1. Definition and classification of mental retardation There are various definitions of mental retardation, but the current understanding has converged. 1985 WHO proposed the definition of MR: general intellectual functioning during the developmental period is significantly lower than the average level at the same age, accompanied by adaptive behavioral deficits, i.e., there is a clear deficiency in the ability to adapt to the daily demands of the social environment. That is, the dual criteria for the diagnosis of MR are currently recognized and widely used. Since the definition of MR is mainly determined by the two aspects of intellectual functioning and adaptive capacity, its grading is also based on these two aspects. According to the child’s Intelligence Quotient (IQ)/developmental quotient (DQ), MR can be classified into four grades, namely, mild, moderate, severe, and extremely severe: children aged 0-6 years use the DQ diagnostic criteria: extremely severe DQ ≤ 25, severe DQ ∼ 39, moderate DQ ∼ 54, mild DQ ∼ 75, and moderate DQ ∼ 54. Mild DQ ～75; >6 years old children adopt IQ diagnostic criteria: extremely severe IQ <20, severe IQ ～34, moderate IQ ～49, mild IQ ～69, but need to be combined with the results of adaptive behavior assessment to make a comprehensive judgment. It is customary to refer to moderate, severe, and very severe MR collectively as severe MR. Severe MR accounts for about 1/4 to 1/3 of MR, often starting before the age of 6 years, and most of them are caused by biomedical factors, such as genetic disorders or prenatal factors, and are often accompanied by other abnormalities such as facial deformities and epilepsy, which makes it easier to clearly identify the etiology of the diagnosis. Mild MR accounts for about 2/3-3/4 of MR. It is mostly caused by psychosocial and cultural factors, and is commonly found in economically disadvantaged groups. Since there are often no obvious clinical symptoms, most of the cases are not detected until school age, and the etiologic diagnosis is quite difficult. The causes of mental retardation are very complex and can be categorized in a variety of ways. Different categorization methods are helpful in the etiologic diagnosis of MR in clinical practice. At present, the most unified and widely used international classification method was proposed by WHO in 1985, which is divided into ten major categories: ① infections and poisoning; ② mechanical brain injury and hypoxia; ③ metabolic, nutritional, and endocrine disorders; ④ structural brain lesions; ⑤ congenital malformations or hereditary syndromes of the brain; ⑥ chromosomal aberrations; ⑦ perinatal factors; ⑧ accompanying psychiatric illnesses; ⑨ psychosocial factors; ⑩ special sensory deficiencies and other factors. defects and other factors. According to the nature of the etiology, it can be divided into two categories: one is biomedical factors, about 90%, and one is psychosocial and cultural factors, about 10%. According to the time of action of the etiologic factors, they can be divided into three categories: prenatal, perinatal and postnatal. According to the presence or absence of obvious clinical symptoms, it is divided into two categories: ① MR with clinical symptoms, mostly severe, mainly including chromosomal diseases, genetic metabolic diseases, other diseases and other causes of neurological sequelae, etc.; ② MR not accompanied by obvious clinical symptoms, mostly mild and borderline, mostly due to psychosocial and cultural factors. Genetic factors mainly include chromosomal aberrations, genetic syndromes and genetic metabolic diseases, etc. Genetic factors are the most important causative factors for MR/DD patients, accounting for about 50%-70% of the cases with a clear etiological diagnosis, especially chromosome number or structural abnormalities are the most important. Although the number of children born with hereditary diseases has slightly decreased with the development of prenatal screening, genetic counseling and the reduction of consanguineous marriages, these diseases are still the most important cause of severe MR due to their limited therapeutic options. Although the treatment of genetic diseases is still limited and most of them have poor prognosis, a few IMDs, such as phenylketonuria, hepatolabile nuclear degeneration and methylmalonic aciduria, can be treated satisfactorily through early intervention, so early diagnosis and timely treatment can still save some of the affected children. For children with incurable hereditary diseases, early diagnosis is also very important, and after the cause of the disease is clearly identified, genetic counseling can be provided to the family to carry out appropriate pregnancy screening and prenatal diagnosis, thus reducing the birth of children with disabilities, which is of great significance to reduce the burden on the family and the society, and to improve the quality of the population. Therefore, for children with MR/DD who come to the clinic, after a detailed history and careful physical examination, it is significant to choose appropriate laboratory tests according to the clinical characteristics of the child to clarify the etiology of the disease at an early stage of diagnosis. Chromosomal aberrations Diseases caused by numerical or structural abnormalities of chromosomes are called chromosomal disorders, also known as chromosomal aberration syndromes. Chromosomal aberrations have been reported to account for the largest proportion of children with MR/DD, ranging from 4% to 28%. Chromosomal aberrations often involve multiple genes, so they can affect the morphology and function of multiple organs and systems. Clinical manifestations are diverse, and in addition to mental retardation and developmental backwardness, they are often accompanied by multiple malformations: such as special facial features, visceral and skeletal malformations. Chromosomal aberrations that commonly cause MR/DD include 21-3 syndrome, 13-3 syndrome, Turner syndrome, 5p syndrome (cat-call syndrome), Prader-Willi syndrome, Angelman syndrome and fragile X syndrome. In recent years, Fragile X syndrome has been the most widely reported in the literature, and therefore, Fragile X syndrome is used here as a representative of such disorders. Fragile X syndrome (FXS), also known as Martin-Bell syndrome, is a hereditary mental retardation syndrome with a prevalence rate second only to the 21-3 syndrome, accounting for 30% of hereditary mental retardation syndromes. The causative gene is called Fragile X-linked mental retardation type 1 (FMR-1) gene, located at Xq27.3, which has been localized and cloned by Verkerk AJ et al. in 1991. FXS is caused by abnormal amplification of CGG repeats at the 5' end of the FMR-1 gene or abnormal methylation of CpG islands, etc. The gender difference in the incidence of FXS is very obvious, and the incidence of FXS in males is reported to be about 1/1500, with the ratio of male to female incidence being about 4~5:1, and almost all of the affected children in males are severely mentally retarded, while only 30% of female carriers are mentally retarded, with only 30% of them showing mental retardation. Only 30% of female carriers show mental retardation, which is less severe. In addition to mental retardation, FXS may be associated with a long face, large ears, large jaws, and large testes, etc. FXS can be diagnosed by cytogenetic methods, Southern-blot hybridization, and PCR, and more rapid, simple, and inexpensive tests, such as rapid antibody testing for the FMR1 protein in blood smears, have also been reported. Treatment is currently in the exploratory phase, making prenatal screening for FXS important. In general, chromosomal testing should be preferred when children with MR/DD present with the following conditions: ① Combined congenital malformations (e.g., craniofacial malformations, hand and foot anomalies, visceral malformations, etc.); ② Patients with MR/DD in the family; and ③ Mothers with adverse reproductive histories: e.g., recurrent miscarriages, stillbirths, and stillbirths. Due to the improvement of cell culture and staining techniques, the continuous progress of molecular genetics has promoted the development of chromosome localization techniques. In recent years, a large number of chromosomal abnormalities associated with MR/DD have been identified. Since the chromosomal abnormalities in such diseases are usually relatively minor and difficult to detect with conventional chromosomal banding techniques, they are described in a separate section.