Institute of Medical and Human GeneticsCharite Universitatsmedizin BerlinBerlinGermany

Institute of Medical and Human GeneticsCharite Universitatsmedizin BerlinBerlinGermany

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Schoner K.,Justus Liebig University | Bald R.,Clinic of Gynecology and Prenatal MedicineKlinikum LeverkusenLeverkusenGermany | Horn D.,Institute of Medical and Human GeneticsCharite Universitatsmedizin BerlinBerlinGermany | Rehder H.,Justus Liebig University | And 2 more authors.
American Journal of Medical Genetics, Part A | Year: 2017

Pierre-Robin sequence, radial deviation, and ulnar clinodactyly of the index fingers due to an additional phalangeal bone, as well as heart defects are the key features of Catel-Manzke syndrome. Although mutations in TGDS were identified as the cause of this disorder, the pathogenetic mechanism remains unknown. Here, we report on a fetus with severe heart defect, nuchal edema, talipes, Pierre-Robin sequence, and bilateral deviation and clinodactyly of the index and middle fingers. Pregnancy was terminated at the 22nd week of gestation. Postmortem radiographs showed hypoplasia and V-shaped displacement of the second and third proximal phalanges of both hands as well as hypoplasia of the first metatarsals and the phalangeal bones of the halluces. The suggested diagnosis Catel-Manzke syndrome was confirmed by the detection of two compound heterozygous mutations in TGDS: The known variant c.298G>T; p.(Ala100Ser) and the so far undescribed variant c.895G>A; p.(Asp299Asn), located in the predicted substrate binding site of TGDS. This is the first report on the association of mutations in TGDS with additional anomalies of the middle fingers and halluces. We provide a detailed phenotypic characterization of the only fetus with molecularly confirmed Catel-Manzke syndrome, which is relevant for prenatal diagnosis. Our findings widen the phenotype spectrum caused by TGDS mutations and underline the phenotypic overlap with Temtamy preaxial brachydactyly syndrome. This improves our understanding of the prenatal development and the pathogenetic mechanism of Catel-Manzke syndrome. © 2017 Wiley Periodicals, Inc.


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.


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 6 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.

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