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ABSTRACT: On the basis of the Human Cytogenetic Database, a computerized catalog of the clinical phenotypes associated with cytogenetically detectable human chromosome aberrations, we collected from the literature 102 cases with chromosomal aberrations and split hand/foot malformation or absent fingers/toes. Statistical analysis revealed a highly significant association (P<0.001) between the malformation and the chromosomal bands 4q32-q35, 5q15, 6q16-q22 and 7q11.2-q22 (SHFM1). Considering these findings, we suggest additional SHFM loci on chromosome 4q, 6q and probably 5q. The regions 4q and 6q have already been discussed in the literature as additional SHFM loci. We now show further evidence. In the proposed regions, there are interesting candidate genes such as, on 4q: HAND2, FGF2, LEF1 and BMPR1B; on 5q: MSX2, FLT4, PTX1 and PDLIM7; and on 6q: SNX3, GJA1, HEY2 and Tbx18.
European journal of human genetics: EJHG 02/2009; 17(8):1086-91. · 3.56 Impact Factor
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ABSTRACT: Rubinstein-Taybi syndrome (RSTS) is a congenital disorder characterised by growth retardation, facial dysmorphisms, skeletal abnormalities and mental retardation. Broad thumbs and halluces are the hallmarks of the syndrome. RSTS is associated with chromosomal rearrangements and mutations in the CREB-binding protein gene (CREBBP), also termed CBP, encoding the CREB-binding protein. Recently, it was shown that mutations in EP300, coding for the p300 protein, also cause RSTS. CBP and EP300 are highly homologous genes, which play important roles as global transcriptional coactivators.
To report the phenotype of the presently known patients with RSTS (n = 4) carrying germline mutations of EP300.
The patients with EP300 mutations displayed the typical facial gestalt and malformation pattern compatible with the diagnosis of RSTS. However, three patients exhibited much milder skeletal findings on the hands and feet than typically observed in patients with RSTS.
Part of the clinical variability in RSTS is explained by genetic heterogeneity. The diagnosis of RSTS must be expanded to include patients without broad thumbs or halluces.
Journal of Medical Genetics 06/2007; 44(5):327-33. · 6.36 Impact Factor
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Marja Majava,
Kristien P. Hoornaert,
Deborah Bartholdi,
Mieke C. Bouma,
Katelijne Bouman,
Marta Carrera,
Koenraad Devriendt,
Jane Hurst,
George Kitsos, Dunja Niedrist,
Michael B. Petersen,
Debbie Shears,
Irene Stolte-Dijkstra,
J.M. Van Hagen,
Leena Ala-Kokko,
Minna Männikkö,
Geert R. Mortier
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ABSTRACT: A series of 44 unrelated patients in whom COL2A1 screening demonstrated normal results but whose phenotype was nevertheless highly suggestive of either Stickler syndrome (with ocular involvement) or Marshall syndrome were investigated for mutations in the COL11A1 gene. Heterozygous COL11A1 mutations were found in 10 individuals. A splice site alteration (involving introns 47–55) was present in seven cases, with one in intron 50 (c.3816 + 1G > A) occurring in three patients. Two patients had a different deletion, and a missense mutation (Gly1471Asp) was observed in one case. In 4/10 patients the phenotype was classified as Marshall syndrome because of early-onset severe hearing loss and characteristic facial features. These four patients were all heterozygous for a splice site mutation in intron 50. One of these cases had a type 1 vitreous anomaly despite the presence of a COL11A1 mutation. The remaining 6/10 patients had an overlapping Marshall–Stickler phenotype with less pronounced facial features. None of these had a mutation in the hot spot region of intron 50. © 2007 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 01/2007; 143A(3):258 - 264. · 2.39 Impact Factor
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American Journal of Medical Genetics Part A 12/2006; 140(21):2365-7. · 2.39 Impact Factor
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Jeroen H Roelfsema,
Stefan J White,
Yavuz Ariyürek,
Deborah Bartholdi, Dunja Niedrist,
Francesco Papadia,
Carlos A Bacino,
Johan T den Dunnen,
Gert-Jan B van Ommen,
Martijn H Breuning,
Raoul C Hennekam,
Dorien J M Peters
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ABSTRACT: CREB-binding protein and p300 function as transcriptional coactivators in the regulation of gene expression through various signal-transduction pathways. Both are potent histone acetyl transferases. A certain level of CREB-binding protein is essential for normal development, since inactivation of one allele causes Rubinstein-Taybi syndrome (RSTS). There is a direct link between loss of acetyl transferase activity and RSTS, which indicates that the disorder is caused by aberrant chromatin regulation. We screened the entire CREB-binding protein gene (CBP) for mutations in patients with RSTS by using methods that find point mutations and larger rearrangements. In 92 patients, we were able to identify a total of 36 mutations in CBP. By using multiple ligation-dependent probe amplification, we found not only several deletions but also the first reported intragenic duplication in a patient with RSTS. We extended the search for mutations to the EP300 gene and showed that mutations in EP300 also cause this disorder. These are the first mutations identified in EP300 for a congenital disorder.
The American Journal of Human Genetics 05/2005; 76(4):572-80. · 10.60 Impact Factor
