Microdeletions including FMR1 in three female patients with intellectual disability - further delineation of the phenotype and expression studies.
Fragile X syndrome (FXS) is one of the most common causes of intellectual disability/developmental delay (ID/DD), especially in males. It is caused most often by CGG trinucleotide repeat expansions, and less frequently by point mutations and partial or full deletions of the FMR1 gene. The wide clinical spectrum of affected females partly depends on their X-inactivation status. Only few female ID/DD patients with microdeletions including FMR1 have been reported. We describe 3 female patients with 3.5-, 4.2- and 9.2-Mb de novo microdeletions in Xq27.3-q28 containing FMR1. X-inactivation was random in all patients, yet they presented with ID/DD as well as speech delay, macrocephaly and other features attributable to FXS. No signs of autism were present. Here, we further delineate the clinical spectrum of female patients with microdeletions. FMR1 expression studies gave no evidence for an absolute threshold below which signs of FXS present. Since FMR1 expression is known to be highly variable between unrelated females, and since FMR1 mRNA levels have been suggested to be more similar among family members, we further explored the possibility of an intrafamilial effect. Interestingly, FMR1 mRNA levels in all 3 patients were significantly lower than in their respective mothers, which was shown to be specific for patients with microdeletions containing FMR1.
Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
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AM
Zink
Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
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E
Wohlleber
Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
H
H
Engels
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
O K
OK
Rødningen
Applied Human Molecular Genetics, Kennedy Center, Glostrup, Denmark.
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K
Ravn
Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany ; Department of Genomics, Life & Brain Center, Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
S
S
Heilmann
Molecular Genetics and Infertility Unit, Department of Gynecology, Endocrinology and Reproductive Medicine, University Women Hospital, Heidelberg, Germany.
J
J
Rehnitz
Molecular Genetics and Infertility Unit, Department of Gynecology, Endocrinology and Reproductive Medicine, University Women Hospital, Heidelberg, Germany.
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N
Katzorke
Institute of Human Genetics, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany.
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C
Kraus
Pediatric Department L55, Glostrup University Hospital, Glostrup, Denmark.
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S
Blichfeldt
Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany ; Department of Genomics, Life & Brain Center, Rheinische Friedrich-Wilhelms-University, Bonn, Germany ; Medical Genetics, Department of Biomedicine, University Hospital, Basel, Switzerland.
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P
Hoffmann
Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany ; Department of Neonatology, Children's Hospital, Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
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H
Reutter
Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany ; Department of Genomics, Life & Brain Center, Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
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FF
Brockschmidt
Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
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M
Kreiß-Nachtsheim
Molecular Genetics and Infertility Unit, Department of Gynecology, Endocrinology and Reproductive Medicine, University Women Hospital, Heidelberg, Germany.
P H
PH
Vogt
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
T E
TE
Prescott
Applied Human Molecular Genetics, Kennedy Center, Glostrup, Denmark ; Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
Z
Z
Tümer
Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany ; Department of Genomics, Life & Brain Center, Rheinische Friedrich-Wilhelms-University, Bonn, Germany ; Greenwood Genetic Center, Greenwood, S.C., USA.
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JA
Lee
Expression; FMR1; Intellectual disability; Microdeletion; Xq27.3–q28