Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium.
The EuroMRX family cohort consists of about 400 families with non-syndromic and 200 families with syndromic X-linked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probands from these families were tested for mutations in the coding sequence of 90 known and candidate XLMR genes. In total, 73 causative mutations were identified in 21 genes. For 42% of the families with obligate female carriers, the mental retardation phenotype could be explained by a mutation. There was no difference between families with (lod score >2) or without (lod score <2) significant linkage to the X chromosome. For families with two to five affected brothers (brother pair=BP families) only 17% of the MR could be explained. This is significantly lower (P=0.0067) than in families with obligate carrier females and indicates that the MR in about 40% (17/42) of the BP families is due to a single genetic defect on the X chromosome. The mutation frequency of XLMR genes in BP families is lower than can be expected on basis of the male to female ratio of patients with MR or observed recurrence risks. This might be explained by genetic risk factors on the X chromosome, resulting in a more complex etiology in a substantial portion of XLMR patients. The EuroMRX effort is the first attempt to unravel the molecular basis of cognitive dysfunction by large-scale approaches in a large patient cohort. Our results show that it is now possible to identify 42% of the genetic defects in non-syndromic and syndromic XLMR families with obligate female carriers.
de Brouwer
Arjan P M
AP
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. A.debrouwer@antrg.umcn.nl
Yntema
Helger G
HG
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Lugtenberg
Dorien
D
Oudakker
Astrid R
AR
de Vries
Bert B A
BB
van Bokhoven
Hans
H
Van Esch
Hilde
H
Frints
Suzanne G M
SG
Froyen
Guy
G
Fryns
Jean-Pierre
JP
Raynaud
Martine
M
Moizard
Marie-Pierre
MP
Ronce
Nathalie
N
Bensalem
Anissa
A
Moraine
Claude
C
Poirier
Karine
K
Castelnau
Laetitia
L
Saillour
Yoann
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Bienvenu
Thierry
T
Beldjord
Chérif
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des Portes
Vincent
V
Chelly
Jamel
J
Turner
Gillian
G
Fullston
Tod
T
Gecz
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J
Kuss
Andreas W
AW
Tzschach
Andreas
A
Jensen
Lars Riff
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Lenzner
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Kalscheuer
Vera M
VM
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Hans-Hilger
HH
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D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005796:Genes; D006801:Humans; D008126:Lod Score; D008297:Male; D038901:X-Linked Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010641:Phenotype