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Cristofoli F.,Center for Human GeneticsUniversity Hospitals Leuven | Ehmke N.,Institute of Medical and Human GeneticsCharite Universitatsmedizin BerlinBerlinGermany | Fergelot P.,French Institute of Health and Medical Research | Foster A.,Institute of Cancer and Genomic SciencesUniversity of BirminghamBirminghamUnited Kingdom | And 8 more authors.
American Journal of Medical Genetics, Part A | Year: 2016

Mutations in CREBBP cause Rubinstein-Taybi syndrome. By using exome sequencing, and by using Sanger in one patient, CREBBP mutations were detected in 11 patients who did not, or only in a very limited manner, resemble Rubinstein-Taybi syndrome. The combined facial signs typical for Rubinstein-Taybi syndrome were absent, none had broad thumbs, and three had only somewhat broad halluces. All had apparent developmental delay (being the reason for molecular analysis); five had short stature and seven had microcephaly. The facial characteristics were variable; main characteristics were short palpebral fissures, telecanthi, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum. Six patients had autistic behavior, and two had self-injurious behavior. Other symptoms were recurrent upper airway infections (n=5), feeding problems (n=7) and impaired hearing (n=7). Major malformations occurred infrequently. All patients had a de novo missense mutation in the last part of exon 30 or beginning of exon 31 of CREBBP, between base pairs 5,128 and 5,614 (codons 1,710 and 1,872). No missense or truncating mutations in this region have been described to be associated with the classical Rubinstein-Taybi syndrome phenotype. No functional studies have (yet) been performed, but we hypothesize that the mutations disturb protein-protein interactions by altering zinc finger function. We conclude that patients with missense mutations in this specific CREBBP region show a phenotype that differs substantially from that in patients with Rubinstein-Taybi syndrome, and may prove to constitute one (or more) separate entities. © 2016 Wiley Periodicals, Inc. Source


Mackenroth L.,Institute of Medical and Human GeneticsCharite Universitatsmedizin BerlinBerlinGermany | Fischer-Zirnsak B.,Institute of Medical and Human GeneticsCharite Universitatsmedizin BerlinBerlinGermany | Egerer J.,Institute of Medical and Human GeneticsCharite Universitatsmedizin BerlinBerlinGermany | Hecht J.,Institute of Medical and Human GeneticsCharite Universitatsmedizin BerlinBerlinGermany | And 5 more authors.
American Journal of Medical Genetics, Part A | Year: 2016

Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006-1G>A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p.Val1213Ile, p.Gly2592Ser). Analysis of cDNA showed that the COL1A1 splice site mutation led to intron retention causing a frameshift (p.Phe1336Valfs*72). Type 1 collagen secretion by the patient's skin fibroblasts was reduced. Immunostaining of a muscle biopsy obtained from the patient revealed a clear reduction of tenascin-X in the extracellular matrix compared to a healthy control. These findings imply that the combination of the COL1A1 mutation with the TNXB variants might cause the patient's unique phenotype. © 2016 Wiley Periodicals, Inc. Source

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