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Mutation frequencies of X‐linked mental retardation genes in families from the EuroMRX consortium
Author(s) -
de Brouwer Arjan P.M.,
Yntema Helger G.,
Kleefstra Tjitske,
Lugtenberg Dorien,
Oudakker Astrid R.,
de Vries Bert B.A.,
van Bokhoven Hans,
Van Esch Hilde,
Frints Suzanne G.M.,
Froyen Guy,
Fryns JeanPierre,
Raynaud Martine,
Moizard MariePierre,
Ronce Nathalie,
Bensalem Anissa,
Moraine Claude,
Poirier Karine,
Castelnau Laetitia,
Saillour Yoann,
Bienvenu Thierry,
Beldjord Chérif,
des Portes Vincent,
Chelly Jamel,
Turner Gillian,
Fullston Tod,
Gecz Jozef,
Kuss Andreas W.,
Tzschach Andreas,
Jensen Lars Riff,
Lenzner Steffen,
Kalscheuer Vera M.,
Ropers HansHilger,
Hamel Ben C.J.
Publication year - 2007
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9482
Subject(s) - genetics , biology , proband , x chromosome , genetic linkage , mutation , gene
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. © 2007 Wiley‐Liss, Inc.