Diagnosis of intellectual disability/global developmental delay via genetic analysis in a central region of China

Li-hong Liao; Chen Chen; Jing Peng; Li-wen WU; Fang HE; Li-fen Yang; Ci-liu Zhang; Guo-li Wang; Pan Peng; Yu-ping MA; Pu Miao; Fei Yin

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Diagnosis of intellectual disability/global developmental delay via genetic analysis in a central region of China

Author: Li-Hong LIAO ^{1
,

2
,

3} ; Chen CHEN ^{1
,

2} ; Jing PENG ^{1
,

2} ; Li-Wen WU ^{1
,

2} ; Fang HE ^{1
,

2} ; Li-Fen YANG ^{1
,

2} ; Ci-Liu ZHANG ^{1
,

2} ; Guo-Li WANG ^{1
,

2} ; Pan PENG ^{1
,

2} ; Yu-Ping MA ^{1
,

2} ; Pu MIAO ^{1
,

2} ; Fei YIN ^{1
,

2}
Author Information

1. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
2. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China
3. Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China
Publication Type:Journal Article
Keywords: Intellectual disability; Global developmental delay; Children; Gene analysis; Etiology
From: Chinese Medical Journal 2019;132(13):1533-1540
CountryChina
Language:English
Abstract: Background:Advanced technology has become a valuable tool in etiological studies of intellectual disability/global developmental delay (ID/GDD). The present study investigated the role of genetic analysis to confirm the etiology in ID/GDD patients where the cause of the disease was uncertain in central China.
Methods:We evaluated 1051 ID/GDD children aged 6 months to 18 years from March 2009 to April 2017. Data concerning basic clinical manifestations were collected, and the method of etiology confirmation was recorded. Genome-wide copy number variations (CNVs) detection and high-throughput sequencing of exons in the targeted regions was performed to identify genetically-based etiologies. We compared the incidence of different methods used to confirm ID/GDD etiology among groups with differing degrees of ID/GDD using the Chi-square or Fisher exact probability test.
Results:We recruited 1051 children with mild (367, 34.9%), moderate (301, 28.6%), severe (310, 29.5%), and profoundly severe (73, 6.9%) 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. We identified karyotype and/or CNVs variation in 46/96 (47.9%) of cases in severe ID/GDD patients, which was significantly higher than those with mild and moderate ID/GDD of 34/96 (35.4%) and 15/96 (15.6%), respectively. A total of 331/536 (61.8%) patients with clear etiology have undergone genetic analysis while 262/515 (50.9%) patients with unclear etiology have undergone genetic analysis (χ² = 12.645, P < 0.001). 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, 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) were reported in the study.
Conclusions:The present study indicates 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.