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November 1993, Vol 147, No. 11 >
Article | November 1993

Direct DNA Testing for Fragile X Syndrome FREE

Feliciano J. Ramos, MD, PhD; Deborah L. Eunpu, MS; Brenda Finucane, MS; Ellen G. Pfendner, PhD
[+] Author Affiliations

Accepted for publication July 1993.

Reprints not available.


Am J Dis Child. 1993;147(11):1231-1235. doi:10.1001/archpedi.1993.02160350105016.
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• The recent identification of an abnormally amplified trinucleotide (cytosine guanine guanine) repeat in the fragile X gene (FMR-1) of males with fragile X syndrome and their carrier mothers allows the study of the mutation in individuals at risk. In this report, data on 396 patients and 35 normal controls are reported. Included in this sample are patients with no known family history of fragile X syndrome or mental retardation for whom the risks of fragile X syndrome are unclear. All 39 cytogenetically positive affected males and six females had the full mutation, as represented by a restriction fragment size increase (Δ) of 500 base pairs (bp) or more within the cytosine guanine guanine repeat-bearing fragment of the FMR-1 gene; and all 16 of the normal obligate carrier females bore the premutation, as demonstrated by a Δ of 100 to 500 bp. Of 124 patients (62 males and 62 females) with a family history of fragile X syndrome, five (8%) of the males and 25 (40%) of the females had the premutation. Five (2.2%) of the 231 mentally impaired patients with no confirmed family history of fragile X syndrome were found to have the full mutation. Twelve (33%) of 36 mentally impaired males and one (20%) of five females with unknown family history were found to carry an amplified cytosine guanine guanine repeat. Using this technique, we also reevaluated risk assessments previously generated by linkage analysis and unambiguously determined the carrier status of individual family members.

(AJDC. 1993;147:1231-1235)

REFERENCES

1 +
Heitz D, Rousseau F, Devys D, et al.  Isolation of sequences that span the fragile X and identification of a fragile X-related CpC island . Science . 1991;; 251:1236-1239.
2 +
Hirst MC, Rack K, Nakahori Y, et al.  A YAC contig across the fragile X site defines the region of fragility . Nucleic Acids Res . 1991;;19:3283-3288.
3 +
Verkerk A), Pieretti M, Sutcliffe JS, et al.  Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome . Cell . 1991;;65:905-914.
4 +
Kremer EJ, Yu S, Pritchard M, et al.  Isolation of a human DNA sequence which spans the fragile X . Am J Hum Genet . 1991;;49:656-661.
5 +
Dietrich A, Kioschis P, Monaco, et al.  Molecular cloning and analysis of the fragile X region . Nucleic Acids Res . 1991;;19:2567-2572.
6 +
Yu S, Pritchard M, Kremer E, et al.  Fragile X genotype characterized by an unstable region of DNA . Science . 1991;;252:1179-1181.
7 +
Fu Y-H, Kuhl DP, Pizzuti, et al.  Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox . Cell . 1991;;67:1047-1058.
8 +
Oberle L, Rousseau F, Heitz D, et al.  Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome . Science . 1991;;252: 1097-1102.
9 +
Rousseau F, Heitz D, Biancalana V, et al.  Directdiagnosis by DNAanalysis of the fragile X syndrome of mental retardation . N Engl J Med . 1991;;325: 1673-1681.
10 +
Pieretti M, Zhang F, Fu Y, et al.  Absence of expression of the FMR-1 gene in the fragile X syndrome . Cell . 1991;;66:81 7-822.
11 +
Hirst M, Knight S, Davies K, et al.  Prenatal diagnosis of fragile X syndrome . Lancet . 1991;;338:956-958.
12 +
Sutherland GR, Gedeon A, Kornman L, et al.  Prenatal diagnosis of fragile X syndrome by direct detection of the unstable DNA sequence . New Engl J Med . 1991;;325:1720-1722.
13 +
Jacky P, Ahuja Y, Anyame-eboa K, et al.  Guidelines for the preparation and analysis of the fragile X chromosome in lymphocytes . Am J Med Genet . 1991;;38:400-403.
14 +
Thibodeau S, Dorkins H, Faulk k, et al.  Linkage analysis using multiple DNA polymorphic markers in normal families and in families with fragile X syndrome . Hum Genet . 1988;;79:219-227.
15 +
Camerino G, Mattei M, Mattei J, Jaye M, Mandel JL.  Close linkage of fragile X mental retardation syndrome to haemophilia B and transmission through a normal male . Nature . 1983;;306:701-704.
16 +
Hofker MH, Bergen AA, Skraastad Ml, et al.  Efficient isolation of X chromosome specific single copy probes from a cosmid library of a human X/hamster hybrid cell line: mapping of new probes close to the locus for X linked mental retardation . Am J Med Genet . 1987;;40:312-328.
17 +
Boggs B, Nussbaum R.  Two anonymous X specific human sequences detecting restriction fragment length polymorphisms in region Xq26-qter . Somatic Cell Mol Genet . 1984;;10:607-613.
18 +
Oostra BA, Hupkes PE, Perdon LF, et al.  New polymorphic DNA marker close to the fragile site FRAXA . Genomics . 1990;;6:129-132.
19 +
Suthers G, Callen D, Hyland V, et al.  A new marker tightly linked to the fragile X locus (FRAXA) . Science . 1989;;246:1298-1300.
20 +
Patterson M, Bell M, Bloomfield J, et al.  Genetic and physical mapping of a novel region close to the fragile X site on the human X chromosome . Genomics . 1989;;4:570-578.
21 +
Dahl N, Hammarstrom-Heeroma K, Goonewardena P, et al.  Isolation of a DNA probe of potential use for diagnosis of the fragile X syndrome . Hum Genet . 1989;;82:216-218.
22 +
Oberle I, Drayna D, Camerino G, White R, Mandel J-L.  The telomeric region of the human X chromosomes long arms: presence of a highly polymorphic DNA marker and analysis of recombination frequency . Proc Natl Acad Sci U S A . 1985;;82:2824-2828.
23 +
Lathrop G, Lalouel J, Julier C, et al.  Multilocus linkage analysis in humans: detection of linkage and estimation of recombination . Am J Hum Genet . 1985;;37:482-498.
24 +
Sherman SL, Jacobs p, Morton N, et al.  Further segregation analysis of the fragile X syndrome with special reference to transmitting males . Hum Genet . 1985;;69:289-299.
25 +
Riggins GJ, Sherman SL, Oostra BA, et al.  Characterization of a highly polymorphic dinucleotide repeat 150kb proximal to the fragile X site . Am J Med Genet . 1992;;43:282-289.
26 +
Yu S, Mulley J, Loesch D, et al.  Fragile X syndrome: unique genetics of the heritable unstable element . Am J Hum Genet . 1992;;50:968-980.
27 +
Jacobs PA.  The fragile X syndrome . J Med Genet . 1991;;28:809-810.
28 +
Sherman SL, Rogatko A, Turner G.  Recurrence risks for relatives in families with an isolated case of the FXS . Am J Med Genet . 1988;;31:753-765.
29 +
de Vries B, Wiegers AM, de Graaff E, et al.  Mental status and fragile X expression in relation to FMR-1 gene mutation . Eur JHum Genet . 1993;;1:72-79.

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References

1 +
Heitz D, Rousseau F, Devys D, et al.  Isolation of sequences that span the fragile X and identification of a fragile X-related CpC island . Science . 1991;; 251:1236-1239.
2 +
Hirst MC, Rack K, Nakahori Y, et al.  A YAC contig across the fragile X site defines the region of fragility . Nucleic Acids Res . 1991;;19:3283-3288.
3 +
Verkerk A), Pieretti M, Sutcliffe JS, et al.  Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome . Cell . 1991;;65:905-914.
4 +
Kremer EJ, Yu S, Pritchard M, et al.  Isolation of a human DNA sequence which spans the fragile X . Am J Hum Genet . 1991;;49:656-661.
5 +
Dietrich A, Kioschis P, Monaco, et al.  Molecular cloning and analysis of the fragile X region . Nucleic Acids Res . 1991;;19:2567-2572.
6 +
Yu S, Pritchard M, Kremer E, et al.  Fragile X genotype characterized by an unstable region of DNA . Science . 1991;;252:1179-1181.
7 +
Fu Y-H, Kuhl DP, Pizzuti, et al.  Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox . Cell . 1991;;67:1047-1058.
8 +
Oberle L, Rousseau F, Heitz D, et al.  Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome . Science . 1991;;252: 1097-1102.
9 +
Rousseau F, Heitz D, Biancalana V, et al.  Directdiagnosis by DNAanalysis of the fragile X syndrome of mental retardation . N Engl J Med . 1991;;325: 1673-1681.
10 +
Pieretti M, Zhang F, Fu Y, et al.  Absence of expression of the FMR-1 gene in the fragile X syndrome . Cell . 1991;;66:81 7-822.
11 +
Hirst M, Knight S, Davies K, et al.  Prenatal diagnosis of fragile X syndrome . Lancet . 1991;;338:956-958.
12 +
Sutherland GR, Gedeon A, Kornman L, et al.  Prenatal diagnosis of fragile X syndrome by direct detection of the unstable DNA sequence . New Engl J Med . 1991;;325:1720-1722.
13 +
Jacky P, Ahuja Y, Anyame-eboa K, et al.  Guidelines for the preparation and analysis of the fragile X chromosome in lymphocytes . Am J Med Genet . 1991;;38:400-403.
14 +
Thibodeau S, Dorkins H, Faulk k, et al.  Linkage analysis using multiple DNA polymorphic markers in normal families and in families with fragile X syndrome . Hum Genet . 1988;;79:219-227.
15 +
Camerino G, Mattei M, Mattei J, Jaye M, Mandel JL.  Close linkage of fragile X mental retardation syndrome to haemophilia B and transmission through a normal male . Nature . 1983;;306:701-704.
16 +
Hofker MH, Bergen AA, Skraastad Ml, et al.  Efficient isolation of X chromosome specific single copy probes from a cosmid library of a human X/hamster hybrid cell line: mapping of new probes close to the locus for X linked mental retardation . Am J Med Genet . 1987;;40:312-328.
17 +
Boggs B, Nussbaum R.  Two anonymous X specific human sequences detecting restriction fragment length polymorphisms in region Xq26-qter . Somatic Cell Mol Genet . 1984;;10:607-613.
18 +
Oostra BA, Hupkes PE, Perdon LF, et al.  New polymorphic DNA marker close to the fragile site FRAXA . Genomics . 1990;;6:129-132.
19 +
Suthers G, Callen D, Hyland V, et al.  A new marker tightly linked to the fragile X locus (FRAXA) . Science . 1989;;246:1298-1300.
20 +
Patterson M, Bell M, Bloomfield J, et al.  Genetic and physical mapping of a novel region close to the fragile X site on the human X chromosome . Genomics . 1989;;4:570-578.
21 +
Dahl N, Hammarstrom-Heeroma K, Goonewardena P, et al.  Isolation of a DNA probe of potential use for diagnosis of the fragile X syndrome . Hum Genet . 1989;;82:216-218.
22 +
Oberle I, Drayna D, Camerino G, White R, Mandel J-L.  The telomeric region of the human X chromosomes long arms: presence of a highly polymorphic DNA marker and analysis of recombination frequency . Proc Natl Acad Sci U S A . 1985;;82:2824-2828.
23 +
Lathrop G, Lalouel J, Julier C, et al.  Multilocus linkage analysis in humans: detection of linkage and estimation of recombination . Am J Hum Genet . 1985;;37:482-498.
24 +
Sherman SL, Jacobs p, Morton N, et al.  Further segregation analysis of the fragile X syndrome with special reference to transmitting males . Hum Genet . 1985;;69:289-299.
25 +
Riggins GJ, Sherman SL, Oostra BA, et al.  Characterization of a highly polymorphic dinucleotide repeat 150kb proximal to the fragile X site . Am J Med Genet . 1992;;43:282-289.
26 +
Yu S, Mulley J, Loesch D, et al.  Fragile X syndrome: unique genetics of the heritable unstable element . Am J Hum Genet . 1992;;50:968-980.
27 +
Jacobs PA.  The fragile X syndrome . J Med Genet . 1991;;28:809-810.
28 +
Sherman SL, Rogatko A, Turner G.  Recurrence risks for relatives in families with an isolated case of the FXS . Am J Med Genet . 1988;;31:753-765.
29 +
de Vries B, Wiegers AM, de Graaff E, et al.  Mental status and fragile X expression in relation to FMR-1 gene mutation . Eur JHum Genet . 1993;;1:72-79.

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