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Uncombable hair syndrome is a hair shaft condition in which the hair is frizzy, light in color (silver to light brown), and cannot be combed flat. Autosomal dominant (with complete or incomplete penetrance), autosomal recessive, and sporadic cases have been reported. In 2016 causative mutations in three genes were identified for uncombable hair syndrome, all with an autosomal recessive inheritance pattern: PADI3, TGM3, and TCHH. In many cases, however, there is still no molecular diagnosis. Here, we describe a case of autosomal recessive uncombable hair syndrome resulting from maternal uniparental disomy of chromosome 1.

Deletions that include the gene TAB2 and TAB2 loss-of-function variants have previously been associated with congenital heart defects and cardiomyopathy. However, other features, including short stature, facial dysmorphisms, connective tissue abnormalities and a variable degree of developmental delay, have only been mentioned occasionally in literature and thus far not linked to TAB2. In a large-scale, social media-based chromosome 6 study, we observed a shared phenotype in patients with a 6q25.1 deletion that includes TAB2. To confirm if this phenotype is caused by haploinsufficiency of TAB2 and to delineate a TAB2-related phenotype, we subsequently sequenced TAB2 in patients with matching phenotypes and recruited patients with pathogenic TAB2 variants detected by exome sequencing. This identified 11 patients with a deletion containing TAB2 (size 1.68-14.31 Mb) and 14 patients from six families with novel truncating TAB2 variants. Twenty (80%) patients had cardiac disease, often mitral valve defects and/or cardiomyopathy, 18 (72%) had short stature and 18 (72%) had hypermobility. Twenty patients (80%) had facial features suggestive for Noonan syndrome. No substantial phenotypic differences were noted between patients with deletions and those with intragenic variants. We then compared our patients to 45 patients from the literature. All literature patients had cardiac diseases, but syndromic features were reported infrequently. Our study shows that the phenotype in 6q25.1 deletions is caused by haploinsufficiency of TAB2 and that TAB2 is associated not just with cardiac disease, but also with a distinct phenotype, with features overlapping with Noonan syndrome. We propose the name "TAB2-related syndrome".

Collaboration from previous work institution. Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30737479/ Analyses in our diagnostic DNA laboratory include genes involved in autosomal recessive (AR) lysosomal storage disorders such as glycogenosis type II (Pompe disease) and mucopolysaccharidosis type I (MPSI, Hurler disease). We encountered 4 cases with apparent homozygosity for a disease-causing sequence variant that could be traced to one parent only. In addition, in a young child with cardiomyopathy, in the absence of other symptoms, a diagnosis of Pompe disease was considered. Remarkably, he presented with different enzymatic and genotypic features between leukocytes and skin fibroblasts. All cases were examined with microsatellite markers and SNP genotyping arrays. We identified one case of total uniparental disomy (UPD) of chromosome 17 leading to Pompe disease and three cases of segmental uniparental isodisomy (UPiD) causing Hurler-(4p) or Pompe disease (17q). One Pompe patient with unusual combinations of features was shown to have a mosaic segmental UPiD of chromosome 17q. The chromosome 17 UPD cases amount to 11% of our diagnostic cohort of homozygous Pompe patients (plus one case of pseudoheterozygosity) where segregation analysis was possible. We conclude that inclusion of parental DNA is mandatory for reliable DNA diagnostics. Mild or unusual phenotypes of AR diseases should alert physicians to the possibility of mosaic segmental UPiD. SNP genotyping arrays are used in diagnostic workup of patients with developmental delay. Our results show that even small Regions of Homozygosity that include telomeric areas are worth reporting, regardless of the imprinting status of the chromosome, as they might indicate segmental UPiD. info:eu-repo/semantics/publishedVersion

Proximal 6q (6q11-q15) deletions are extremely rare and little is known about their phenotypic consequences. Since parents and caregivers now use social media to seek information on rare disorders, the Chromosome 6 Project has successfully collaborated with a Facebook group to collect data on individuals worldwide. Here we describe a cohort of 20 newly identified individuals and 25 literature cases with a proximal 6q deletion. Microarray results and phenotype data were reported directly by parents via a multilingual online questionnaire. This led to phenotype descriptions for five subregions of proximal 6q deletions; comparing the subgroups revealed that 6q11q14.1 deletions presented less severe clinical characteristics than 6q14.2q15 deletions. Gastroesophageal reflux, tracheo/laryngo/bronchomalacia, congenital heart defects, cerebral defects, seizures, and vision and respiratory problems were predominant in those with 6q14.2q15 deletions. Problems related to connective tissue (hypermobility, hernias and foot deformities) were predominantly seen in deletions including the COL12A1 gene (6q13). Congenital heart defects could be linked to deletions of MAP3K7 (6q15) or TBX18 (6q14.3). We further discuss the role of ten genes known or assumed to be related to developmental delay and/or autism (BAI3, RIMS1, KCNQ5, HTR1B, PHIP, SYNCRIP, HTR1E, ZNF292, AKIRIN2 and EPHA7). The most influential gene on the neurodevelopmental phenotype seems to be SYNCRIP (6q14.3), while deletions that include more than two of these genes led to more severe developmental delay. We demonstrate that approaching individuals via social media and collecting data directly from parents is a successful strategy, resulting in better information to counsel families.

We studied the presence of benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) in patients with a 16p11.2 deletion including PRRT2 or with a PRRT2 loss-of-function sequence variant. Index patients were recruited from seven Dutch university hospitals. The presence of BIE, PKD and PKD/IC was retrospectively evaluated using questionnaires and medical records. We included 33 patients with a 16p11.2 deletion: three (9%) had BIE, none had PKD or PKD/IC. Twelve patients had a PRRT2 sequence variant: BIE was present in four (p = 0.069), PKD in six (p

We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring HSD17B10, HUWE1, and the microRNAs miR-98 and let-7f-2 in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the HUWE1 locus only. Consequently, increased mRNA levels were detected for HUWE1, but not HSD17B10. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of HUWE1 (exon 28 to 3' untranslated region), including miR-98 and let-7f-2. Our findings thus demonstrate that HUWE1 is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and in silico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of HUWE1-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial HUWE1 copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of HUWE1 causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements.

The range of commercially available array platforms and analysis software packages is expanding and their utility is improving, making reliable detection of copy-number variants (CNVs) relatively straightforward. Reliable interpretation of CNV data, however, is often difficult and requires expertise. With our knowledge of the human genome growing rapidly, applications for array testing continuously broadening, and the resolution of CNV detection increasing, this leads to great complexity in interpreting what can be daunting data. Correct CNV interpretation and optimal use of the genotype information provided by single-nucleotide polymorphism probes on an array depends largely on knowledge present in various resources. In addition to the availability of host laboratories' own datasets and national registries, there are several public databases and Internet resources with genotype and phenotype information that can be used for array data interpretation. With so many resources now available, it is important to know which are fit-for-purpose in a diagnostic setting. We summarize the characteristics of the most commonly used Internet databases and resources, and propose a general data interpretation strategy that can be used for comparative hybridization, comparative intensity, and genotype-based array data. Hum Mutat 33: 930-940, 2012. (C) 2012 Wiley Periodicals, Inc.

A partial deletion of chromosome band 2p25.3 (2pter) is a rarely described cytogenetic aberration in patients with intellectual disability (ID). Using microarrays we identified deletions of 2p25.3, sized 0.37-3.13 Mb, in three adult siblings and three unrelated patients. All patients had ID, obesity or overweight and/or a square-shaped stature without overt facial dysmorphic features. Combining our data with phenotypic and genotypic data of three patients from the literature we defined the minimal region of overlap which contained one gene, i.e., MYT1L. MYT1L is highly transcribed in the mouse embryonic brain where its expression is restricted to postmitotic differentiating neurons. In mouse-induced pluripotent stem cell (iPS) models, MYT1L is essential for inducing functional mature neurons. These resemble excitatory cortical neurons of the forebrain, suggesting a role for MYT1L in development of cognitive functions. Furthermore, MYT1L can directly convert human fibroblasts into functional neurons in conjunction with other transcription factors. MYT1L duplication was previously reported in schizophrenia, indicating that the gene is dosage-sensitive and that shared neurodevelopmental pathways may be affected in ID and schizophrenia. Finally, deletion of MYT1, another member of the Myelin Transcription Factor family involved in neurogenesis and highly similar to MYT1L, was recently described in ID as well. The identification of MYT1L as candidate gene for ID justifies further molecular studies aimed at detecting mutations and for mechanistic studies on its role in neuron development and on neuropathogenic effects of haploinsufficiency. (C) 2011 Wiley Periodicals, Inc.

The correct interpretation of copy number gains in patients with developmental delay and multiple congenital anomalies is hampered by the large number of copy number variations (CNVs) encountered in healthy individuals. The variable phenotype associated with copy number gains makes interpretation even more difficult. Literature shows that inheritence, size and presence in healthy individuals are commonly used to decide whether a certain copy number gain is pathogenic, but no general consensus has been established. We aimed to develop guidelines for interpreting gains detected by array analysis using array CGH data of 300 patients analysed with the 105K Agilent oligo array in a diagnostic setting. We evaluated the guidelines in a second, independent, cohort of 300 patients. In the first 300 patients 797 gains of four or more adjacent oligonucleotides were observed. Of these, 45.4% were de novo and 54.6% were familial. In total, 94.8% of all de novo gains and 87.1% of all familial gains were concluded to be benign CNVs. Clinically relevant gains ranged from 288 to 7912 kb in size, and were significantly larger than benign gains and gains of unknown clinical relevance (P

High-resolution genome-wide array analysis enables detailed screening for cryptic and submicroscopic imbalances of microscopically balanced de novo rearrangements in patients with developmental delay and/or congenital abnormalities. In this report, we added the results of genome-wide array analysis in 54 patients to data on 117 patients from seven other studies. A chromosome imbalance was detected in 37% of all patients with two-breakpoint rearrangements. In 49% of these patients, the imbalances were located in one or both breakpoint regions. Imbalances were more frequently (90%) found in complex rearrangements, with the majority (81%) having deletions in the breakpoint regions. The size of our own cohort enabled us to relate the presence of an imbalance to the clinical features of the patients by using a scoring system, the De Vries criteria, that indicates the complexity of the phenotype. The median De Vries score was significantly higher (P=0.002) in those patients with an imbalance (5, range 1-9) than in patients with a normal array result (3, range 0-7). This study provides accurate percentages of cryptic imbalances that can be detected by genome-wide array analysis in simple and complex de novo microscopically balanced chromosome rearrangements and confirms that these imbalances are more likely to occur in patients with a complex phenotype. European Journal of Human Genetics (2011) 19, 1152-1160; doi:10.1038/ejhg.2011.120; published online 29 June 2011

Postaxial polydactyly type A2 (PAP-A2; OMIM 602085) is a common feature seen in patients with a partial duplication of the long arm of chromosome 13. Dose dependency has been shown for digital malformations in this region, deletions resulting in oligodactyly and duplications in polydactyly. We aimed to narrow down the critical region for PAP-A2 in order to identify candidate genes. We performed chromosomal analysis, FISH and array-CGH in a patient with an interstitial duplication of chromosome 13q31.3q32.1 and a mild phenotype including postaxial polydactyly. The duplicated region spanned 5.59 Mb (89.67-95.25 Mb) and contained eleven known genes, including GPC5 and GPC6. GPC5 and GPC6 show homology with GPC3 and GPC4, genes involved in Simpson-Golabi-Behmel syndrome, an overgrowth syndrome in which also polydactyly can occur. Mouse studies have shown expression of both GPC5 and GPC6 in developing limbs. Therefore, we propose that GPC5 and GPC6 are the most likely candidate genes for PAP-A2. © 2009 Elsevier Masson SAS. All rights reserved.

We report on three patients with split hand/foot malformation type 1 (SHFM1). We detected a deletion in two patients and an inversion in the third, all involving chromosome 7q21q22. We performed conventional chromosomal analysis, array comparative genomic hybridization and fluorescence in situ hybridization. Both deletions included the known genes associated with SHFM1 (DLX5, DLX6 and DSS1), whereas in the third patient one of the inversion break points was located just centromeric to these genes. These observations confirm that haploinsufficiency due to either a simultaneous deletion of these genes or combined downregulation of gene expression due to a disruption in the region between these genes and a control element could be the cause of the syndrome. We review previously reported studies that support this hypothetical mechanism. European Journal of Human Genetics (2009) 17, 1432-1438; doi:10.1038/ejhg.2009.72; published online 29 April 2009

We report on a female patient with XY sex reversal with clitoromegaly, neonatal male testosterone and AMH levels, and a normal urine steroid profile. Array CGH revealed a de novo microdeletion of chromosome 9q33.3, including the NR5A1 gene. NR5A1 encodes for the steroidogenic factor-1 (SF-1) and heterozygous mutations in this gene were recently identified as an important cause of XY sex reversal. However, a deletion of NR5A1 has only been reported once. Patients with a mutation in NR5A1, have severe underandrogenisation with mild testicular dysgenesis. Müllerian structures may be present, while postnatal testosterone levels may be normal. This points towards a predominantly early embryonic effect of low, local, androgen levels, with or without reduced AMH levels. We recommend not only NR5A1 mutation screening, but also copy number analysis in patients with 46,XY sex reversal of unknown cause, even in the absence of dysmorphisms or congenital abnormalities.

Nablus mask-like facial syndrome (NMFLS) is a rare microdeletion syndrome with a mask-like facial appearance as the most characteristic feature. In 2000, Teebi, was the first to report on a 4 years old boy affected with NMFLS. Since then two additional patients have been reported. Three years later, with the development of the array CGH technology, Shieh et al., elucidated the etiology of NMFLS by showing that the two patients studied share a similar to 4 Mb microdeletion in the long arm of chromosome 8 (q21.3-q22.1). Here we report on two NMFLS patients among which the first patient described by Teebi in 2000, and present newly described clinical findings including the common happy behaviour of the children. Array CGH analysis of these two patients permitted to reveal a deletion in the same region, 8q21.3-q22.1. Combining the available literature and our data, we were able to narrow the common deleted region to 2.78 Mb (93.56-96.34 Mb) in 8q22.1. Direct relations between the clinical findings with (one of) the genes in the critical region have to await further studies on NFMLS patients with overlapping or smaller deletions. (C) 2009 Elsevier Masson SAS. All rights reserved.

We report on a male patient with intra-uterine growth retardation, microcephaly, coloboma, laryngomalacia and developmental delay. Array CGH analysis revealed a 649 kb duplication on chromosome 1p34.1. Only five patients with overlapping duplications have been reported thus far. Ten known genes are located in the duplicated region, including the POMGNT1 gene encoding for O-mannose beta-1,2-N-acetylglucosaminyltransferase. This gene, mutated in muscle-eye-brain disease, might be causative for the observed phenotype in our patient. (C) 2009 Elsevier Masson SAS. All rights reserved.

We reevaluated a unique family with two sibs who had a presumed autosomal recessively inherited syndrome characterized by mental retardation, microcephaly, short stature and absent phalanges. This family was originally described by Drayer et al. in 1977. Using modern molecular techniques, we demonstrated that the syndrome is caused by the recurrence of an apparently de novo 15qter deletion of 5.8 Mb. Analysis of polymorphic markers revealed that the deletion was of maternal origin in both cases, indicating germline mosaicism in the clinically unaffected mother. This study demonstrates the possibility of parental mosaicism and the risk of recurrence in sibs for terminal subtelomeric deletions.

Chromosomal instability in colon tumors implies the presence of numerical and structural chromosome aberrations and is further characterized by the absence of microsatellite instability and the occurrence of KRAS and/or TP53 mutations. In a previous screening of 194 colon tumors for both microsatellite instability and TP53 mutation, we found 25 microsatellite-unstable tumors, in 9 (36%) of which, presumed to be chromosomally stable, there were TP53 mutations. This prompted us to investigate whether a TP53 mutation in these microsatellite-unstable tumors would be an indicator of chromosomal instability, that is, whether this would be a category of tumors showing both microsatellite and chromosomal instability. For chromosomal instability assessment, we performed array-comparative genomic hybridization analysis of tumor and control DNA extracted from formalin-fixed, paraffin-em bedded stage III colon tumor specimens. The array consisted of 435 subtelomere-specific BACs. We compared all but one (whose DNA was of bad quality) of the microsatellite-unstable TP53 mutation-containing tumors (8) with a similarly sized group of microsatellite-unstable tumors without TP53 mutation (11). Microsatellite-unstable tumors with a TP53 mutation showed on average 0.9 aberrations (range 0-3) when assessed with this array system. Those without a TP53 mutation showed on average 0.7 aberrations (range 0-2). Thus, microsatellite-unstable tumors showed few chromosomal abnormalities regardless of TP53 mutation status. Because, in our study, the microsatellite-stable tumors had on average 3.4 chromosomal abnormalities (range 0-7), a clear difference exists between microsatellite-unstable and -stable tumors. Because a substantial proportion of microsatellite-unstable colon tumors carry a TP53 mutation while showing relatively few chromosomal aberrations, a TP53 mutation in these tumors cannot be considered to be an indicator of chromosomal instability. (c) 2005 Wiley-Liss, Inc.

The detection of chromosomal aberrations is essential for the diagnosis and therapy of acute myeloid leukaemia (AML). We report two cases of de novo AML with translocations involving the breakpoint 6p22 first detected at relapse. Chromosomes were identified by conventional and molecular cytogenetics. At diagnosis, one patient presented a normal karyotype and the other one a trisomy 11 and a del(7)(q31q36). In the first case, cytogenetic analyses at relapse revealed a t(3;6)(q21;p22). The second patient showed a t(1;6)(q21;p22) at relapse. Detailed characterization of the breakpoints on the short arm of chromosome 6 was performed using array comparative genomic hybridization (CGH) on a platform specific for chromosome 6. In both cases, array CGH showed a terminal deletion and a small internal duplication of the short arm of chromosome 6. The region 6p22 is involved in several aberrations in tumours. Translocation partners are distributed throughout the human genome. We identified 3q21, a recurrent breakpoint in AML, for the first time as a translocation partner. The fragile site FRA6C, located in 6p22.2, and possibly the genes that reside within it, may play a role in tumorigenesis. The occurrence of translocations involving 6p22 after chemotherapy or radiation therapy suggests that one or more therapeutic agents might play a role in their origin.

We describe several relatives within one renal cell cancer (RCC) family sharing a constitutional t(2;3) (q35;q21). Based on molecular studies on several independent primary tumors in this family, a causative role for this translocation in tumor development was suggested. Subsequent positional cloning of the 3q21 chromosomal breakpoint revealed that this breakpoint disrupts a novel gene, DIRC2 (disrupted in renal cancer 2). This gene encodes an evolutionary conserved transmembrane protein and represents a novel member of the MFS superfamily of transporters. To evaluate whether DIRC2 is also targeted in sporadic RCC cases with cytogenetically defined 3q21 breakpoints, fluorescence in situ hybridization analysis was performed on metaphase spreads and/or interphase nuclei of 12 primary sporadic RCC using genomic clones from a 3q21 breakpoint-spanning contig as probes. Three breakpoints were mapped proximal to the familial breakpoint and nine breakpoints were mapped distal to this breakpoint. Two of the latter breakpoints were mapped in the contig within 1 Mb distance from the familial breakpoint. Because these clustered 3q21 breakpoints do not coincide with the familial 3q21 breakpoint, they most likely affect genes distinct from DIRC2.

Cardiac myxomas are significant causes of cardiovascular morbidity and mortality. Their genetic background is presently unknown. Recently, linkage analysis in cardiac myxomas of Carney complex patients has indicated that 2p16 and 17q2 might carry genes responsible for the development of hereditary cardiac myxomas. Less is known about sporadic cardiac myxomas. To date, cytogenetic analysis has been performed on 13 sporadic cases, and no specific rearrangement has been deduced. We studied 15 sporadic cardiac myxomas and reviewed the literature. Ten of the present cases revealed abnormal karyotypes with clonal and nonclonal rearrangements including dicentric chromosomes and telomeric associations. No cytogenetic evidence was found for a role of 2p16 in the development of sporadic cases. Region 17q2 was involved in structural rearrangements, but to a lesser extent than other regions. Structural rearrangements involving regions 12p1 and 17p1 are more frequently present and might therefore harbor genes important for the development of sporadic cardiac myxomas.

Metastatic disease is a well-known complicating factor in the treatment of renal cell cancer. Whereas radical nephrectomy usually is curative in cases of localized disease, no adequate treatment has been established for metastatic renal tumors. Identification of specific chromosome changes or genes responsible for metastatic behavior may lead to new strategies of treatment in the future. In light of this, we cytogenetically analyzed a metastasis of a chromophobe renal cell carcinoma arising in a 73-year-old male and compared the results with genetic data on primary chromophobe renal tumors. The chromosomal pattern of the present case showed, next to the extensive chromosome losses specific for the chromophobe subtype, structural rearrangements involving chromosomes 1, 5, 12, 15, and 18. Determining whether or not (some of) the observed structural changes are important for the metastatic behavior of chromophobe renal cell tumors will have to await further genetic studies on metastases of renal cancer. (C) Elsevier Science Inc., 1998.

Contains fulltext : 138213.pdf (Publisher’s version ) (Open Access) BACKGROUND: Characteristic genomic abnormalities in patients with B cell chronic lymphocytic leukemia (CLL) have been shown to provide important prognostic information. Fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA), currently used in clinical diagnostics of CLL, are targeted tests aimed at specific genomic loci. Microarray-based genomic profiling is a new high-resolution tool that enables genome-wide analyses. The aim of this study was to compare two recently launched genomic microarray platforms, i.e., the CytoScan HD Array (Affymetrix) and the HumanOmniExpress Array (Illumina), with FISH and MLPA to ascertain whether these latter tests can be replaced by either one of the microarray platforms in a clinical diagnostic setting. RESULT: Microarray-based genomic profiling and FISH were performed in all 28 CLL patients. For an unbiased comparison of the performance of both microarray platforms 9 patients were evaluated on both platforms, resulting in the identification of exactly identical genomic aberrations. To evaluate the detection limit of the microarray platforms we included 7 patients in which the genomic abnormalities were present in a relatively low percentage of the cells (range 5-28%) as previously determined by FISH. We found that both microarray platforms allowed the detection of copy number abnormalities present in as few as 16% of the cells. In addition, we found that microarray-based genomic profiling allowed the identification of genomic abnormalities that could not be detected by FISH and/or MLPA, including a focal TP53 loss and copy neutral losses of heterozygosity of chromosome 17p. CONCLUSION: From our results we conclude that although the microarray platforms exhibit a somewhat lower limit of detection compared to FISH, they still allow the detection of copy number abnormalities present in as few as 16% of the cells. By applying similar interpretation criteria, the results obtained from both platforms were comparable. In addition, we conclude that both microarray platforms allow the identification of additional potential prognostic relevant abnormalities such as focal TP53 deletions and copy neutral losses of heterozygosity of chromosome 17p, which would have remained undetected by FISH or MLPA. The prognostic relevance of these novel genomic alterations requires further evaluation in prospective clinical trials.

22q11.2 deletion syndrome is one of the most common microdeletion syndromes. Most patients have a deletion resulting from a recombination of low copy repeat blocks LCR22-A and LCR22-D. Loss of the TBX1 gene is considered the most important cause of the phenotype. A limited number of patients with smaller, overlapping deletions distal to the TBX1 locus have been described in the literature. In these patients, the CRKL gene is deleted. Haploinsufficiency of this gene has also been implicated in the pathogenesis of 22q11.2 deletion syndrome. To distinguish these deletions (comprising the LCR22-B to LCR22-D region) from the more distal 22q11.2 deletions (located beyond LCR22-D), we propose the term central 22q11.2 deletions. In the present study we report on 27 new patients with such a deletion. Together with information on previously published cases, we review the clinical findings of 52 patients. The prevalence of congenital heart anomalies and the frequency of de novo deletions in patients with a central deletion are substantially lower than in patients with a common or distal 22q11.2 deletion. Renal and urinary tract malformations, developmental delays, cognitive impairments and behavioral problems seem to be equally frequent as in patients with a common deletion. None of the patients had a cleft palate. Patients with a deletion that also encompassed the MAPK1 gene, located just distal to LCR22-D, have a different and more severe phenotype, characterized by a higher prevalence of congenital heart anomalies, growth restriction and microcephaly. Our results further elucidate genotype-phenotype correlations in 22q11.2 deletion syndrome spectrum. (c) 2014 Wiley Periodicals, Inc.

Cytogenetic and molecular genetic investigations in cancer are important tools to address problems of oncogenesis and tumor progression, of classification, and of diagnosis of tumors. A combination of advanced molecular genetic, cytogenetic, and (immuno) histopathologic analysis will contribute significantly to the elucidation of the oncogenic steps that lead to immortalization and subsequent malignant behavior. In this review written on the occasion of Dr. Avery Sandberg's 75th anniversary, we will present a model for the pathogenesis of renal cell tumors based on a new cytomorphologic classification and our (cyto)genetic analysis of about 175 renal cell tumors, together with the accumulated data in the literature.

This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the -isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders. (c) 2013 Wiley Periodicals, Inc.

A combination of Southern blot analysis on a panel of tumor-derived somatic cell hybrids and fluorescence in situ hybridization (FISH) techniques was used to map a series of DNA markers relative to the 1q21 breakpoint of the renal cell carcinoma (RCC)-associated (X;1)-(p11;q21) translocation. This breakpoint maps between several members of the S100 family which are clustered in the 1q21 region and a conserved region between man and mouse containing the markers SPTA1-CRP-APCS-FcER1A-ATP1A2-APOA2. The location of the breakpoint coincides with the transition of a region of synteny of human chromosome 1 with mouse chromosomes 3 and 1.

Renal carcinoids are very rare neoplasms. We were able to culture and subsequently karyotype a carcinoid located in the isthmus of a horseshoe kidney, which revealed the following chromosomal pattern: 47,XX,+13[8]/46,XX,t(13;14)(q31;q11.2)[5]/46,XX[2]. The DNA index was 1. Our results, compared with the sparse data from the literature, suggest that carcinoid of the kidney has no cytogenetic aberrations in common with carcinoids from other anatomical sites reported. On the other hand, numerical and structural aberrations of chromosome 13 seem to play a crucial role in the development of metanephric-derived renal tumors.

Many of the reported oncocytomas have different chromosome abnormalities, indicating that they comprise a cytogenetically heterogenous group of tumors consisting of potentially cytogenetic subgroups. We have performed cytogenetic studies on nine renal oncocytomas. Clonal abnormalities were present in eight tumors. The findings most observed were the loss of the Y chromosome, and abnormalities of chromosomes 1 and 22. We also observed telomeric associations (tas) in two tumors and structural aberrations of chromosomes 9p and 19q, as well as monosomy 10. In two cases we found a similar reciprocal t(5;11)(q35;q13) in two cases. Review of the literature disclosed one other oncocytoma with a t(5;11) (q35;q13). This suggests that t(5;11)(q35;q13) defines a (second) subset of oncocytomas apart from the subgroup specifically associated with the loss of chromosomes 1 and Y.

Several human renal cell carcinomas with X;autosome translocations have been reported in recent years. The t(X; I)(p11.2;q21) appears to be a specific primary anomaly, suggesting that tumors with this translocation form a distinct subgroup of RCC. Here we report two new cases, one with a t(X;10)(p11.2;q23), the other with a t(X;1)(p11.2;p34). The common breakpoint in Xp11.2 suggests that they belong to the above-mentioned subset of RCC. Using FISH in conjunction with X-specific YAC clones, we demonstrate that the two new cases exhibited distinct breakpoints within Xp11.2. (C) 1995 Wiley-Liss, Inc.

A malignant fibrous histiocytoma (MFH) of bone arising in the fibula of a 21-year-old woman is described. Clinical, radiologic, and histologic findings demonstrated rapid tumor progression. Chromosomal analysis of the biopsy specimen showed great karyotypic heterogeneity, whereas the resection specimen four weeks later displayed a rather homogeneous karyotype. Both revealed a clonal t(14;22)(q11;p12). Several other clonal and non-clonal chromosomal aberrations were observed. Some of these were previously described in giant cell tumor of bone (GCTB) and may correlate with aggressive behavior, e.g., aberrations involving 8p11, 19q13, and 20q13. The change from karyotypic heterogeneity to relative homogeneity may be related to tumor progression. The chromosomal findings further suggest that the giant cell type of MFH of bone may be related to malignant GCTB. (C) 1994 Wiley-Liss, Inc.

Contains fulltext : 88561.pdf (Publisher’s version ) (Closed access) BACKGROUND: Chromosome 17p13.3 contains extensive repetitive sequences and is a recognised region of genomic instability. Haploinsufficiency of PAFAH1B1 (encoding LIS1) causes either isolated lissencephaly sequence or Miller-Dieker syndrome, depending on the size of the deletion. More recently, both microdeletions and microduplications mapping to the Miller-Dieker syndrome telomeric critical region have been identified and associated with distinct but overlapping phenotypes. METHODS: Genome-wide microarray screening was performed on 7678 patients referred with unexplained learning difficulties and/or autism, with or without other congenital abnormalities. Eight and five unrelated individuals, respectively, were identified with microdeletions and microduplications in 17p13.3. RESULTS: Comparisons with six previously reported microdeletion cases identified a 258 kb critical region, encompassing six genes including CRK (encoding Crk) and YWHAE (encoding 14-3-3epsilon). Clinical features included growth retardation, facial dysmorphism and developmental delay. Notably, one individual with only subtle facial features and an interstitial deletion involving CRK but not YWHAE suggested that a genomic region spanning 109 kb, encompassing two genes (TUSC5 and YWHAE), is responsible for the main facial dysmorphism phenotype. Only the microduplication phenotype included autism. The microduplication minimal region of overlap for the new and previously reported cases spans 72 kb encompassing a single gene, YWHAE. These genomic rearrangements were not associated with low-copy repeats and are probably due to diverse molecular mechanisms. CONCLUSIONS: The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations. 01 mei 2010

Contains fulltext : 80583.pdf (Publisher’s version ) (Closed access) It was shown that Lynch syndrome can be caused by germline hypermethylation of the MLH1 and MSH2 promoters. Furthermore, it has been demonstrated very recently that germline deletions of the 3' region of EPCAM cause transcriptional read-through which results in silencing of MSH2 by hypermethylation. We wanted to determine the prevalence of germline MLH1 promoter hypermethylation and of germline and somatic MSH2 promoter hypermethylation in a large group of Lynch syndrome-suspected patients. From a group of 331 Lynch Syndrome-suspected patients we selected cases, who had no germline MLH1, MSH2, or MSH6 mutation and whose tumors showed loss of MLH1 or MSH2, or, if staining was unavailable, had a tumor with microsatellite instability. Methylation assays were performed to test these patients for germline MLH1 and/or MSH2 promoter hypermethylation. Two patients with germline MLH1 promoter hypermethylation and no patients with germline MSH2 promoter hypermethylation were identified. In the subgroup screened for germline MSH2 promoter hypermethylation, we identified 3 patients with somatic MSH2 promoter hypermethylation in their tumors, which was caused by a germline EPCAM deletion. In the group of 331 Lynch Syndrome-suspected patients, the frequencies of germline MLH1 promoter hypermethylation and somatic MSH2 promoter hypermethylation caused by germline EPCAM deletions are 0.6 and 0.9%, respectively. These mutations, therefore, seem to be rather infrequent. However, the contribution of germline MLH1 hypermethylation and EPCAM deletions to the genetically proven Lynch syndrome cases in this cohort is very high. Previously 27 pathogenic mutations were identified; the newly identified mutations now represent 16% of all mutations.

Behavioural differences have been described in patients with type I deletions (between breakpoints 1 and 3 (BP1-BP3)) or type II deletions (between breakpoints 2 and 3) of the 15q11.2 Prader-Willi/Angelman region. The larger type I deletions appear to coincide with more severe behavioural problems (autism, ADHD, obsessive-compulsive disorder). The non-imprinted chromosomal segment between breakpoints 1 and 2 involves four highly conserved genes, TUBGCP5, NIPA1, NIPA2, and CYFIP1; the latter three are widely expressed in the central nervous system, while TUBGCP5 is expressed in the subthalamic nuclei. These genes might explain the more severe behavioural problems seen in type I deletions.We describe nine cases with a microdeletion at 15q11.2 between BP1-BP2, thus having a haploinsufficiency for TUBGCP5, NIPA1, NIPA2, and CYFIP1 without Prader-Willi/Angel man syndrome. The clinical significance of a pure BP1-BP2 microdeletion has been debated, however, our patients shared several clinical features, including delayed motor and speech development, dysmorphisms and behavioural problems (ADHD, autism, obsessive-compulsive behaviour). Although the deletion often appeared to be inherited from a normal or mildly affected parent, it was de novo in two cases and we did not find it in 350 healthy unrelated controls.Our results suggest a pathogenic nature for the BP1-BP2 microdeletion and, although there obviously is an incomplete penetrance, they support the existence of a novel microdeletion syndrome in 15q11.2. (C) 2009 Elsevier Masson SAS. All rights reserved.

Imbalances of 3p telomeric sequences cause 3p- and trisomy 3p syndrome, respectively, showing distinct, but also shared clinical features. No causative genes have been identified in trisomy 3p patients, but for the 3p- syndrome, there is growing evidence that monosomy for one or more of four genes at 3pter, CHL1, CNTN4, CRBN and MEGAP/srGAP3, may play a causative role. We describe here an analysis of a complex chromosome 3p aberration in a severely mentally retarded patient that revealed two adjacent segments with different copy number gains and a distal deletion. The deletion in this patient included the loci for CHL1, CNTN4, and CRBN, and narrowed the critical segment associated with the 3p- syndrome to 1.5 Mb, including the loci for CNTN4 and CRBN. We speculate that the deletion contributes more to this patient's phenotype than the gains that were observed. We suggest that 3p- syndrome associated features are primarily caused by loss of CNTN4 and CRBN, with loss of CHL1 probably having an additional detrimental effect on the cognitive functioning of the present patient. (c) 2006 Wiley-Liss, Inc.

A 62-year-old woman presented with a solitary diffuse neurofibroma; a second recurrence showed features indicative of malignancy, but insufficient for a certain histologic diagnosis. Cytogenetic analysis revealed abnormalities previously described in malignant peripheral nerve sheath tumors and not in their benign counterparts, thus supporting the histologic suspicion of emerging malignancy. (C) 1997 Elsevier Science Inc., 1997.

Muscle-type carnitine palmitoyltransferase I (M-CPT 1) is a key enzyme in the control of beta-oxidation of long-chain fatty acids in the heart and skeletal muscle. Because knowledge of the mammalian genes encoding M-CPT I may aid in studies of disturbed energy metabolism, we obtained new genomic and cDNA data for M-CPT I for the human, mouse, rat, and sheep. The introns of these compact genes are 80% (mouse versus rat) and 60% (mouse versus human) identical. Sheep and goat, but not cow, pig, rodent, or human promoter sequences contain a short interspersed repeated sequence (SINE) upstream of highly conserved regulatory elements. These elements constitute two promoters in humans, sheep, and mice, and, contrary to previous reports, there is a second promoter in rats as well. Thus, the transcriptional organization of these genes is more uniform than previously supposed, with interspecies differences in. the 5'-ends of the mRNAs reflecting differences in splicing-, only in humans extensive splicing and splice variation is found in the 5% and W-untranslated regions. In the mouse, intron retention was detected in heart, muscle, and testes and may indicate an additional mechanism of regulation of M-CPT I expression. Splice variation in the coding region was previously proposed to lead to expression of CPT I enzymes with altered malonyl-CoA sensitivity (Yu, G. S., Lu, Y. C., and Gulick, T. (1998) Biochem. J. 334,225-231). However, when expressed in the yeast Pichia pastoris, none of three earlier described splice variants had CPT I activity. Therefore, the involvement of splice variation of M-CPT I in the modulation of malonyl-CoA inhibition of fatty acid oxidation may be less relevant than hitherto assumed.

Renal-cell cancer comprises a heterogeneous group of tumors, which currently can be sub-divided into morphologically distinct entities, each characterized by a specific combination of genetic changes. Sarcomatoid transformation might occur in any of the sub-types, resulting in tumors consisting of both carcinomatous and sarcomatous components. The specific diagnosis of these neoplasms, as to tumor sub-type, is usually made on the histologic properties of the carcinomatous tissue present. However, this might not reflect the true nature of the sarcomatous component. Since the genetic changes associated with the development of the different sub-types of renal-cell cancer are well established, this knowledge might serve as a tool in diagnosing sarcomatoid tumors. Assessing the genetic constitution of the latter may lead to correct diagnosis, It may also provide valuable information about the genetic changes associated with sarcomatoid transformation. Hence we performed a genetic characterization of a case of sarcomatoid renal cell cancer, histologically diagnosed as being of the chromophilic type. The observed genetic changes included loss of 3p, 6q, 8p, 9, 13, 14 and 17p, and gain of 5, 12 and 20, as well as a mutation in the coding region of the p53 gene. This combination of genetic changes points to clear-cell rather than chromophilic origin of the sarcomatoid tumor investigated, indicating that the genetic constitution of sarcomatoid tumors may be a more reliable indicator of tumor sub-type than histologic appearance. (C) 1997 Wiley-Liss, Inc.

Renal oncocytomas comprise a cytogenetically heterogeneous group of tumors consisting potentially of cytogenetic distinguishable subgroups. Review of the literature revealed loss of chromosome 1 and Y as a possible anomaly for at least one subset of oncocytomas. The frequent finding of rearrangements involving chromosome 11 band q13 characterizes another subset of oncocytomas. We report the cytogenetic and pathological features of a renal oncocytoma diagnosed in a 72-year-old woman and found a t(9;11)(p23;q13) as a consistent abnormality. This supports the idea that translocations involving 11q13 define a further subset of oncocytoma. (C) Elsevier Science Inc., 1997.

The cytogenetic analysis of a patient with a myxoid liposarcoma exhibiting cartilaginous differentiation is presented. A complex translocation involving chromosome 12, 16, and 19 was found, instead of the t(12;16), specific for myxoid liposarcoma. The involvement of 19q13 in a tumor with cartilaginous differentiation, and the assignment of TGF beta 1 to 19q13.1-13.2, which appears to play a role in the formation of bone and cartilage, suggest a possible relation between both. (C) Elsevier Science Inc., 1996

Chromosome aberrations were studied in short-term cultures of non-neoplastic renal tissue and tumor tissue in 60 patients, 41 male and 19 female, with renal cell cancer (RCC), and in normal renal parenchyma from two cases, one male and one female, at autopsy with non-kidney related disease. Cytogenetic analysis of the non-neoplastic renal tissue from the patents with RCC revealed clonal chromosome aberrations in 32 of 60 (53%) cases: -Y, +Y, +X, +5, +7, +10, +12, +13, +18, +21, and del(9)(q12). In all other cases, non-clonal numerical and structural chromosome aberrations were observed, except for three cases of culture failure. Forty-two cases of RCC yielded clonal chromosomal abnormalities. Trisomy 7 was present in 23 cases, loss of Y in 14, trisomy 5 and 12 in three, trisomy 18 in two cases, and trisomy 10 in one case. Clonal chromosomal anomalies found in two cases from kidneys without neoplasia were trisomy 7, trisomy 12, and trisomy 18 in one case, and monosomy of chromosome 15 in the other. The proportion of aberrant cells in both cases (with clonal and non-clonal aberrations) was, on average, 24%. Apparently, chromosomal abnormalities only play a role in the process of oncogenesis when they are in the appropriate stage and lineage of differentiation.

Recently, we reported on the cytogenetic analysis of a case of cardiac myxoma, revealing a 46,XY,der(7)t(7;17)(p21;p11), add (10) (q22), add (12) (p12), del(17)(p11) chromosomal pattern. In this article we present the cytogenetic analysis of another case of cardiac myxoma, in which we found several clonal and nonclonal abnormalities including dicentric chromosomes and telomeric associations (tas). One of the clonal aberrations was a translocation between chromosomes 1 and 12, involving a breakpoint at 12p12, as observed in the case described earlier. This finding suggest that 12p12 might play an important role in the histogenesis of cardiac myxomas.

Chondrosarcomas are a heterogeneous group of bone neoplasms of which the basic neoplastic tissue is cartilaginous. Frequently the histologic diagnosis and grading of chondrosarcomas is difficult and the histologic appearance does not always reflect the biologic behavior of these tumors. Therefore, it is important to find other parameters that can be of help in the proper diagnosing and grading of these neoplasms. To this end, we attempted to correlate the chromosomal pattern of chondrosarcomas to their histologic subtypes and grades. The cytogenetic analysis of two intermediate-grade chondrosarcomas of bone, and a review of the literature, are presented.

The cytogenetic study of a case of cardiac myxoma revealed a 46,XY,der(7)t(7;17) (p21;p11),+der(10)t(10;?)(q22;?),+der(12)t(12;?)(p12;?),del(17)(p11) chromosomal pattern. This case adds a new example of chromosomal abnormalities in benign neoplasms.