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Biomedical subjects

Gabriele Gillessen-Kaesbach

Publications and source records attributed to Gabriele Gillessen-Kaesbach.

At least 19 recordsLinked to original sources
PubMed2007

A family with autosomal dominant oculo-auriculo-vertebral spectrum.

Oculo-auriculo-vertebral spectrum (MIM 164210) is a term suggested by Gorlin to summarize the different phenotypic expressions of a continuum that has been known as hemifacial microsomia, Goldenhar syndrome, or first and second branchial arch anomalies. The different terms indicate the extremely variable clinical findings, including especially defects of aural, oral and mandibular development. Additionally, cardiac, renal, skeletal and other anomalies occur. The majority of oculo-auriculo-vertebral spectrum cases are sporadic; nevertheless, several families have been reported with proof of both autosomal dominant and autosomal recessive inheritance. We describe a family with transmission of oculo-auriculo-vertebral spectrum from a mother to her two daughters indicating an autosomal dominant mode of inheritance. Our literature review reveals that patients with autosomal dominant inheritance of oculo-auriculo-vertebral spectrum are more often bilaterally affected than patients with sporadic occurrence of oculo-auriculo-vertebral spectrum. In addition, hearing loss, absent or narrow external auditory canal, anomalies of the mouth and epibulbar dermoids seem to occur less frequently in patients with autosomal dominant oculo-auriculo-vertebral spectrum compared with sporadic oculo-auriculo-vertebral spectrum.

Adult↗
PubMed2006

Towards mapping phenotypical traits in 18p- syndrome by array-based comparative genomic hybridisation and fluorescent in situ hybridisation.

Molecular karyotyping holds the promise of improving genotype-phenotype correlations for frequent chromosome conditions such as the 18p- syndrome. In spite of more than 150 reported cases with deletions in 18p, no reliable phenotype map for the characteristic clinical findings such as mental retardation, post-natal growth retardation and typical facial features has been established yet. Here, we report on four patients with partial monosomy 18p of different sizes owing to unbalanced translocations that were thoroughly characterised clinically and by molecular karyotyping. One patient had a terminal deletion of 1.6 Mb in 18p and a trisomy of 8q24.23-qter as determined by array-based comparative genomic hybridisation and large insert clone fluorescent in situ hybridisation. In two sibs and a fourth patient, cytogenetic and molecular-cytogenetic analyses showed the terminal deletions in 18p (8.0 and 13.84 Mb, respectively) to be accompanied by partial trisomies of 20p. Literature analyses of typical phenotypic features of 18p-, 8q+ and 20p+ syndromes allowed the attribution of clinical findings in our patients to the respective chromosomal aberration. Based on these data, we propose a phenotype map for several clinical features of the 18p- syndrome: Round face was tentatively mapped to the distal 1.6 Mb of 18p; post-natal growth retardation and seizures to the distal 8 Mb and ptosis and short neck to the proximal half of 18p.

Adolescent↗
PubMed2006

Is there a higher incidence of maternal uniparental disomy 14 [upd(14)mat]? Detection of 10 new patients by methylation-specific PCR.

Maternal uniparental disomy for chromosome 14 [upd(14)mat] is associated with a characteristic phenotype including pre- and postnatal growth retardation, muscular hypotonia, feeding problems, motor delay, small hands and feet, precocious puberty and truncal obesity. Patients with upd(14)mat show features overlapping with Prader-Willi syndrome (PWS) and are probably underdiagnosed. Maternal upd(14) is frequently described in carriers of a Robertsonian translocation involving chromosome 14, but is also found in patients with a normal karyotype. Based on the above mentioned criteria we have identified six patients with upd(14)mat including two patients with a normal karyotype, one patient with a de novo Robertsonian translocation (14;21), one patient with a familial Robertsonian translocation (13;14) and two patients with a marker chromosome. In addition, we analyzed a cohort of 33 patients with low birth weight, feeding difficulties and consecutive obesity in whom PWS had been excluded by methylation analysis of SNRPN. In four of these patients (12%) we detected upd(14)mat. For rapid testing of upd(14)mat we analyzed the methylation status of the imprinted MEG3 locus. In conclusion, we recommend considering upd(14)mat in patients with low birth weight, growth retardation, neonatal feeding problems, muscular hypotonia, motor delay, precocious puberty and truncal obesity as well as in patients with a PWS like phenotype presenting with low birth weight, feeding difficulties and obesity.

Adolescent↗
PubMed2006

Syndrome identification based on 2D analysis software.

Clinical evaluation of children with developmental delay continues to present a challenge to the clinicians. In many cases, the face provides important information to diagnose a condition. However, database support with respect to facial traits is limited at present. Computer-based analyses of 2D and 3D representations of faces have been developed, but it is unclear how well a larger number of conditions can be handled by such systems. We have therefore analysed 2D pictures of patients each being affected with one of 10 syndromes (fragile X syndrome; Cornelia de Lange syndrome; Williams-Beuren syndrome; Prader-Willi syndrome; Mucopolysaccharidosis type III; Cri-du-chat syndrome; Smith-Lemli-Opitz syndrome; Sotos syndrome; Microdeletion 22q11.2; Noonan syndrome). We can show that a classification accuracy of >75% can be achieved for a computer-based diagnosis among the 10 syndromes, which is about the same accuracy achieved for five syndromes in a previous study. Pairwise discrimination of syndromes ranges from 80 to 99%. Furthermore, we can demonstrate that the criteria used by the computer decisions match clinical observations in many cases. These findings indicate that computer-based picture analysis might be a helpful addition to existing database systems, which are meant to assist in syndrome diagnosis, especially as data acquisition is straightforward and involves off-the-shelf digital camera equipment.

Adolescent↗
PubMed2006

Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.

Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders.

Amino Acid Sequence↗
PubMed2006

Histone acetylation dependent allelic expression imbalance of BAPX1 in patients with the oculo-auriculo-vertebral spectrum.

The oculo-auriculo-vertebral spectrum (OAVS) (OMIM % 164210) is a common developmental disorder characterized by hemifacial microsomia, epibulbar tumours, ear malformation and vertebral anomalies. Although rare familial cases suggest that OAVS has a genetic basis, no genetic defect has been identified so far. In a patient with OAVS and a chromosomal translocation t(4;8) we have found that the chromosome 4 breakpoint is 76.4 kb distal to the BAPX1 gene, which plays an essential role in craniofacial development. We did not detect any BAPX1 mutation in 105 patients, but observed a strong allelic expression imbalance (sAEI) in fibroblasts from five of 12 patients, but not in nine normal controls (Fisher's exact test, P=0.038). sAEI was de novo in one patient and inherited in two other patients. Prolonged cell culture or treatment with the histone deacetylase inhibitor Trichostatin A led to reactivation of the downregulated allele. We propose that epigenetic dysregulation of BAPX1 plays an important role in OAVS.

Allelic Imbalance↗
PubMed2005

Identification of mutations in CUL7 in 3-M syndrome.

Intrauterine growth retardation is caused by maternal, fetal or placental factors that result in impaired endovascular trophoblast invasion and reduced placental perfusion. Although various causes of intrauterine growth retardation have been identified, most cases remain unexplained. Studying 29 families with 3-M syndrome (OMIM 273750), an autosomal recessive condition characterized by severe pre- and postnatal growth retardation, we first mapped the underlying gene to chromosome 6p21.1 and then identified 25 distinct mutations in the gene cullin 7 (CUL7). CUL7 assembles an E3 ubiquitin ligase complex containing Skp1, Fbx29 (also called Fbw8) and ROC1 and promotes ubiquitination. Using deletion analysis, we found that CUL7 uses its central region to interact with the Skp1-Fbx29 heterodimer. Functional studies indicated that the 3-M-associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1. These results suggest that impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans.

Carrier Proteins↗
PubMed2005

Oculo-auriculo-vertebral spectrum (OAVS): clinical evaluation and severity scoring of 53 patients and proposal for a new classification.

Oculo-auriculo-vertebral spectrum (OMIM164210) is a phenotypically and probably also a genetically heterogeneous disorder, characterized by anomalies of the ear (mostly microtia), hemifacial microsomia, and defects of the vertebral column. Associated clinical findings include anomalies of the eye and brain, and developmental delay. We have evaluated the clinical data and photographs of 53 unrelated patients with OAVS, all presenting with either isolated microtia or preauricular tags in association with hemifacial microsomia as minimal diagnostic criteria; five had a positive family history for OAVS. Based on the main clinical findings and unilateral or bilateral involvement, we have developed a new classification system for OAVS, consisting of six subgroups. There is a statistically significant correlation between the subgroup and number of associated clinical findings, and a statistically significant difference regarding prognosis in uni- and bilaterally affected patients, suggesting that this classification is clinically relevant to the categorization of patients with OAVS. The newly developed scoring system (two points for each main clinical finding and one for each associated clinical finding) presented here, also aids prognosis, especially for delay of motor development and brain anomalies, and statistical analysis revealed significant clustering between different clinical findings of OAVS confirming the clinical impression previously published by several authors.

Abnormalities, Multiple↗
PubMed2005

Clinical and mutational spectrum of Mowat-Wilson syndrome.

Mowat-Wilson Syndrome is a recently delineated mental retardation syndrome usually associated with multiple malformations and a recognizable facial phenotype caused by defects of the transcriptional repressor ZFHX1B. To address the question of clinical and mutational variability, we analysed a large number of patients with suspected Mowat-Wilson Syndrome (MWS). Without prior knowledge of their mutational status, 70 patients were classified into "typical MWS", "ambiguous" and "atypical" groups according to their facial phenotype. Using FISH, qPCR and sequencing, ZFHX1B deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS. No ZFHX1B defect was apparent in the remaining 15 cases with ambiguous facial features or in the 27 atypical patients. Genotype-phenotype analysis confirmed that ZFHX1B deletions and stop mutations result in a recognizable facial dysmorphism with associated severe mental retardation and variable malformations such as Hirschsprung disease and congenital heart defects. Our findings indicate that structural eye anomalies such as microphthalmia should be considered as part of the MWS spectrum. We also show that agenesis of the corpus callosum and urogenital anomalies (especially hypospadias) are significant positive predictors of a ZFHX1B defect. Based on our observation of affected siblings and the number of MWS cases previously reported, we suggest a recurrence risk of around 1%. The lack of missense mutations in MWS and MWS-like patients suggests there may be other, as yet unrecognized phenotypes, associated with missense mutations of this transcription factor.

Abnormalities, Multiple↗
PubMed2005

Prader-Willi syndrome with a karyotype 47,XY,+min(15)(pter->q11.1:) and maternal UPD 15--case report plus review of similar cases.

Prader-Willi (PWS) and Angelman (AS) are syndromes of developmental impairment that can result either from a 15q11-q13 deletion, paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. A small cytogenetic subset of PWS and AS patients are carriers of a so-called small supernumerary marker chromosome (sSMC). Here, we report on an previously unreported PWS case with a karyotype 47,XY,+min(15)(pter->q11.1:) plus maternal heterodisomic UPD 15. A review of the literature revealed, that for both, PWS and AS patients, cases with (1) a sSMC plus microdeletion of the PWS/AS critical region, (2) inv dup(15) plus uniparental disomy (UPD) 15 and (3) cases without exclusion of a microdeletion an UBE3A mutation or UPD are described. The present case as well as the review of similar cases provides further evidence for the necessity to test UPD in prenatal cases with a de novo sSMC and in postnatal cases with otherwise unexplainable clinical phenotype.

Angelman Syndrome↗
PubMed2005

Further delineation of Kabuki syndrome in 48 well-defined new individuals.

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases-providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined.

Abnormalities, Multiple↗
PubMed2005

Mild phenotypes in a series of patients with Opitz GBBB syndrome with MID1 mutations.

Opitz syndrome (OS; MIM 145410 and MIM 300000) is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal (LTE) abnormalities, imperforate anus, developmental delay, and cardiac defects. The X-linked form (XLOS) is caused by mutations in the MID1 gene, which encodes a microtubule-associated RBCC protein. In this study, phenotypic manifestations of patients with and without MID1 mutations were compared to determine genotype-phenotype correlations. We detected 10 novel mutations, 5 in familial cases, 2 in sporadic cases, and 3 in families for whom it was not clear if they were familial or sporadic. The genotype and phenotype was compared for these 10 families, clinically diagnosed OS patients found not to have MID1 mutations, and 4 families in whom we have previously reported MID1 mutations. This combined data set includes clinical and mutation data on 70 patients. The XLOS patients with MID1 mutations were less severely affected than patients with MID1 mutations reported in previous studies, particularly in functionally significant neurologic, LTE, anal, and cardiac abnormalities. Minor anomalies were more prevalent in patients with MID1 mutations compared to those without mutations in this study. Female MID1 mutation carriers had milder phenotypes compared to male MID1 mutation carriers, with the most common manifestation being hypertelorism in both sexes. Most of the anomalies found in the patients of the present study do not correlate with the MID1 mutation type, with the possible exception of LTE malformations. This study demonstrates the wide spectrum of severity and manifestations of OS. It also shows that XLOS patients with MID1 mutations may be less severely affected than indicated in prior reports.

Exons↗
PubMed2005

A rapid microarray based whole genome analysis for detection of uniparental disomy.

To date, uniparental disomy (UPD) with phenotypic relevance is described for different chromosomes and it is likely that additional as yet unidentified UPD phenotypes exist. Due to technical difficulties and limitations of time and resources, molecular analyses for UPD using microsatellite markers are only performed in cases with specific phenotypic features. In this study, we carried out a whole genome UPD screening based on a microarray genotyping technique. Six patients with the diagnosis of both complete or segmental UPD including Prader-Willi syndrome (PWS; matUPD15), Angelman syndrome (AS; patUPD15), Silver-Russell syndrome (SRS; matUPD7), Beckwith-Wiedemann syndrome (BWS; patUPD11p), pseudohypoparathyroidism (PHP; patUPD20q) and a rare chromosomal rearrangement (patUPD2p, matUPD2q), were genotyped using the GeneChip Human Mapping 10K Array. Our results demonstrate the presence of UPD in the patients with high efficiency and reveal clues about the mechanisms of UPD formation. We thus conclude that array based SNP genotyping is a fast, cost-effective, and reliable approach for whole genome UPD screening.

Angelman Syndrome↗
PubMed2005

The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype.

Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by mental retardation and congenital microcephaly with a head circumference at least 4 SD below age and sex means, in the absence of other significant malformations or neurological deficits. Truncating alterations in the MCPH1 gene have previously been shown to exhibit a distinct cellular phenotype, with a high proportion of prophase-like cells (>10%) due to premature chromosome condensation in early G2- and delayed decondensation in early G1-phase of the cell cycle. We report here the first patient with a homozygous substitution of a highly conserved threonine residue by an arginine (c.80C>G, Thr27Arg) localized in the N-terminal BRCT domain of MCPH1. The cellular and clinical phenotype of this patient is much less pronounced than that of previously described patients with truncating alterations in the MCPH1 gene. Firstly, the fraction of prophase-like cells accounts for just 3-4% of the cell population. Secondly, clinically, he has only a very mild mental retardation with predominantly delayed motor skills but normal verbal IQ attainment. Additionally, head circumference was less severely affected, being -2.4 SD at birth and -3 SD at the age of six years. This justifies reconsideration and widening of the clinical phenotype definition of MCPH1.

Amino Acid Sequence↗
PubMed2005

Novel mutations in BCOR in three patients with oculo-facio-cardio-dental syndrome, but none in Lenz microphthalmia syndrome.

Oculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked dominant condition with male lethality characterized by microphthalmia, congenital cataracts, facial dysmorphic features, congenital heart defects, and dental anomalies. Mutations in BCOR (BCL6 co-repressor) located in Xp11.4 have been described to cause OFCD syndrome. Lenz microphthalmia syndrome is inherited in an X-linked recessive pattern comprising microphthalmia/anophthalmia, mental retardation, malformed ears, digital, skeletal, and urogenital anomalies (synonym: microphthalmia with associated anomalies (MAA)). One locus for MAA has been mapped to Xq27-q28. Nonetheless, linkage and subsequent mutation analysis revealed a single missense mutation (p.P85L) in BCOR in a large family with presumed Lenz microphthalmia syndrome (MAA2). We describe novel mutations in BCOR in three patients with OFCD syndrome, two small deletions (c.2488_2489delAG and c.3286delG) and a submicroscopic deletion of about 60 kb encompassing at least BCOR exons 2-15. No BCOR mutation was detected in eight patients with Lenz microphthalmia syndrome. Our data confirm that BCOR is the causative gene for OFCD syndrome; however, the failure to identify any mutation in patients with Lenz microphthalmia syndrome together with the oligosymptomatic phenotype in the reported MAA2 patients suggest that BCOR is not the major gene for this syndrome.

Abnormalities, Multiple↗
PubMed2004

Somatic mosaicism in patients with Angelman syndrome and an imprinting defect.

Angelman syndrome is a neurogenetic disorder caused by the loss of function of the imprinted UBE3A gene in 15q11-q13. In a small group of patients, the disease is due to an imprinting defect (ID) that silences the maternal UBE3A allele. The presence of a faint maternal band detected by methylation-specific PCR analysis of the SNURF-SNRPN locus in approximately one-third of patients who have an ID but no imprinting center deletion suggested that these patients are mosaics of ID cells and normal cells. In two patients studied, somatic mosaicism was proven by molecular and cellular cloning, respectively. X inactivation studies of cloned fibroblasts from one patient suggest that ID occurred before the blastocyst stage. To quantify the degree of mosaicism, we developed a novel quantitative methylation assay based on real-time PCR. In 24 patients tested, the percentage of normal cells ranged from <1% to 40%. Regression analysis suggests that patients with a higher percentage of normally methylated cells tend to have milder clinical symptoms than patients with a lower percentage. In conclusion, we suggest that the role of mosaic imprinting defects in mental retardation is underestimated.

Angelman Syndrome↗
PubMed2004

SNURF-SNRPN and UBE3A transcript levels in patients with Angelman syndrome.

The imprinted domain on human chromosome 15 consists of two oppositely imprinted gene clusters, which are under the control of an imprinting center (IC). The paternally expressed SNURF-SNRPN gene hosts several snoRNA genes and overlaps the UBE3A gene, which is encoded on the opposite strand, expressed - at least in brain cells - from the maternal chromosome only, and affected in patients with Angelman syndrome (AS). In contrast to SNURF-SNRPN, imprinted expression of UBE3A is not regulated by a 5' differentially methylated region. Here we report that splice forms of the SNURF-SNRPN transcript overlapping UBE3A in an antisense orientation are present in brain but barely detectable in blood. In contrast, splice forms that do not overlap with UBE3A are of similar abundance in brain and blood. The tissue distribution of the splice forms parallels that of the snoRNAs encoded in the respective parts of the SNURF-SNRPN transcript. Using a quantitative PCR assay, we have found that the ratio of SNURF-SNRPN/UBE3A transcript levels is increased in blood cells of AS patients with an imprinting defect, but not in AS patients with a UBE3A mutation or an unknown defect. Our findings are compatible with the assumption that imprinted UBE3A expression is regulated through the SNURF-SNRPN sense- UBE3A antisense transcript.

Alternative Splicing↗