توالی آمیزشی کامل بیماری های متضاد در دوقلوهای منوسیگوتیک با سندرم داون جهش هایی را برای نقص مادرزادی قلب و تشنج های صرعی نشان می دهد

Discordant phenotypes and diseases in Monozygotic twins (MZ) are always intriguing and genetics is the exclusive reason. Down syndrome is one such disorder, which shows heterogeneity, with occurrences of incidental diseases discordant between cases. When such disease discordance is noted in Down syndromic MZ twins, it becomes a true genetic case and the necessity to uncover the pathogenic variants becomes imperative. One such case of MZ twins reported by an earlier study failed to identify the pathogenic variants behind the discordance between Congenital Heart Defect (CHD) and Epilepsy. In the current study, using the Whole Exome Sequencing (WES) datasets of the original investigators along with our custom variant identification pipeline, we investigated the consequences of damaging novel and rare discordant mutations in TGFBR2, for CHD; ITPR1 and RYR2 for Epilepsy. TGFBR2 was identified with a frameshift deletion resulting in a stop gain mutation and appeared to be dominant in function causing Ventricular Septal Defect in the older Down syndrome twin, while nonsynonymous heterozygous substitutions was identified in ITPR1 and RYR2, causing epileptic seizures in the younger twin. Pathway analysis on mutant genes revealed disruption of several processes such as vascular septal formation for TGFBR2, and calcium signalling for ITPR1 and RYR2. The present investigation identified novel discordant mutations relevant to the discordant disease presented, using appropriate analysis and pipelines.