Fragile X syndrome (FXS) is the most common monogenic form of inherited intellectual disability and autism spectrum disorder (ASD). More than 99% of individuals with FXS are caused by the unstable expansion of CGG repeats located within the 5\'-untranslated region of the FMR1 gene. The clinical features of FXS include various degrees of cognitive deficit, physical, behavioral and psychiatric problems. Early treatment and prevention from having further affected children can be guided by molecular genetic testing of the FMR1 gene. The following guideline has combined the relevant research, guidelines and consensus worldwide, and summarized the genetic knowledge and clinical treatment for FXS in order to achieve a standardized diagnosis, treatment and prevention for patients and families affected by this disease.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. Many providers offer preconception or prenatal FXS carrier screening. However, guidelines recommend screening only for those with a family history or undergoing fertility evaluation. Wider screening has been resisted because of concerns about patient understanding of FXS-associated inheritance patterns and phenotypes. Additionally, the clinical utility has been questioned.
We addressed these concerns by analyzing reproductive decision-making and pregnancy management informed by post-test genetic consultation among 122 FMR1 premutation carriers identified by expanded carrier screening.
Sixty-three percent of those screened met guidelines screening criteria; the remaining 37% did not. Ninety-eight percent had undergone post-test genetic consultation. Of respondents screened preconceptionally, 74% reported planning or pursuing actions to reduce the risk of an affected pregnancy; the extent to which couples planned/pursued these actions was not significantly different between those meeting either screening criterion (76%) versus those meeting neither criterion (55%). Of respondents screened prenatally, 41% pursued prenatal diagnostic testing; the extent to which couples pursued prenatal diagnosis was not significantly different between those who met either screening criterion (37%) versus those who met neither criterion (31%).
These results support the expansion of FXS screening criteria in guidelines.

Fragile X Syndrome (FXS) is the most common genetic cause of inherited intellectual disability and autism spectrum disorder (ASD). Early identification results in appropriate management and improvement in functioning. Risk assessment in other family members can lead to prevention of the disorder. This necessitated the formulation of IAP recommendations for the diagnosis and management of FXS in Indian children and adolescents.
The meeting on formulation of national consensus guidelines on Fragile X syndrome was organized by the Indian Academy of Pediatrics in New Delhi on 25th February, 2017. The invited experts included Pediatricians, Developmental Pediatricians, Psychiatrists, Pediatric Neurologists, Gynecologists, Geneticists, Clinical Psychologists and Remedial Educators, and representatives of Parent Organizations. Guidelines were framed after extensive discussions. A writing committee was formed that drafted the manuscript, which was circulated among members for critical appraisal, and finalized.
The committee recommended that early diagnosis of FXS is crucial for early, timely and appropriate management. The interventions including timely occupational therapy, speech therapy and behavioral modifications help to improve the developmental potential and reduce the maladaptive behavior. Pharmacotherapy may be needed to control and improve behavioral symptoms. In addition, the emergence of targeted treatments such as low dose sertraline, metformin and /or minocycline may also be helpful for behavior, and perhaps cognition. Genetic counselling is helpful to communicate the risk for future children with FXS or permutation involvement.

Different mutations occurring in the unstable CGG repeat in 5\' untranslated region of FMR1 gene are responsible for three fragile X-associated disorders. An expansion of over ∼200 CGG repeats when associated with abnormal methylation and inactivation of the promoter is the mutation termed \'full mutation\' and is responsible for fragile X syndrome (FXS), a neurodevelopmental disorder described as the most common cause of inherited intellectual impairment. The term \'abnormal methylation\' is used here to distinguish the DNA methylation induced by the expanded repeat from the \'normal methylation\' occurring on the inactive X chromosomes in females with normal, premutation, and full mutation alleles. All male and roughly half of the female full mutation carriers have FXS. Another anomaly termed \'premutation\' is characterized by the presence of 55 to ∼200 CGGs without abnormal methylation, and is the cause of two other diseases with incomplete penetrance. One is fragile X-associated primary ovarian insufficiency (FXPOI), which is characterized by a large spectrum of ovarian dysfunction phenotypes and possible early menopause as the end stage. The other is fragile X-associated tremor/ataxia syndrome (FXTAS), which is a late onset neurodegenerative disorder affecting males and females. Because of the particular pattern and transmission of the CGG repeat, appropriate molecular testing and reporting is very important for the optimal genetic counselling in the three fragile X-associated disorders. Here, we describe best practice guidelines for genetic analysis and reporting in FXS, FXPOI, and FXTAS, including carrier and prenatal testing.

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Molecular genetic testing of the FMR1 gene is commonly performed in clinical laboratories. Mutations in the FMR1 gene are associated with fragile X syndrome, fragile X tremor ataxia syndrome, and premature ovarian insufficiency. This document provides updated information regarding FMR1 gene mutations, including prevalence, genotype-phenotype correlation, and mutation nomenclature. Methodological considerations are provided for Southern blot analysis and polymerase chain reaction amplification of the FMR1 gene, including triplet repeat-primed and methylation-specific polymerase chain reaction. In addition to report elements, examples of laboratory reports for various genotypes are also included.

Fragile X syndrome (FXS) is one of several clinical disorders associated with mutations in the X-linked Fragile X Mental Retardation-1 (FMR1) gene. With evolving knowledge about the phenotypic consequences of FMR1 transcription and translation, sharp clinical distinctions between pre- and full mutations have become more fluid. The complexity of the issues surrounding genetic testing and management of FMR1-associated disorders has increased; and several aspects of genetic counseling for FMR1 mutations remain challenging, including risk assessment for intermediate alleles and the widely variable clinical prognosis for females with full mutations. FMR1 mutation testing is increasingly being offered to women without known risk factors, and newborn screening for FXS is underway in research-based pilot studies. Each diagnosis of an FMR1 mutation has far-reaching clinical and reproductive implications for the extended family. The interest in large-scale population screening is likely to increase due to patient demand and awareness, and as targeted pharmaceutical treatments for FXS become available over the next decade. Given these developments and the likelihood of more widespread screening, genetic counselors across a variety of healthcare settings will increasingly be called upon to address complex diagnostic, psychosocial, and management issues related to FMR1 gene mutations. The following guidelines are intended to assist genetic counselors in providing accurate risk assessment and appropriate educational and supportive counseling for individuals with positive test results and families affected by FMR1-associated disorders.

Genetic testing is recommended for patients with ASD; however specific recommendations vary by specialty. American Academy of Pediatrics and American Academy of Neurology guidelines recommend G-banded karyotype and Fragile X DNA. The American College of Medical Genetics recommends Chromosomal Microarray Analysis (CMA). We determined the yield of CMA (N = 85), karyotype (N = 119), and fragile X (N = 174) testing in a primary pediatrics autism practice. We found twenty (24%) patients with abnormal CMA results (eight were clinically significant), three abnormal karyotypes and one Fragile X syndrome. There was no relationship between CMA result and cognitive level, seizures, dysmorphology, congenital malformations or behavior. We conclude that CMA should be the clinical standard in all specialties for first tier genetic testing in ASD.

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