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Diagnosis of intellectual disability/global developmental delay via genetic analysis in a central region of China.
Chin Med J (Engl) 2019; 132(13):1533-1540CM

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 (χ = 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.

Authors+Show Affiliations

Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China. Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China.Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China.Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China.Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China.Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China.Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China.Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China.Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China.Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China.Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China.Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China.Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410008, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31205075

Citation

Liao, Li-Hong, et al. "Diagnosis of Intellectual Disability/global Developmental Delay Via Genetic Analysis in a Central Region of China." Chinese Medical Journal, vol. 132, no. 13, 2019, pp. 1533-1540.
Liao LH, Chen C, Peng J, et al. Diagnosis of intellectual disability/global developmental delay via genetic analysis in a central region of China. Chin Med J. 2019;132(13):1533-1540.
Liao, L. H., Chen, C., Peng, J., Wu, L. W., He, F., Yang, L. F., ... Yin, F. (2019). Diagnosis of intellectual disability/global developmental delay via genetic analysis in a central region of China. Chinese Medical Journal, 132(13), pp. 1533-1540. doi:10.1097/CM9.0000000000000295.
Liao LH, et al. Diagnosis of Intellectual Disability/global Developmental Delay Via Genetic Analysis in a Central Region of China. Chin Med J. 2019 Jul 5;132(13):1533-1540. PubMed PMID: 31205075.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diagnosis of intellectual disability/global developmental delay via genetic analysis in a central region of China. AU - Liao,Li-Hong, AU - Chen,Chen, AU - Peng,Jing, AU - Wu,Li-Wen, AU - He,Fang, AU - Yang,Li-Fen, AU - Zhang,Ci-Liu, AU - Wang,Guo-Li, AU - Peng,Pan, AU - Ma,Yu-Ping, AU - Miao,Pu, AU - Yin,Fei, PY - 2019/6/18/pubmed PY - 2019/6/18/medline PY - 2019/6/18/entrez SP - 1533 EP - 1540 JF - Chinese medical journal JO - Chin. Med. J. VL - 132 IS - 13 N2 - 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 (χ = 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. SN - 2542-5641 UR - https://www.unboundmedicine.com/medline/citation/31205075/Diagnosis_of_intellectual_disability/global_developmental_delay_via_genetic_analysis_in_a_central_region_of_China L2 - http://dx.doi.org/10.1097/CM9.0000000000000295 DB - PRIME DP - Unbound Medicine ER -