Fragile X screening program in New York State

Most fragile X [fra(X)] males in New York State have not been identified. Hence, a large number of female relatives are unaware of their risks for having an affected child. A program was established in New York State in 1987 to screen for the fra(X) syndrome in mentally retarded males with living relatives. The goal of the program is to identify affected males and inform their families about the diagnosis. In this way relatives would be able to assess their risks for having a fra(X) male. In order to identify the males a screening form was developed to assess 10 features which included physical characteristics, behavior, and family history. Males who exhibited at least 5 of these manifestations were selected for cytogenetic analysis. Any male who had macroorchidism or a family history of mental retardation was also included. A total of 995 males have been screened of which 352 (35%) were selected for cytogenetic analyses. Seventeen (10.5%) of the 161 completed studies were positive for fra(X). A large number of possible female carriers were identified in the families of the propositi. This program identifies fra(X) males in a population of the mentally retarded for whom there had been no previous diagnosis. By using a two-step procedure, it is possible to screen a large population of the mentally retarded for fra(X) without testing each male cytogenetically.     

Preventive screening for the fragile X syndrome

In an Australian population of 1.2 million, we screened 1977 intellectually handicapped persons, who were identified through the public schools and sheltered workshops, for the X-linked semidominant fragile X syndrome. We excluded 527 because they had another known diagnosis. The remaining 1450 were offered chromosomal analysis. Of the 1117 who consented (77 percent), an additional 196 were excluded, and among the 921 who were tested cytogenetically, 40 probands were found. Prevalence rates for persons with an intellectual handicap and the fragile X syndrome in the public school population were 1:2610 for males and 1:4221 for females. Family studies identified 84 women who were either obligate carriers or at high risk of being carriers, who were under the age of 35 and had no children. These women were given genetic counseling, and the availability of antenatal diagnosis was explained to them. If each of these 84 women had two children, 27 of their sons would have an intellectual handicap. We recommend cytogenetic screening for the fragile X syndrome in all currently identified intellectually handicapped people, followed by routine screening of children newly identified as intellectually handicapped in the school system.     

应用PCR快速筛查脆性X综合征患儿

目的应用PCR快速筛查脆性X综合征患儿。方法采用PCR和聚丙烯酰胺凝胶电泳技术,对24例不明原因智力低下患儿的脆性X基因（CGG）n重复序列进行检测。结果在24例不明原因智力低下患儿中,筛查出1例脆性X综合征患者。结沦采用PCR技术扩增脆性X基因的（CGG）n重复序列,可对脆性X综合征患者进行快速筛查。     

脆性X综合征的快速PCR筛查

目的建立一种简便、快速、经济的脆性X综合征基因筛查PCR方法.方法通过提高预变性温度联合应用betaine扩增FMR1基因的三核苷酸重复序列.结果本方法扩增正常等位基因效率高,重复性好.结论该方法简便、价廉,可用于高危人群的快速筛查.     

Maternal attitudes to newborn screening for fragile X syndrome

Although fragile X syndrome (FXS) is the commonest cause of inherited intellectual disability the mean age of diagnosis in Australia is 5.5 years. Newborn screening for FXS can provide an early diagnosis, preventing the “diagnostic odyssey”, allowing access to early interventions, and providing reproductive information for parents. Parents of affected children support newborn screening, but few clinical studies have evaluated community attitudes. A pilot study in 2009–2010 was performed in a tertiary hospital to explore feasibility and maternal attitudes. FXS testing of male and female newborns was offered to mothers in addition to routine newborn screening. Mothers were provided with information about FXS, inheritance pattern, carrier status, and associated adult‐onset disorders. One thousand nine hundred seventy‐one of 2,094 mothers (94%) consented to testing of 2,000 newborns. 86% completed the attitudinal survey and 10% provided written comments. Almost all parents (99%) elected to be informed of both premutation and full mutation status and there was little concern about identification of carrier status or associated adult‐onset disorders. Most mothers (96%) were comfortable being approached in the postnatal period and supported testing because no extra blood test was required. Mothers considered an early diagnosis beneficial to help prepare for a child with additional needs (93%) and for reproductive planning (64%). Some were anxious about the potential test results (10%) and others felt their feelings towards their newborn may change if diagnosed with FXS (16%). High participation rates and maternal attitudes indicate a high level of maternal acceptance and voluntary support for newborn screening for FXS. © 2013 Wiley Periodicals, Inc.     

Brief screening questionnaire for determining affected state in fragile X syndrome: a consensus recommendation.

New molecular research has provided strong evidence for different forms of the fragile X mutation. These findings suggest the need to develop a more standardized and sensitive method for determining neurobehavioral effects of the fragile X gene(s), particularly for molecular studies of patients who do not have obvious mental retardation. This report describes a brief screening questionnaire designed to increase the detection of neurobehavioral dysfunction in individuals from fragile X families who are included in new molecular studies. Improved detection of the affected state in fragile X syndrome will allow more valid clinical data to be correlated with the important molecular information currently being collected.     

Newborn screening for Tyr-I: two years' experience of the New York State program

In 2 years, the New York newborn screening program has analyzed approximately 500,000 samples for succinylacetone (SUAC), the biomarker for Tyrosinemia, type I. There have been five screen-positive results. Two of these results were considered borderline, and a repeat specimen was requested. In three cases, an immediate referral was made to a specialty care center. Two of those three cases were confirmed for Tyr-I.     

Applicability of a checklist for clinical screening of the fragile X syndrome

In a population of 340000 in Southern Häme, Finland, there were 541 intellectually disabled adult males (> 16 years) known to the District Organisation for the Care of the Mentally Retarded in August 1993. Of these, 197 already had a confirmed etiological diagnosis, with 20 having the fragile X syndrome. The other 344 males were screened for the fragile X syndrome using a three-step method: a clinical checklist used by a specialist nurse, a clinical examination by a physician who was very familiar with the fragile X syndrome, and the FRAXA-locus gene test. Six new fragile X males were found. The minimum prevalence of the fragile X syndrome in the district was calculated to be 1:4400.     

A systematic review of population screening for fragile X syndrome

PurposeTo conduct a systematic review of literature regarding population-based screening for fragile X syndrome in newborns and women of reproductive age, either before or during pregnancy.MethodsSeven electronic databases were searched for English language studies published between January 1991 and November 2009. Data extraction was performed for all included studies. Results were synthesized using a narrative approach.ResultsOne article that examined offering newborn screening for fragile X syndrome and 10 that examined the offer of fragile X syndrome screening to women of reproductive age were identified. Two of these articles also addressed psychosocial aspects of population screening for fragile X syndrome such as attitudes to screening and experiences of screening, and a further nine addressed these issues alone. Studies exploring psychosocial issues demonstrated challenges for counseling arising from a lack of awareness or personal experience with fragile X syndrome in the general population.ConclusionsTargeted counseling and educational strategies will be essential to support women from the general population. It is crucial that future studies offering screening for fragile X syndrome explore a range of psychosocial aspects in addition to looking at uptake of testing and mutation frequency.     

Molecular screening for fragile X syndrome in mentally handicapped children in Korea.

Fragile X syndrome is one of the most common forms of inherited mental retardation and is caused by the expansion of the CGG trinucleotide repeats in the FMR-1 gene. This study was aimed to facilitate the molecular screening of fragile X syndrome in Korean children with mental retardation of unknown etiology. The subjects were tested by Expand Long Template PCR system in the presence of 7-deaza-dGTP, and then by Southern blot analysis. The PCR method provided rapid and reliable results for the identification of fragile X negative and positive patients. One hundred one mentally retarded children (78 males and 23 females) were screened by PCR amplification, which detected only one abnormal sample. The PCR-positive case was confirmed by the CGG repeat expansion on Southern blot analysis with a positive cytogenetic result. In conclusion, Expand Long Template PCR may be used as the first screening test for detecting the fragile X syndrome.     

The fragile X syndrome.

The fragile X syndrome is characterised by mental retardation, behavioural features, and physical features, such as a long face with large protruding ears and macro-orchidism. In 1991, after identification of the fragile X mental retardation (FMR1) gene, the cytogenetic marker (a fragile site at Xq27.3) became replaced by molecular diagnosis. The fragile X syndrome was one of the first examples of a "novel" class of disorders caused by a trinucleotide repeat expansion. In the normal population, the CGG repeat varies from six to 54 units. Affected subjects have expanded CGG repeats (>200) in the first exon of the FMR1 gene (the full mutation). Phenotypically normal carriers of the fragile X syndrome have a repeat in the 43 to 200 range (the premutation). The cloning of the FMR1 gene led to the characterisation of its protein product FMRP, encouraged further clinical studies, and opened up the possibility of more accurate family studies and fragile X screening programmes.     

Clinical screening score for the fragile X (Martin-Bell) syndrome

A clinical score based on the manifestations of the fragile(X) syndrome has been formulated and applied to all individuals included in a fragile(X) case finding program in New South Wales. The total score can vary from 0 to 10. Individuals are scored 0, 1, or 2 in each of 5 categories considered indicative of the fragile(X) phenotype: family history of intellectual handicap, face length, ear configuration, personality, and body habitus. In a study of 1,206 individuals where the clinical scores were prospective (i.e., they had been given before the cytogenetic results were known) the percentage of those with the fragile(X) increased from 0.6% of those with scores of 4 or less to 14.6% with scores 5-7 and to 67% of those with scores 8-10. We have found the score simple to use in the circumstances where screening takes place (sheltered workshops and schools) and have reduced the number of individuals tested cytogenetically by 45%.     

Slowdown PCR法产前快速筛查脆性X综合征

目的研究产前快速筛查脆性X综合征的基因检测方法。方法收集临床疑似脆性X综合征的男性智力低下患儿病例,采集相应患儿外周血,同时收集需要进行胎儿脆性X综合征产前筛查和诊断的孕妇病例,在孕20w收集孕妇的羊水。通过slowdownPCR方法检测FMR1基因(CGG)n三核苷酸重复顺序基因组,并采用测序方法进行验证。结果共检测疑似病例30例,通过slowdown PCR方法简化了检测步骤,缩短了检测时间,整个检测过程缩短至2h,检测PCR产物片段与测序结果完全吻合。结论采用Slowdown PCR方法替代传统普通的PCR,提高了基因扩增效率,解决了由于基因CG含量过高导致PCR扩增困难和稳定性差的技术难题。