECP2 gene was the most recurrently mutated gene (n = 6; 20%) in the present cohort. Majority of the affected genes identified in the study cohort are involved in synaptic formation, transcription and its regulation, ubiquitination and chromatin remodeling. CONCLUSIONS: Our study suggests de novo variants as a major cause of ASD in the Indian population, with Rett syndrome as the most commonly detected disorder. Furthermore, we provide evidence of a significant difference in the diagnostic yield between CMA (3%) and WES (30%) which supports the implementation of WES as a first-tier test for genetic diagnosis of ASD in India.

Low molecular weight heparin (enoxaparin) reverses pregangrene in a preterm neonate.

A 34-week-old, 1.6 kg preterm boy was admitted for management of mild respiratory distress syndrome. On the third day of life 1 min after an intravenous cannulation attempt at the right cubital fossa, he developed pregangrene bluish discoloration of all fingertips up to the distal interphalangial joint and pallor of right palm. Pulsations on right forearm were reduced. There was no evidence of sepsis.Enoxaparin, a low molecular weight heparin (1.5 mg/kg (standard dose)) was injected subcutaneously in the abdomen in two doses 12 h apart within 2 h of the event. At 6 h after the first dose, brachial artery pulsation was bilaterally symmetrical. After the second dose, bilateral radial artery pulsation became symmetrical. The pregangrene changes returned to normal within 20 h as the distal phalanges became pink and warm. He was discharged on the eighth day of life. Enoxaparin was safe and effective in this preterm infant for reversal of pregangrene.