To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS). After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary. Of the 200 participants, 52 (26%) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West. A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.

中文翻译：

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基于NGS的北印度人口遗传疾病扩展携带者筛查显示出意想不到的结果–一项初步研究

通过使用下一代测序（NGS）来确定北印度人口中常见遗传疾病的携带者频率和致病变异。经过测试前咨询，通过NGS技术筛选了88个基因中200个无关的个体（包括88对夫妇）的致病变异。根据美国医学遗传学标准将变体分类。除常规过滤器外，还对病原体和可能的病原体进行了彻底的文献整理。没有报道未知意义的变体。建议个人解释结果的含义，并在必要时建议进行级联筛查。在200名参与者中，有52名（26％）被发现是一种或多种疾病的携带者。确定有十二个人是先天性耳聋的携带者，给出四个测试基因之一（SLC26A4，GJB2，TMPRSS3和TMC1降序排列）的载波频率，为17分之一。观察到有9个人是囊性纤维化的携带者，频率为22分之一。检测到3个人是庞贝病的携带者（频率为67分之一）。筛选出的88对夫妇中没有发现是同一疾病的携带者。在许多疾病（例如耳聋，囊性纤维化，庞贝病，卡纳万病，原发性高草酸尿症，交界性表皮松解性大疱，半乳糖血症，中链酰基CoA缺乏症等）中观察到的致病变异与西方国家常见。遗传性耳聋，囊性纤维化和庞贝病的载频更高，这是出乎意料的，这与人们普遍认为他们在亚洲印第安人中的流行情况相反。尽管样本量较小，但这项研究表明，针对印度的基于人群的携带者筛查小组与西方国家不同，因此应谨慎选择。测试应包括通过NGS研究所有编码外显子及其在基因中的边界，因为所有变体均未得到很好的表征。只有研究基因中的整个编码区，才能以足够的效率检测出携带者，以减轻印度和其他资源贫乏国家的遗传疾病负担。测试应包括通过NGS研究所有编码外显子及其在基因中的边界，因为所有变体均未得到很好的表征。只有研究基因中的整个编码区，才能以足够的效率检测出携带者，以减轻印度和其他资源贫乏国家的遗传疾病负担。测试应包括通过NGS研究所有编码外显子及其在基因中的边界，因为所有变体均未得到很好的表征。只有研究基因中的整个编码区，才能以足够的效率检测出携带者，以减轻印度和其他资源贫乏国家的遗传疾病负担。