Sandal Sapna, Verma Ishwar Chander, Mahay Sunita Bijarnia, Dubey Sudhisha, Sabharwal R K, Kulshrestha Samarth, Saxena Renu, Suman Praveen, Kumar Praveen, Puri Ratna Dua
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.
Department of Pediatric Neurology, Sir Ganga Ram Hospital, New Delhi, India.
Indian J Pediatr. 2024 Jul;91(7):682-695. doi: 10.1007/s12098-023-04820-5. Epub 2023 Oct 7.
To determine the diagnostic yield of next generation sequencing (NGS) in patients with moderate/severe/profound intellectual disability (ID) unexplained by conventional tests and to assess the impact of definitive diagnosis on the clinical management and genetic counselling of these families.
This was a ambi-directional study conducted at Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi. The study comprised 227 patients (prospective cohort - 126, retrospective cohort - 101) in whom NGS based tests were performed.
The mean age of study cohort was 4.5 ± 4.4 y (2.5 mo to 37.3 y). The male: female ratio was 1.6:1. The overall diagnostic yield of NGS was 53.3% (121/227) with causative variants identified in 84 known ID genes. Autosomal recessive intellectual disability (ARID) (23.3%, 53/227) was the most common followed by autosomal dominant intellectual disability (ADID) (20.7%, 47/227) and X-linked intellectual disability (XLID) (9.2%, 21/227). The diagnostic yield was notably higher for ID plus associated condition group (55.6% vs. 20%) (p = 0.0075, Fisher's exact test) compared to isolated ID group. The impact of diagnosis on active or long-term management was observed in 17/121 (14%) and on reproductive outcomes in 26/121 (21.4%) families.
There is paucity of data on molecular genetic spectrum of ID from India. The current study identifies extensive genetic heterogeneity and the impact of NGS in patients with ID unexplained by standard genetic tests. The study identified ARID as the most common cause of ID with additional implications for reproductive outcomes. It reiterates the importance of phenotype in genetic testing.
确定新一代测序（NGS）在常规检测无法解释的中度/重度/极重度智力残疾（ID）患者中的诊断率，并评估明确诊断对这些家庭临床管理和遗传咨询的影响。
这是一项在新德里甘加拉姆爵士医院医学遗传学和基因组学研究所进行的双向研究。该研究包括227例患者（前瞻性队列-126例，回顾性队列-101例），对其进行了基于NGS的检测。
研究队列的平均年龄为4.5±4.4岁（2.5个月至37.3岁）。男女比例为1.6:1。NGS的总体诊断率为53.3%（121/227），在84个已知的ID基因中鉴定出致病变异。常染色体隐性智力残疾（ARID）（23.3%，53/227）最为常见，其次是常染色体显性智力残疾（ADID）（20.7%，47/227）和X连锁智力残疾（XLID）（9.2%，21/227）。与单纯ID组相比，ID加相关病症组的诊断率显著更高（55.6%对20%）（p=0.0075，Fisher精确检验）。在121个家庭中的17个（14%）观察到诊断对积极或长期管理的影响，在26个（21.4%）家庭中观察到对生殖结果的影响。
来自印度的关于ID分子遗传谱的数据匮乏。当前研究确定了广泛的遗传异质性以及NGS在标准基因检测无法解释的ID患者中的影响。该研究确定ARID是ID最常见的原因，并对生殖结果有额外影响。它重申了表型在基因检测中的重要性。
