Translocation and deletion around SOX9 in a patient with acampomelic campomelic dysplasia and sex reversal.

Campomelic dysplasia (MIM 114290) is a severe malformation syndrome frequently accompanied by male-to-female sex reversal. Causative are mutations within the SOX9 gene on 17q24.3 as well as chromosomal aberrations (translocations, inversions or deletions) in the vicinity of SOX9. Here, we report on a patient with muscular hypotonia, craniofacial dysmorphism, cleft palate, brachydactyly, malformations of thoracic spine, and gonadal dysgenesis with female external genitalia and müllerian duct derivatives in the presence of a male karyotype. X-ray examination and clinical examinations revealed no signs of campomelia. The combination of molecular cytogenetic analysis and array CGH revealed an unbalanced translocation between one chromosome 7 and one chromosome 17 [46,XY,t(7;17)(q33;q24).ish t(7;17)(wcp7+,wcp17+;wcp7+wcp17+)] with a deletion of approximately 4.2 Mb located about 0.5 Mb upstream of SOX9. STS analysis confirmed the deletion of chromosome 17, which has occurred de novo on the paternal chromosome. The proximal breakpoint on chromosome 17 is localized outside the known breakpoint cluster regions. The deletion on chromosome 17q24 removes several genes. Among these genes PRKAR1A is deleted. Inactivating mutations of PRKAR1A cause Carney complex. To our knowledge, this is the first report of a patient with acampomelic campomelic dysplasia, carrying both a deletion and a translocation.

Predictive diagnosis of the cancer prone Li-Fraumeni syndrome by accident: new challenges through whole genome array testing.

BACKGROUND: Li-Fraumeni syndrome greatly increases the risk of developing several types of cancer and is usually caused by TP53 germline mutations. Predictive testing of at-risk family members is only offered after a complex genetic counselling process. Recently the clinical implementation of array comparative genomic hybridisation (CGH) has revolutionised the diagnosis of patients with syndromic or non-syndromic mental retardation and has evolved to a routinely performed high resolution whole genome scan. METHODS AND RESULTS: When using array CGH to identify the cause for mental retardation in a 7-year-old child we found a submicroscopic de novo deletion of chromosome 17p13.1, which includes several genes likely to be causative for her phenotype, and also of TP53. CONCLUSION: Thus, array CGH resulted in an unintended predictive diagnosis of an increased tumour susceptibility as observed in Li-Fraumeni syndrome.

Mental retardation in a girl with a subtelomeric deletion on chromosome 20q and complete deletion of the myelin transcription factor 1 gene (MYT1).

A great number of syndromes and inborn errors of metabolism associated with impaired development have been observed, but the aetiology of mental retardation remains unclear in a considerable proportion of cases. Here, we present the clinical and molecular data from a patient with a new de novo subtelomeric deletion on chromosome 20 [46,XX.ish del(20)(qter-)]. For further refinement, bacterial artificial chromosome clones are used. The deletion spans exactly two genes called MYT1 and PCMTD2. Both genes play an important role in myelination and regulating neural differentiation. Loss of these two genes seems to be responsible for the severe mental retardation and mild facial dysmorphic features in our young patient. It might show the phenotypic picture of this specified deletion.

Distal monosomy 16p13.3/distal trisomy 2p24.2-pter: molecular-cytogenetic characterisation and phenotype.

We describe a 4-year-old boy with various facial dysmorphic features such as downslanting palpebral fissures, ptosis, hypertelorism, broad nasal bridge, small and low-set ears, broad philtrum, and micrognathia. In addition, profound mental retardation, myopia, muscular hypotonia as well as genital and cardiovascular abnormalities are also present. Refinement of the breakpoints by cytogenetic techniques, in particular the increase of banding resolution in conventional cytogenetic analysis, has enabled the correct diagnosis, as proven by fluorescence in situ hybridisation (FISH) using whole chromosome painting and single copy probes. We were able to demonstrate an unbalanced translocation that the patient inherited from his father resulting in a submicroscopic monosomy 16p13.3 and a trisomy 2p24.2-pter.

Characterization of a de novo complex chromosome rearrangement (CCR) involving chromosomes 2 and 12, associated with mental retardation and impaired speech development.

We report on a currently six-year-old patient with a de novo complex chromosome rearrangement (CCR) involving chromosomes 2 and 12. A translocation 2;12 that appeared to be reciprocal after standard banding turned out to be a complex event with seven breaks after molecular cytogenetic analyses. Array CGH analysis showed no imbalances at the breakpoints but revealed an additional microdeletion of about 80 kb on chromosome 11. The same deletion was also present in the phenotypically normal father. The patient showed relatively mild mental retardation, defined mainly as impaired speech development (orofacial dyspraxia) and psychomotor retardation. In addition, mild dysmorphic facial features like hypertelorism, a prominent philtrum and down-turned corners of the mouth were observed. We narrowed down all breakpoint regions to about 100 kb, using a panel of mapped bacterial artificial chromosome (BAC) clones for fluorescence in situ hybridization (FISH). BACs spanning or flanking all seven breakpoints were identified and no chromosomal imbalances were found consistent with the array CGH results. Our investigations resulted in the following karyotype: 46,XY,t(2;12)(2pter-->2p25.3::2p23.3-->2p25.2::2p23.3-->2p14::2q14.3-->2p14::2q14.3-->2q14.3::12q 12-->12qter;12pter-->12q12::2p25.3-->2p25.2::2q14.3-->2qter).

[Genetic risk factors in schizophrenia]. / Genetische Risikofaktoren für schizophrene Erkrankungen.

The high pathogenetic relevance of genetic factors in schizophrenia is beyond doubt based on the findings of epidemiological studies. By means of a complex mode of transmission, it is likely that several genes with weak to moderate effect jointly constitute a genetic basis for a vulnerability to schizophrenia that may well vary for different individuals. Other organic and psychosocial factors also play an individually different -- in some cases significant -- role in terms of pathogenesis, as a result of which an oligogenic/polygenic multifactor model is assumed from the standpoint of aetiopathogenetics. Molecular genetic methods consist in linkage analyses and association analyses. Positive linkage findings accumulate particularly for the chromosomes 1q, 6p, 8p, 13q and 22q. By themselves, individual mutations contribute little to the range of schizophrenic feature characteristics, it was not possible -- irrespective of some subtypes -- to replicate genes of major effect. From the large number of possible candidate genes, although studies on DRD3, DRD2 and HTR2A produced positive results, the magnitudes of effect were low. The findings for alleles of dysbindin, neuregulin 1, DAO, COMT, PRODH, ZDHHC and DISC are less clear. The search for schizophrenia-relevant mutations is hampered by the possibility of a heterogeneous phenotype of schizophrenia in case of a homogeneous genotype as much as by the possibility of inter-individually homogeneous phenotypical characteristics in case of schizophrenia-relevant heterotype in the genome. With the aid of the concept of endo-phenotypes, based on neurobiological phenomena, it might be possible to take a more direct approach that leads from relevant mutations to the risk of schizophrenias. However, replacing schizophrenic alienation with neurobiological aspects leads to difficulties in explaining these complex disorder profiles. Schizophrenic diseases require an explanatory approach that also incorporates personality and developmental psychological aspects from the outset, if the aim is not to restrict type of schizophrenic disease exclusively to loci of molecular genetic changes.

Characterisation of a 19-year-old "long-term survivor" with Edwards syndrome.

Trisomy 18 is the second most frequent autosomal aneuploidy affecting about 1 in 8,000 new-borns. Similar to trisomy 13 more than 90% of the patients die within the first year. Main causes of death are failure of vital organ function, in most cases of brain, heart, kidney, and gut, sometimes combined with severe infections. The degree to which essential organs are affected at birth and the clinical course differ considerably. Unknown genetic factors and various environmental effects are most likely involved. A less severe course of Edwards syndrome can be caused by a partial trisomy due to a deletion of the extra chromosome 18 or somatic mosaicism with a trisomic and a normal cell-line in the patient. In this report conventional chromosome analysis, FISH, and QF-PCR have been performed on a 19-year-old female patient with trisomy 18 to investigate a large number of cells including non-mitotic cells from various different tissues. This study supports evidence for an apparently pure form of trisomy 18 in this "long-living" patient with Edwards syndrome.

Molecular characterization of a unique de novo 15q deletion associated with Prader-Willi syndrome and central visual impairment.

We report a 2-year-old boy with Prader-Willi Syndrome (PWS) caused by a deletion of the PWS critical region as a result of an unbalanced translocation t(3;15). Additional features, including central visual impairment, relative macrocephaly, retrognathia, preauricular tags, and bilateral club-feet, were noticed. The extension of the deletion was determined by fluorescence in situ hybridization (FISH) analysis using 11 region-specific YAC clones. Nine YACs were found to be deleted, allowing us to determine that the deletion is larger than in patients with typical PWS deletions. The karyotype of this patient can thus be designated: 45,XY,-15,der(3)t(3;15)(qter;q14).ish der(3)t(3;15)(qter;q14) (wcp3+,wcp15+,D15S10-,PML+,D15Z1-,D3S4560+,801_f_9x1, 815_e_6x2) de novo. Molecular analyses using seven polymorphic markers helped to narrow down the breakpoint between marker ACTC.PC3 and the distal end of the YAC 815_e_6. These results provide evidence that haploinsufficiency for genes in 15q13-q14, not affected in common PWS deletions, is associated with the additional features found in the patient, including a central visual impairment.

Terminal tandem duplication of 16p: a case with "pure" partial trisomy (16)(pter-->p13).

A new-born infant was found to have multiple congenital anomalies Including bilateral cleft of lip and palate, club-hands and feet, and heart defects. High resolution chromosome analysis showed a de novo tandem duplication of the terminal part of the short arm of chromosome 16, resulting in a dup(16)(pter-->p13). Fluorescent in situ hybridization with a chromosome 16-specific paint confirmed that the extra material belonged to chromosome 16.

Chromosomal localization and genomic organization of the human Linker for Activation of T cells (LAT) gene.

We have mapped the LAT gene by radiation hybrid mapping and fluorescence in situ hybridization to chromosome 16p11.2. The complete cDNA sequence of LAT was generated using assembled sequences of cDNA fragments already available. BLAST analysis using the cDNA sequence led to the identification of BAC clone CTB-134H23 (GenBank Accession No. AC112166). The genomic structure of the human LAT gene consists of 11 exons, encompassing 5.7 kb. Alternative splicing variants were identified.

[Psoriasis and hypogonadism in chronic blepharokeratoconjunctivitis. A case report]. / Psoriasis und Hypogonadismus bei chronischer Blepharokeratokonjunktivitis. Ein Fallbericht.

BACKGROUND: Ocular symptoms occur in approximately 10% of patients with psoriasis vulgaris. PATIENT: We report the clinical course of a 35-year-old male patient with obstructive meibomian gland dysfunction, keratoconjunctivitis and reduced reflex secretion of both eyes. Psoriasis vulgaris and hypothalamic hypogonadism were also present. Genetic testing (cytogenetic and DNA analysis) was performed because of additional facial dysmorphia, brachydactylia and obesity. No chromosomal anomaly was found and no genetic syndrome has yet been diagnosed. The therapeutic regimen included preservative-free artificial tears, occlusion of the puncta and a systemic dose of doxycycline. Dermatological symptoms were treated topically and the hypogonadism was treated with intramuscular injections of testosterone. CONCLUSION: Lacrimal and meibomian glands are influenced by androgens. Therefore hormonal dysfunction can also have contributed to the blepharokeratoconjunctivitis in this patient.

Mild phenotype due to inverse duplication 4p16.3 - P15.3 including the Wolf-Hirschhorn critical region.

Duplication of distal 4p results in a recognizable clinical phenotype. We report here on a 3 year old girl with a de novo inverse duplication of the chromosome segment 4p16.3-p15.3. The symptoms in this patient are milder than those of previously described patients with 4p duplication syndrome and include a deep hairline, deep-set eyes, short pug nose, full cheeks, simian crease, clinodactily of the fifth digit, no speech development and a moderate psychomotor retardation. Fluorescence in situ hybridization (FISH) using a chromosome 4 painting probe confirmed that the extra material is of chromosome 4 origin. Further analysis with the Wolf-Hirschhorn critical region probe demonstrated the duplication of this region. The lysosomal hydrolase alpha-L-iduronidase (IDUA) gene which is mutated in mucopolysaccaridosis type I (MPS I) and mapped to 4p16.3 might be responsible for some of the MPS like facial features. A phenotype-genotype correlation analysis in combination with literature review was undertaken to allow a further delineation of partial trisomy 4p syndromes.

Clinical and molecular cytogenetic characterization of two patients with partial trisomy 1q41-qter: further delineation of partial trisomy 1q syndrome.

We report the clinical and molecular cytogenetic characterization of two patients with partial trisomy 1q. The first patient is a currently 11-year-old female proposita with a de novo unbalanced translocation 46,XX,der(8)(8qter-8p23.3::1q41-1qter), leading to a partial trisomy 1q41-qter and a partial monosomy for 8p23.3-pter. The most prominent clinical features of the girl are a triangular face, almond-shaped eyes, low-set ears, short stature with relatively long legs, and mild psychomotor retardation. To our knowledge, the cytogenetic aberration in this girl is the most proximal partial trisomy 1q leading to a mild phenotype. Recently, we identified a second patient with a similar partial trisomy 1q combined with a cri du chat syndrome caused by a de novo unbalanced translocation 46,XX,der(5)(5qter-5p13.1::1q41-1qter). Comparison of the phenotype of the two girls as well as with already published trisomy 1q cases was performed, and fluorescence in situ hybridization probes from selected YACs were used to delineate the extent of the partial trisomy in more detail.

Chronic myeloid leukemia with a rare variant Philadelphia translocation: t(9;10;22)(q34;q22;q11).

We report a 59-year-old, male, chronic myeloid leukemia patient with a rare variant Philadelphia (Ph) translocation t(9;10;22)(q34;q22;q11). Fluorescence in situ hybridization with whole chromosome paints was used to confirm the cytogenetic findings. With a BCR/ABL-specific probe, the known rearrangement on the derivative chromosome 22 was found. The prognostic implications as well as the relevance of the additional breakpoint region 10q22 are discussed.

Phenotype of five patients with Greig syndrome and microdeletion of 7p13.

Here we describe five patients with Greig cephalopolysyndactyly syndrome (GCPS), including one pair of monozygotic twin boys with a de novo microdeletion involving the chromosomal band 7p13, where various clinical manifestations, in addition to GCPS, were recognized. Besides the twin pair, all patients are unrelated. Since there is a considerable lack of well-defined clinical delineation of the few patients with microdeletions involving 7p13 with GCPS described so far, we focus on the symptoms that are not typically related to GCPS, such as moderate psychomotor retardation, seizures, muscle fiber anomalies, cardiac anomalies, hyperglycemia, and hirsutism. Our observations suggest that in all cases of atypical GCPS, the presence of a cytogenetically detectable microdeletion or a submicroscopic deletion of 7p13 should be suspected.

Candidate region for Gilles de la Tourette syndrome at 7q31.

Gilles de la Tourette Syndrome (GTS) is a complex neuropsychiatric disorder characterized by motor and vocal tics. The cause of this syndrome is unknown, although based on family studies there is evidence of a strong genetic component. We report on a 13-year-old boy with GTS, minor physical anomalies, and a de novo partial duplication of chromosome 7q [dup(7)(q22.1-q31.1)]. The distal breakpoint in our patient is similar to the breakpoint of an apparently balanced familial translocation t(7;18) segregating with GTS. Together, these cases provide evidence that a gene located in the breakpoint region at 7q31 can be involved in the formation of GTS.