Subtelomeric deletion of chromosome 10p15.3: clinical findings and molecular cytogenetic characterization.

We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with isolated, submicroscopic 10p15.3 deletion have been reported to date; however, only limited clinical information is available for these probands and the deleted region has not been molecularly mapped. Comprehensive clinical history was obtained for 12 of the 19 individuals described in this study. Common features among these 12 individuals include: cognitive/behavioral/developmental differences (11/11), speech delay/language disorder (10/10), motor delay (10/10), craniofacial dysmorphism (9/12), hypotonia (7/11), brain anomalies (4/6) and seizures (3/7). Parental studies were performed for nine of the 19 individuals; the 10p15.3 deletion was de novo in seven of the probands, not maternally inherited in one proband and inherited from an apparently affected mother in one proband. Molecular mapping of the 19 individuals reported in this study has identified two genes, ZMYND11 (OMIM 608668) and DIP2C (OMIM 611380; UCSC Genome Browser), mapping within 10p15.3 which are most commonly deleted. Although no single gene has been identified which is deleted in all 19 individuals studied, the deleted region in all but one individual includes ZMYND11 and the deleted region in all but one other individual includes DIP2C. There is not a clearly identifiable phenotypic difference between these two individuals and the size of the deleted region does not generally predict clinical features. Little is currently known about these genes complicating a direct genotype/phenotype correlation at this time. These data however, suggest that ZMYND11 and/or DIP2C haploinsufficiency contributes to the clinical features associated with 10p15 deletions in probands described in this study.

Interstitial long-arm deletion of chromosome 7 and ectrodactyly

An interstitial deletion of 7q21 was found in a boy with mental retardation, microcephaly, convergent strabismus, micrognathia, genital anomalies, and other findings, including ectrodactyly.

A case of terminal long arm deletion of chromosome 6

A four-year-old girl with deletion of chromosomal band 6q24 → qter is described. Clinical features include growth and psychomotor retardation, microcephaly, convergent strabismus, bulbous nose, long philtrum, short neck and cardiopathy.

High-resolution SNP microarray investigation of copy number variations on chromosome 18 in a control cohort

Copy number variations (CNVs) as described in the healthy population are purported to contribute significantly to genetic heterogeneity. Recent studies have described CNVs using lymphoblastoid cell lines or by application of specifically developed algorithms to interrogate previously described data. However, the full extent of CNVs remains unclear. Using high-density SNP array, we have undertaken a comprehensive investigation of chromosome 18 for CNV discovery and characterisation of distribution and association with chromosome architecture. We identified 399 CNVs, of which loss represents 98%, 58% are less than 2.5 kb in size and 71% are intergenic. Intronic deletions account for the majority of copy number changes with gene involvement. Furthermore, one-third of CNVs do not have putative breakpoints within repetitive sequences. We conclude that replicative processes, mediated either by repetitive elements or microhomology, account for the majority of CNVs in the healthy population. Genomic instability involving the formation of a non-B structure is demonstrated in one region.

Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.

Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+), but not paternal (m+/p-), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.

Frequency of deletion 508 among Irish cystic fibrosis patients

We estimate the incidence of cystic fibrosis in Ireland to be at least 1 case per 1838 live births. We have analysed DNA from 44 Irish CF patients for the presence of deletion 508, using the polymerase chain reaction. The deletion was found in 76% of their chromosomes, and approximately 58% of the patients are homozygous for this deletion. Our results are not significantly different from those found in Canadian or UK patient populations, in which frequencies are higher than those found in Southern European countries.

An atypical 7q11.23 deletion in a normal IQ Williams-Beuren syndrome patient.

Williams-Beuren syndrome (WBS; OMIM no. 194050) is a multisystemic neurodevelopmental disorder caused by a hemizygous deletion of 1.55 Mb on chromosome 7q11.23 spanning 28 genes. Haploinsufficiency of the ELN gene was shown to be responsible for supravalvular aortic stenosis and generalized arteriopathy, whereas LIMK1, CLIP2, GTF2IRD1 and GTF2I genes were suggested to be linked to the specific cognitive profile and craniofacial features. These insights for genotype-phenotype correlations came from the molecular and clinical analysis of patients with atypical deletions and mice models. Here we report a patient showing mild WBS physical phenotype and normal IQ, who carries a shorter 1 Mb atypical deletion. This rearrangement does not include the GTF2IRD1 and GTF2I genes and only partially the BAZ1B gene. Our results are consistent with the hypothesis that hemizygosity of the GTF2IRD1 and GTF2I genes might be involved in the facial dysmorphisms and in the specific motor and cognitive deficits observed in WBS patients.

Frequent p53 mutations and occasional loss of chromosome 4 in invasive bladder carcinoma induced by N-butyl-N-(4-hydroxybutil)nitrosamine in B6D2F1 mice

B6D2F1 mice (45/group) were treated with N-butyl-N-(4- hydroxybutyl)nitrosamine (BBN) or uracil as follows: Group 1 received 0.05% BBN in drinking water for the entire experiment, Group 2 received 5 mg of BBN by gastric gavage in 0.1 mL of 20% ethanol twice per week for 10 wk, Group 3 received a 2.5% uracil-containing diet for the entire experiment, and Group 4 was controls (received 0.1 mL of 20% ethanol by gavage twice per week for 10 wk). The surviving mice in Group 1 were killed after week 26 and those in the other groups after week 30. By week 15, three of 11 Group 1 and one of 15 Group 2 mice had bladder carcinoma. By 26 and 30 wk, respectively, invasive carcinomas were observed in 33 of 34 and six of 21 mice in Groups 1 and 2 and renal pelvic carcinomas in 11 of 34 and three of 21 mice in Groups 1 and 2. Four of 19 uracil-treated mice had bladder nodular hyperplasia. By polymerase chain reaction-single-strand conformation polymorphism and sequence analyses, 16 of 20 and two of five bladder carcinomas from Groups 1 and 2, respectively, showed mutations in the p53 gene. Ha-ras mutation was present in one case. Loss of heterozygosity analysis with simple-sequence length polymorphism markers for chromosome 4 showed that 10 of 21, two of 15, and nine of 13 mice in Groups 1-3, respectively, had heterozygous or homozygous deletions. B6D2F1 mice are therefore susceptible to the urothelial carcinogenic effects of BBN and develop frequent p53 mutations and chromosome 4 deletions. Chromosome 4 deletions were also seen with uracil.

Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith-Magenis syndrome

Smith-Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of ∼139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS. © 2012 Macmillan Publishers Limited All rights reserved.

Molecular basis of complete C4 deficiency. A study of three patients.

The highly polymorphic fourth component of human complement (C4) is usually encoded by two genes, C4A and C4B, adjacent to the 21-hydroxylase (21-OH) genes and is also remarkable by the high frequency of the null alleles, C4A*Q0 and C4B*Q0. Complete C4 deficiency is exceptional because this condition appears only in homozygotes for the very rare double-null haplotype C4AQ0,BQ0. This condition in most cases gives rise to systemic lupus erythematosus and an increased susceptibility to infections. The molecular basis for complete C4 deficiency has not yet been established. Therefore we studied the DNA of three previously described C4 deficient patients belonging to unrelated families by restriction fragment length polymorphism analysis using C4 and 21-OH probes. These studies revealed a deletion of the C4B and 21-OHA genes in two patients and no deletion at all in the third patient. Therefore, complete C4 deficiency as a result of homozygosity for the C4AQ0, BQ0 haplotype is not a consequence of a deletion of the C4 genes. The molecular basis of this genetic abnormality is certainly very complex and may vary also from one case to another.

A t(7;12) balanced translocation with breakpoints overlapping those of the Williams-Beuren and 12q14 microdeletion syndromes.

The molecular characterization of balanced chromosomal rearrangements have always been of advantage in identifying disease-causing genes. Here, we describe the breakpoint mapping of a de novo balanced translocation t(7;12)(q11.22;q14.2) in a patient presenting with a failure to thrive associated with moderate mental retardation, facial anomalies, and chronic constipation. The localization of the breakpoints and the co-occurrence of Williams-Beuren syndrome and 12q14 microdeletion syndrome phenotypes suggested that the expression of some of the dosage-sensitive genes of these two segmental aneuploidies were modified in cells of the proposita. However, we were unable to identify chromosomes 7 and/or 12-mapping genes that showed disturbed expression in the lymphoblastoids of the proposita. This case showed that position-effect might operate in some tissues, but not in others. It also illustrates the overlap of phenotypes presented by patients with the recently described 12q14 structural rearrangements.

Velocardiofacial syndrome with a rare t(2;22)

Rearrangements involving chromosomes 2 and 22 were described not only as acquired abnormalities in a variety of human neoplasias but also in the constitutional karyotype suggesting the existence of a greater fragility in some specific regions in these chromosomes. Patients with DiGeorge and Velocardiofacial syndromes have a deletion on 22q11 leading to haploinsufficiency for one or more gene(s). We report a patient with velocardiofacial syndrome in which cytogenetic and fluorescence in situ hybridization analysis showed a rare t(2;22) and deletion in the 22q11 region. © 2007 Lippincott Williams & Wilkins, Inc.

A rare non-Robertsonian translocation involving chromosomes 15 and 21

CONTEXTO:Translocações robertsonianas (TR) estão entre os rearranjos estruturais balanceados mais comuns em humanos e compreendem a fusão da cromatina completa do braço longo de dois cromossomos acrocêntricos. No entanto, são raras as translocações não Robertsonianas envolvendo esses cromossomos.RELATO DE CASO:Nós descrevemos uma translocação não balanceada de novo envolvendo os cromossomos 15 e 21. A recém-nascida era filha de uma mãe de 29 anos e de um pai de 42 anos, casal não consanguíneo. Os achados clínicos levaram ao diagnóstico de síndrome de Down (SD) com defeitos cardíacos congênitos graves (persistência do canal arterial e defeito do septo atrioventricular completo), além de baixos comprimento e peso ao nascimento (< 5o e < 10o percentil em curvas de medidas específicas para SD, respectivamente). A análise citogenética convencional revelou o cariótipo 46,XX,der(15)(15pter→15q26.2

GENETIC EVENTS PREDISPOSING TO WILMS' TUMOR

Wilms' tumor (WT) is a childhood embryonic tumor of the kidney. In some cases, WT has been associated with a chromosome deletion in the region 11p13. The majority of WT cases, however, have normal karyotypes with no discernable deletions or rearrangements of chromosome 11.^ To study the genetic events predisposing to the development of WT, I have used a number of gene markers specific for chromosome 11. Gene probes for human catalase and apolipoprotein A1 were localized to chromosome 11 by in situ hybridization. A number of other probes previously mapped to chromosome 11 were also used. Nine WT patients who were heterozygous for at least one 11p marker were shown to lose heterozygosity in their tumor DNA. Gene dosage experiments demonstrated that two chromosomes 11 were present although loss of heterozygosity had occurred in all but two cases. By using gene probes from the short and long arms of chromosome 11, I discerned that loss of heterozygosity was due to somatic recombination in four cases, chromosome deletion in two cases, and chromosome loss and reduplication or somatic recombination in these cases. Examination of DNAs from the parents of six of these patients indicated that the alleles that were lost in tumor tissues were alleles inherited from the mother. In sporadic WT cases one would expect the loss of alleles to be random. These data suggest that the loss of alleles resulting in the development of WT is not a random event, however, the significance of this is not known. ^