Ganguly Agnish, Pal Samudra, Chatterjee Srilagna, Das Madhusudan, Sarkar Sumantra, Ghosh Sujay
Cytogenetics-Genomics and Down syndrome Research Unit, Department of Zoology, University of Calcutta, Kolkata, West Bengal, India.
Department of Biotechnology, School of Life Sciences, Swami Vivekananda University, Barrackpore, West Bengal, India.
PLoS One. 2025 Jun 26;20(6):e0326566. doi: 10.1371/journal.pone.0326566. eCollection 2025.
Individuals with Down syndrome (DS) exhibit a higher incidence of congenital heart defects (CHD). The objective of the present study was to investigate ethnicity-specific genetic variants that increase the risk of CHD in children with DS from the Indian Bengali population. We conducted whole exome sequencing of the genomes of Down syndrome children with and without CHD and subsequently tested the identified variants in a larger cohort (N = 1798). Our findings revealed two rare variants, KIF7 rs138354681 and GJA1 rs778110855, as well as one novel variant, PDE1C PP785745, present in children with DS and CHD but absent in those without CHD. In-silico analyses indicated that these variants are pathogenic. The frequencies of the heterozygous genotypes for KIF7 rs138354681, GJA1 rs778110855, and PDE1C PP785745 were recorded as 0.027, 0.016, and 0.032, respectively. Among the 31 carriers identified, 18 individuals exhibited two variants, while four were found to have three co-occurring variants. The majority of these individuals required surgical intervention for correction, in contrast to single variant carriers, of whom only three out of nine needed surgeries. A polygenic risk score analysis revealed higher score to be significantly associated with both the presence of multiple variants and the subsequent need for surgical correction. We hypothesise that the synergistic effects of multiple variants heighten the severity of CHD, particularly in cases of ventricular septal defects, thereby necessitating surgical correction. These findings significantly enhance our understanding of the unique population-specific aetiology of CHD and the basis for the severity of its clinical presentation in individuals with Down syndrome.
唐氏综合征（DS）患者先天性心脏病（CHD）的发病率较高。本研究的目的是调查特定种族的基因变异，这些变异会增加印度孟加拉人群中患有DS的儿童患CHD的风险。我们对患有和未患有CHD的唐氏综合征儿童的基因组进行了全外显子组测序，随后在一个更大的队列（N = 1798）中对鉴定出的变异进行了检测。我们的研究结果显示，有两个罕见变异，即KIF7 rs138354681和GJA1 rs778110855，以及一个新变异，PDE1C PP785745，存在于患有DS和CHD的儿童中，但在未患有CHD的儿童中不存在。计算机模拟分析表明这些变异具有致病性。KIF7 rs138354681、GJA1 rs778110855和PDE1C PP785745杂合基因型的频率分别记录为0.027、0.016和0.032。在鉴定出的31名携带者中，18人表现出两种变异，而4人被发现有三种共同出现的变异。与单一变异携带者相比，这些个体中的大多数需要手术干预来进行矫正，单一变异携带者中九人只有三人需要手术。多基因风险评分分析显示，较高的评分与多种变异的存在以及随后进行手术矫正的需求显著相关。我们假设多种变异的协同作用会加剧CHD的严重程度，特别是在室间隔缺损的情况下，从而需要进行手术矫正。这些发现显著增强了我们对CHD独特的人群特异性病因以及唐氏综合征患者临床症状严重程度基础的理解。
