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X fragile - Europe

X fragile : diagnostic (méthode recommandée par les Généticiens)

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http://www.x-fragile.eu//documents/2012xfrarecommendationsregardingFMR1testing_be21c563a2334b0e9fa70feb279153d1.doc
 

Dear all, 

I would like to comment on the question of Mr Compere regarding this novel test and regarding population screening. 

This novel test is one of the many commercially available tests on the market. 

However, in all 8 genetic centers in Belgium the classical FMR1 test is done conform guidelines and accreditation. For example in Leuven our diagnostic lab is accredited. There is currently no need to use other commercially available test since population-wide screening is not performed in our country. 

In this regard, the clinical working group of the Belgian Society for Human Genetics has provided recommendations for many genetic tests, on request of the High Council. I have attached the document about good clinical practice for FMR1 testing for your reading.  

I will not be able to come on 30/11 because I am at a meeting abroad. 

Kind regards, 

Hilde 

prof. dr. Hilde Van Esch
adjunct-kliniekhoofd
centrum menselijke erfelijkheid - center for human genetics 

Hilde.VanEsch@uzleuven.be 

tel. secr. +32 16 34 59 03 fax +32 16 34 60 51 

UZ Leuven | campus Gasthuisberg | Herestraat 49 | B - 3000 Leuven | www.uzleuven.be 

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BeSHG Workgroup 29 april 2011-04-28 - Clinical indications for FMR-1 analysis  

Frequency of Fragile X pre/full mutation. 

- males with the full mutation : 1/4000. 

- women carriers of the premutation : 1/246 to 1/550. 

- screening children with learning difficulties reveals a ‘new’ case of fragile X syndrome in about 1%. 

Technology of testing 

The diagnostic procedures are mainly based on southern blotting or on direct amplification of the CGG repeat using flanking primers. 

Indications for screening 

FMR1 testing is indicated in several clinical situations: 

 

I. Fragile X syndrome : 

FMR1 testing is indicated in the evaluation of patients (male and female) with intellectual disability, learning disorder, and/or autism. 

- FMR1 testing is indicated as part of the first line of the etiological work-up in :  

Individuals of either sex with mental retardation, developmental delay, or autism, in the presence of : 

(a) physical or behavioral characteristics of fragile X syndrome*.  

and/or 

(b) a family history of fragile X syndrome, if the pedigree structure indicates that the patient is at risk of inheriting the mutated gene. 

and/or 

(c) male or female relatives with undiagnosed mental retardation, and a pedigree structure indicating a possible X linked transmission. 

*The clinical features of Fragile X are subtle, and there is commonly a delay in making a specific diagnosis. 

The degree of impairment can vary from profound handicap through to isolated learning problems but most affected males have a severe to moderate degree of impairment, with IQs in the range of 35–49. 

Typical, but not specific behavioural problems include: avoidance of gaze, repetitive mannerism and obsessional traits, hyperactivity, repetitive speech patterns (unusual rhythm and perseverative phraseology). 

Physical signs include: large heads for their age (greater than the 50th centile), large ears and a ‘long’ face. Macroorchidism is present only in 20% of prepubertal boys. 

- FMR1 testing is recommended as part of the etiological work-up in individuals of either sex with mental retardation, developmental delay, or autism. In these situations, FMR1 testing should be performed as part of a comprehensive genetic evaluation that includes cytogenetic analysis (CGH array). Cytogenetic studies are critical, since constitutional chromosome abnormalities have been identified as frequently or more frequently than fragile X mutations in mentally retarded individuals referred for fragile X testing. 

 

II. Premature ovarian failure 

 

FMR1 testing is indicated for women who have reproductive or fertility problems associated with an elevated level of follicule stimulating hormone (FSH) before the age of 40 years.  

Especially, but not only, if they have  

(a) a family history of premature ovarian failure, and a pedigree history consistent with an X linked transmission. 

and/or 

(b) a family history of fragile X syndrome, if the pedigree structure indicates that the patient is at risk of inheriting the mutated gene. 

and/or 

(c) male or female relatives with undiagnosed mental retardation and a pedigree structure indicating a possible X-linked transmission. 

 

III. Tremor/ataxia syndrome (FXTAS): 

 

FMR1 testing is indicated in men and women who are experiencing late onset intention tremor and cerebellar ataxia of unknown origin, especially if they have : 

(a) a family history of movement disorders, and a pedigree structure consistent with an X linked transmission. 

and/or 

(b) a family history of fragile X syndrome, if the pedigree structure indicates that the patient is at risk of inheriting the mutated gene. 

and/or 

(c) male or female relatives with undiagnosed mental retardation, and a pedigree structure consistent with an X-linked transmission 

and/or 

(d) a brain MRI suggestive of FXTAS (white matter lesions in the middle cerebellar peduncles and/or brain stem). 

 

IV. Genetic counselling 

 

1) Individuals seeking reproductive counselling 

(a) Fragile X testing is indicated for a woman with a family history of fragile X syndrome, fragile X tremor/ataxia syndrome, or premature ovarian failure (in more than one family member) if the pedigree structure indicates that she is at risk of inheriting the mutated gene. Referral to a medical geneticist for counselling and assessment should be considered in these cases. 

(b) Fragile X testing is indicated for a woman with a family history of undiagnosed mental retardation, if the pedigree structure is consistent with an X-linked transmission, and is indicating that the patient is at risk of inheriting the mutated gene. 

 

2) Foetuses of known carrier mothers. 

Prenatal fetal testing via chorionic villus sampling or amniocentesis should be offered to women who are confirmed to be carriers of a premutation or full mutation of the FMR-1 gene. 

Ideally DNA testing should be performed on cultured amniocytes obtained by amniocentesis after 14 weeks’ gestation, but in this case the result is available around 18 weeks’gestation. DNA testing can be performed on chorionic villi obtained by CVS at 10 to 12 weeks’ gestation, but the results must be interpreted with caution because the methylation status of the FMR1 gene is often not yet established in chorionic villi at the time of sampling. A follow-up amniocentesis may be necessary to resolve an ambiguous result. 

 

3) “Cascade counselling” 

FMR1 testing should be offered to relatives of carriers of an FMR1 full-or premutation. 

Simulations indicate that case-finding and cascade counselling can reach about half of the premutation carriers, if index cases in the family were used as starting points and testing extended to fifth-degree relatives. If performed in the case of a full FMR1 mutation, identified carrier would include most of those at the highest risk of having a child with fragile X syndrome, as permutation in these families has demonstrated its unstability. 

Cascade counselling should be performed by a medical geneticist. Individuals should be tested at an appropriate life stage. 

 

4) Population screening 

Population carrier screening is not recommended at this time, except as part of a well-defined clinical research protocol.  

While the DNA test is very accurate, two issues limit the application of FMR1 testing as a general prenatal population screening. 

a. An uncertainty remains about the risks for women from the general population with FMR1 premutation with 55–65 CGG repeats. 30% of woman identified with an FMR1 permutation have CGG repetition between 56-65 (in a study where woman with CGG repetition between 50 and 55 account for 40% of the identified permutation carriers (Toledano-Alhadef et al)). The repartition of the number of CGG repeat in this population, and its low but uncertain risk of expansion to a full mutation might lead to a high number of undue prenatal testing.  

Considerable work must be done before instituting general population screening protocols regarding identification and management of intermediate allele carriers. 

b. The nature of different phenotypes associated with the FMR1 mutation in its premutation and full mutation forms and the inheritance pattern are complex, the approach to genetic counseling for different phenotypes including early onset disorder of mental retardation, adult onset of premature ovarian failure, and a late onset disorder associated with neurodegeneration, all within the same family has not yet been addressed at a clinical level much less a population screening level. 

References 

Pembrey ME, Barnicoat AJ, Carmichael B, Bobrow M, Turner G. An assessment of screening strategies for fragile X syndrome in the UK. Health Technol Assess. 2001;5(7):1-95. 

Allyn McConkie-Rosell, Brenda Finucane, Amy Cronister, Liane Abrams, Robin L. Bennett, and Barbara J. Pettersen. Genetic Counseling for Fragile X Syndrome: Updated Recommendations of the National Society of Genetic Counselors. Journal of Genetic Counseling, 2005. Vol. 14, No. 4. 249-70. 

Sherman S, Pletcher BA, Driscoll DA.  Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005 Oct;7(8):584-7. 

Chitayat DWyatt PRWilson RDJohnson JAAudibert FAllen VGagnon ALanglois SBlight CBrock JADésilets VFarell SAGeraghty MNelson TNikkel SMSkidmore D,Shugar. Fragile X testing in obstetrics and gynaecology in Canada. AJ Obstet Gynaecol Can. 2008 Sep;30(9):837-46. 

Toledano-Alhadef H, Basel-Vanagaite L, Magal N, Davidov B, Ehrlich S, Drasinover V, Taub E, Halpern GJ, Ginott N, Shohat M. Fragile-X carrier screening and the prevalence of premutation and full-mutation carriers in Israel. Am J Hum Genet. 2001 Aug;69(2):351-60. Epub 2001 Jul 6. 

Nolin SL, Dobkin C, Brown WT  Molecular analysis of fragile X syndrome. Curr Protoc Hum Genet. 2003 Nov;Chapter 9:Unit9.5.