Supplementary Material

Table 1a1 Methodological quality of all studies reporting chromosome investigations

AuthorMidenet AitkenMoserNewtonWarter JacobsAllySoudekNarahara MogheKodama Proops

Year197019711971197219751978197919791981198519821983

Reference number32203334,35363738,392840414243

Study group

  • Description A++++++++++++ ++++
  • Clinical relevance B++++++++++++++ ++++

Karyotyping

  • Applied to: C+++++++++++++++++ +++++
  • Applied conform reference standard D+++++++++++++++++ ++++++
  • Description results E+++++++++++ ++ + +

Diagnoses

  • Quality of description diagnoses / categories F+++++++++++++++ ++++++
  • Relation diagnoses with MR G+++++++++++ + +++

General appraisal of study

  • Score H+++++++++++ ++++

Table 1a1 (cont’d)

AuthorOp’t HofNielsen Fryns Lamont DereymaekerHagerman Asthana Chudley FrynsVolckeWuuHapeslagh

Year198519831984 1986 19881988 1990 1990 1990199119911991

Reference number 444546 47 4849 50 51 52 535455

Study group

  • Description A+++ + ++ + + ++++
  • Clinical relevance B++++++ ++ ++ ++ ++ +++++++

Karyotyping

  • Applied to: C+++++ ++ ++++ + ++ +++++++
  • Applied conform reference standard D++++++ ++ +++ + + ++++++++
  • Description results E++++ ++ ++ + + ++++

Diagnoses

  • Quality of description diagnoses / categories F++++++ ++ ++++ ++ ++ +++++++
  • Relation diagnoses with MR G+++ + ++ ++ + +++++

General appraisal of study

  • Score H+++ ++ ++ + + +++++

Table 1a1 (cont’d)

AuthorOhdoGrahamMajnemer Matilainen Schaap Devriendt L-CruzStromme Hunter v Karnebeek

Year199219931995 1995 1995 199819992000 20002002

Reference number565758 59 60 616263 6465

Study group

  • Description A+++ ++ + ++++++++
  • Clinical relevance B++++++ ++ + +++++++++

Karyotyping

  • Applied to: C++++ ++ ++ ++++++
  • Applied conform reference standard D+++++ + + ++++++++++
  • Description results E++++ + + +++++++

Diagnoses

  • Quality of description diagnoses / categories F++++++ ++ ++ ++++++++++
  • Relation diagnoses with MR G+++++ + + +++++

General appraisal of study

Score H++++ + + +++++

Table 1a2 (cont’d) Methodological quality of all studies reporting subtelomeric FISH investigations

AuthorRossiSismaniAnderlidClarksonv Karnebeek

Year20012001200220022002

Reference number6667686965

Study group

  • Description A++++++
  • Clinical relevance B+++++++++

Karyotyping

  • Applied to: C+++++++++
  • Applied conform reference standard D++++++++++
  • Description results E+++++++++

Diagnoses

  • Quality of description diagnoses / categories F++++++++++
  • Relation diagnoses with MR G++++++++++

General appraisal of study

Score H++++++++++

Table 1b1 Methodological quality of all studies reporting cytogenetic Fragile X investigations

AuthorNielsenBlomquistFishburnFrosterKahkonenBundeyOp ‘t HofArinamiLamontTurner

Year1982198319831983198319851985198619861986

Reference number45707172737444754776

Study group

  • Description A++++++++++++
  • Clinical relevance B+++++++++++++++++++

Cytogenetic FraX investigation

  • Applied to: C++++++++++++++++++++
  • Applied conform reference standard D++ +++++++++++++++++
  • Description results E+++++++++++++++++

Diagnoses

  • Quality of description diagnoses / categories F+++++++++++++++++
  • Relation diagnoses with MR G++++++++++++++++++

General appraisal of study

  • Score H+++++++++++++++++

Table 1b1 (cont’d)

AuthorHagermanAsthanaVolckeHapeslaghTurnerButlerGrahamMatilainenSchaapElango

Year1988199019911991199219931993199519951996

Reference number49505355777857596079

Study group

  • Description A+++++++++++
  • Clinical relevance B+++++++++++++++++

Cytogenetic FraX investigation

  • Applied to: C+++++++++++++++++
  • Applied conform reference standard D++++++++++++++++++++
  • Description results E+++++++++++++++

Diagnoses

  • Quality of description diagnoses / categories F+++++++++++++++++
  • Relation diagnoses with MR G+++++++++++++++

General appraisal of study

  • Score H++++++++++++++

Table 1b1 (cont’d)

AuthorHouLantigua-Cruz

Year19981999

Reference number8062

Study group

  • Description A++++
  • Clinical relevance B+++

Cytogenetic FraX investigation

  • Applied to: C++
  • Applied conform reference standard D++++
  • Description results E++

Diagnoses

  • Quality of description diagnoses / categories F++++
  • Relation diagnoses with MR G+++

General appraisal of study

  • Score H++

Table 1b2 (cont’d) Methodological quality of all studies reporting molecular Fragile X investigations

AuthorGiangrecoArvioGerardMilaO’Dwyer De VriesFaradzPatsalisPangHaddadGonzales

Year19961997199719971997 1997/199919991999200019992000

Reference number8182838485 19;868788899091

Study group

  • Description A+++++++ +++++++
  • Clinical relevance B++++++++ ++++++++++

Molecular FraX investigation

  • Applied to: C+++++++++ ++++++++++++
  • Applied conform reference standard D++++++++++ ++++++++++++
  • Description results E++++++++ +++++++++

Diagnoses

  • Quality of description diagnoses / categories F++++++++++ ++++++++++++
  • Relation diagnoses with MR G+++++++++ ++++++++++++

General appraisal of study

  • Score H+++++++++ +++++++++++

Table 1b2 (cont’d

AuthorTanRuangdaragonTzengHuntervan Karnebeek

Year20002000200020002002

Reference number9293946465

Study group

  • Description A+++++++
  • Clinical relevance B++++++++++

Molecular FraX investigation

  • Applied to: C++++++++
  • Applied conform reference standard D+++++++++
  • Description results E+++++++++

Diagnoses

  • Quality of description diagnoses / categories F++++++++++
  • Relation diagnoses with MR G+++++++++

General appraisal of study

  • Score H++++++++++

Table 1c Methodological quality of all studies reporting metabolic urinary investigations

AuthorCenterwallRobertsKutterPunekarSinclairGurryHolmgrenSchmidTurnerOp ‘t Hof

Year1966196619681968197319731973197419751985

Reference number959697989910010110210344

Study group

  • Description A++++++++++++++
  • Clinical relevance B++++++++++++++++++++

Metabolic urinary investigation

  • Applied to: C+++++++++++++++++++
  • Applied conform reference standard D++ +++++++++++++++++
  • Description results E+++++++++++++++

Diagnoses

  • Quality of description diagnoses / categories F+++++++++++++++
  • Relation diagnoses with MR G++++++++++++++

General appraisal of study

  • Score H+++++++++++++

Table 1c (cont’d)

AuthorICMRFaragMatilainenLantigua-CruzHuntervan Karnebeek

Year199119931995199920002002

Reference number10410559626465

Study group

  • Description A+++++++++++
  • Clinical relevance B+++++++++++

Metabolic urinary investigation

  • Applied to: C++++++++
  • Applied conform reference standard D++++++++++
  • Description results E+++++++

Diagnoses

  • Quality of description diagnoses / categories F+++++++++++
  • Relation diagnoses with MR G+++++++++

General appraisal of study

  • Score H++++++++++

Table 1d Methodological quality of all studies reporting neurologic investigations

AuthorMcDonaldHagbergHunterStrommevan Karnebeek

Year19731981200020002002

Reference number106107646365

Study group

  • Description A+++++++++
  • Clinical relevance B++++++++++

Neurologic investigation

  • Applied to: C++++++++
  • Applied conform reference standard D++ ++++++++
  • Description results E++++++

General appraisal of study

  • Score F+++++++++

Table 1e Methodological quality of all studies reporting neuro-imaging investigations

AuthorLingamHarbordKjosDemaerelMajnemerBouhadibaHunterStrommevan Karnebeek

Year198219901990199319952000200020002002

Reference number10810911011158112646365

Study group

  • Description A+++++++++++
  • Clinical relevance B++++++++++++++

Neuro-imaging

  • Applied to: C++++++++++++++
  • Applied conform reference standard D++ ++++++++++++++++
  • Description results E+++++++++++

Diagnoses

  • Quality of description diagnoses / categories F++++++++++++++
  • Relation diagnoses with MR G+++++++++++++

General appraisal of study

  • Score H++++++++++++

Table 1f Methodological quality of all studies reporting dysmorphologic examinations

AuthorRobertsCosteffSinclairMcDonaldLaxovaBundeyArinamiVolckeOhdoMajnemerMatilainen

Year19661972197319731977198519861991199219951995

Reference number9611399106114747553565859

Study group

  • Description A++++++++++++++++
  • Clinical relevance B+++++++++++++++++++++

Clinical History

  • Applied to: C++++++
  • Applied conform reference standard D ++++++
  • Description results E+++

Family History

  • Applied to: C++++++++++++++
  • Applied conform reference standard D+++++++++++++++
  • Description results E++++++++

Physical examination

  • Applied to: C++++
  • Applied conform reference standard D +++++
  • Description results E++

General appraisal of study

  • Score: Clinical history++++

Family history+++++++++++

Physical examination++

Table 1f (cont’d)

AuthorFaragFernellDurkinHouHunterStrommeTanvan Karnebeek

Year19931998199819982000200020002002

Reference number105115238064639265

Study group

  • Description A+++++++++++++
  • Clinical relevance B++++++++++++++++

Clinical History

  • Applied to: C+++
  • Applied conform reference standard D ++++
  • Description results E++++

Family History

  • Applied to: C++++++++++
  • Applied conform reference standard D++++++++++++++
  • Description results E+++++++++

Physical examination

  • Applied to: C++++
  • Applied conform reference standard D ++++
  • Description results E+++

General appraisal of study

Score FClinical History++++

Family History+++++++++

Physical Examination++++

Legends to Tables 1

Items

A- = poor + = moderate ++ = good

B- = not relevant+ = moderately relevant++ = relevant

C -= non-random sample + = random sample /++ = all patients

(selection criteria unclear) non-random sample (selection criteria clear)

D- = not conform reference standard + = in part conform reference standard ++ = conform reference standard

E- = poor + = moderate ++ = good

F- = poor + = moderate ++ = good

G- = not aetiologic+ = uncertain / possibly aetiologic++ = aetiologic

Scoring methods

Apraisal of the general study quality

PoorIf 2 of items A-G are scored as -, and the remaining items as ++ or +

Moderate:If 3-7 of items A-G are scored as +, and the remaining items as ++ or -

If 6 items are scored as ++, and the remaining item as -

Good:if 5-7 of items A-G are scored as ++, and the remaining item(s) as +

Inclusion procedure

A study was considered of sufficient quality for inclusion in the review if the description and clinical relevance of the study group, application of the technique,

description of the yielded results and established diagnoses were at least of moderate quality (+ or ++). Whether or not the listed diagnoses have a causal

relation with MR was not relevant for the selection procedure, but did influence the quality appraisal of the study.