Proband only exome sequencing in 403 Indian children with neurodevelopmental disorders: Diagnostic yield, utility and challenges in a resource-limited setting.

Whole exome sequencing is recommended as the first tier test for neurodevelopmental disorders (NDDs) with trio being an ideal option for the detection of de novo variants. Cost constraints have led to adoption of sequential testing i.e. proband-only whole exome followed by targeted testing of parents. The reported diagnostic yield for proband exome approach ranges between 31 and 53%. Typically, these study designs have aptly incorporated targeted parental segregation before concluding a genetic diagnosis to be confirmed. The reported estimates however do not accurately reflect the yield of proband only standalone whole -exome, a question commonly posed to the referring clinician in self pay medical systems like India. To assess the utility of standalone proband exome (without follow up targeted parental testing), we retrospectively evaluated 403 cases of neurodevelopmental disorders referred for proband-only whole exome sequencing at Neuberg Centre for Genomic Medicine (NCGM), Ahmedabad during the period of January 2019 and December 2021. A diagnosis was considered confirmed only upon the detection of Pathogenic/Likely Pathogenic variants in concordance with patient's phenotype as well as established inheritance pattern. Targeted parental/familial segregation analysis was recommended as a follow up test where applicable. The diagnostic yield of the proband-only standalone whole exome was 31.5%. Only 20 families submitted samples for follow up targeted testing, and a genetic diagnosis was confirmed in twelve cases increasing the yield to 34.5%. To understand factors leading to poor uptake of sequential parental testing, we focused on cases where an ultra-rare variant was detected in hitherto described de novo dominant neurodevelopmental disorder. A total of 40 novel variants in genes associated with de novo autosomal dominant disorders could not be reclassified as parental segregation was denied. Semi-structured telephonic interviews were conducted upon informed consent to comprehend reasons for denial. Major factors influencing decision making included lack of definitive cure in the detected disorders; especially when couples not planning further conception and financial constraints to fund further targeted testing. Our study thus depicts the utility and challenges of proband-only exome approach and highlights the need for larger studies to understand factors influencing decision making in sequential testing.

Applications of hepatic round ligament/falciform ligament flap and graft in abdominal surgery-a review of their utility and efficacy.

BACKGROUND AND PURPOSE: Despite their ubiquitous presence, easy availability and diverse possibilities, falciform ligament and hepatic round ligament have been used less frequently than their potential dictates. This article aims to comprehensively review the applications of hepatic round ligament/falciform ligament flap and graft in abdominal surgery and assess their utility and efficacy. METHODS: Medical literature/indexing databases were searched, using internet search engines, for pertinent articles and analysed. RESULTS: The studied flap and graft have found utility predominantly in the management of diaphragmatic hernias, gastro-oesophageal reflux disease, peptic perforations, biliary reconstruction, venous reconstruction, post-operative pancreatic fistula, post-pancreatectomy haemorrhage, hepatic cyst cavity obliteration, liver bleed, sternal dehiscence, splenectomy, reinforcement of aortic stump, feeding access, diagnostic/therapeutic access into portal system, composite tissue allo-transplant and ventriculo-peritoneal shunting where they have exhibited the desired efficacy. CONCLUSIONS: Hepatic round ligament/falciform ligament flap and graft are versatile and have multifarious applications in abdominal surgery with some novel and unique uses in hepatopancreaticobiliary surgery including liver transplantation. Their evident efficacy needs wider adoption to realise their true potential.