Diagnosis of Intellectual Disability/Global Developmental Delay via Genetic Analysis in a Central Region of China
Intellectual disability (ID), also known as mental retardation, is a disorder characterized by deficits in both intellectual and adaptive functioning in conceptual, social, and practical domains. Global developmental delay (GDD) is a term typically reserved for younger children, usually under 5 years of age, and refers to a significant delay in two or more developmental domains. ID/GDD is a primary global cause of disability, and a confirmed etiologic diagnosis is beneficial for treatment, symptom management, and surveillance for known complications. This study investigates the role of genetic analysis in confirming the etiology of ID/GDD in children from central China, where the cause of the disease was uncertain.
The study recruited 1051 children with ID/GDD aged 6 months to 18 years from March 2009 to April 2017. The severity of ID/GDD was classified as mild (IQ of 55–70), moderate (IQ of 40–54), severe (IQ of 25–39), or profoundly severe (IQ of less than 25). The study evaluated the clinical manifestations, performed genetic analyses, and compared the incidence of different methods used to confirm ID/GDD etiology among groups with differing degrees of ID/GDD.
The main causes of ID/GDD in the children assessed were perinatal factors, such as acquired brain injury, as well as single gene imbalance and chromosomal gene mutation. The study identified karyotype and/or copy number variations (CNVs) in 47.9% of severe ID/GDD patients, which was significantly higher than those with mild and moderate ID/GDD (35.4% and 15.6%, respectively). A total of 61.8% of patients with clear etiology underwent genetic analysis, compared to 50.9% of patients with unclear etiology. Gene structure variation via karyotype analysis and CNV detection increased the proportion of children with confirmed etiology from 51.0% to 56.3%, and second-generation high-throughput sequencing dramatically increased this to 78.9%. Ten novel mutations were detected, including recessive mutations in X-linked genes (ATPase copper transporting alpha and bromodomain and WD repeat domain containing 3) and dominant de novo heterozygous mutations in X-linked genes (cyclin-dependent kinase like 5, protocadherin 19, IQ motif and Sec7 domain 2, and methyl-CpG binding protein 2).
The study highlights that language development retardation was the most common clinical manifestation of mild ID/GDD, noted in 83.5% of the study subjects, followed by learning disabilities in 73.8% and fine motor retardation in 72.8%. In severe ID/GDD, the most common clinical manifestations were a prominent speech delay, gross motor delay since birth, and dysmorphic features. Cerebral imaging revealed abnormal signs in 211 patients, including encephalomalacia foci and ventricular system expansion, brain dysplasia, hydrocephalus, brain atrophy, and abnormal signals in brain white matter.
The study also identified inherited metabolic diseases in eight children, comprising cases of glutaric aciduria type 1 and 2, ornithine ammonia methyltransferase deficiency, pyruvate carboxykinase deficiency, very long-chain acyl-CoA dehydrogenase deficiency, and malonyl-CoA decarboxylase deficiency. Of the 535 ID/GDD cases where karyotype analysis and CNV detection was performed, an abnormal karyotype was observed in 25 cases. Known syndromes were identified in 45.1% of cases, including 1q42-q44 microdeletion syndrome, Angelman syndrome, Prader-Willi syndrome, 1p36 monosomy syndrome, Wolf-Hirschhorn syndrome, cri-du-chat syndrome, Williams-Beuren syndrome, 9p-syndrome, lissencephaly, Smith-Magenis syndrome, Sotos syndrome, 17p12 microduplication syndrome, 22q11.21 microdeletion syndrome, and 22q13 microdeletion syndrome.
The study concludes that genetic analysis is an effective method to increase the proportion of confirmed etiology in ID/GDD children and is highly recommended, especially in ID/GDD children with uncertain etiology. The study also emphasizes the importance of improved pregnancy care and high-risk maternal labor monitoring, improved delivery technology, a reduction in pre-term birth and low birth weight, and timely prevention and treatment of neonatal asphyxia and intracranial hemorrhage as essential measures to reduce ID/GDD children.
The study provides a comprehensive analysis of the etiological characteristics of ID/GDD children in a central region of China, highlighting the significant role of genetic analysis in the early diagnosis and management of ID/GDD. The findings underscore the need for increased awareness and utilization of genetic testing in the diagnostic process of ID/GDD to improve treatment efficacy and life quality for affected children.
doi.org/10.1097/CM9.0000000000000295
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