Duplication 19q13-qter and deletion 19p13-pter arising from an inversion (19)(p13.3q13.3) of maternal origin

Pericentric inversion of chromosome 19 appears to be a rare abnormality with only a few families reported. As far as we are aware, none of them were ascertained because of a recombinant individual. We describe the first identified case due to an affected patient, with duplication deficiency for chromosome 19 arising from a maternal inversion confirmed by FISH and CGH. His features included prenatal growth retardation, microcephaly, dysmorphic facies, congenital heart defect, hypoplasia of corpus callosum and psychomotor delay. The identification of recombinant individuals contribute to calculate a precise risk for inv (19) carriers and to provide a more accurate genetic counselling.     

Trisomy 5q12→q13.3 in a patient with add(13q): Characterization of an interchromosomal insertion by forward and reverse chromosome painting

We report on a patient with azoospermia, mild mental retardation, and minor physical anomalies. Chromosome analysis demonstrated the presence of additional material on the long arm of one chromosome 13. Forward chromosome painting using chromosome-specific libraries showed an insertion of material from chromosome 5. Further characterization with flow sorting of the aberrant chromosome and amplification by DOP-PCR followed by reverse chromosome painting showed specific trisomy of 5q12→q13.3. Am. J. Med. Genet. 73:351–355, 1997. © 1997 Wiley-Liss, Inc.     

Delineation of 15q13.3 microdeletions

Masurel‐Paulet A, Andrieux J, Callier P, Cuisset JM, Le Caignec C, Holder M, Thauvin‐Robinet C, Doray B, Flori E, Alex‐Cordier MP, Beri M, Boute O, Delobel B, Dieux A, Vallee L, Jaillard S, Odent S, Isidor B, Beneteau C, Vigneron J, Bilan F, Gilbert‐Dussardier B, Dubourg C, Labalme A, Gautier A, Pernes P, Bidon C, Pinoit JM, Huet F, Mugneret F, Aral B, Jonveaux P, Sanlaville D, Faivre L. Delineation of 15q13.3 microdeletions. The increasing use of array‐comparative genomic hybridization (array‐CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4–BP5 microdeletion out of a series of 4625 patients screened by array‐CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical ～1.5 Mb BP4–BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.     

Chromosome 11q13.3 variant modifies renal cell cancer risk in a Chinese population

A recent genome-wide association study of renal cell carcinoma (RCC) in European population has identified genetic variants in the regions of 2p21 (rs7579899), 11q13.3 (rs7105934) and 12q24.31 (rs4765623) conferred susceptibility to RCC. In our study, we assessed whether these polymorphisms are also associated with RCC risk in a Chinese population. We genotyped these polymorphisms using TaqMan method and assessed their associations with RCC risk in a case-control study of 710 patients with histologically confirmed RCC and 760 cancer-free controls. Normal renal tissues adjacent to tumors were used to evaluate the functional consequences of these polymorphisms. We found that rs7105934 was significantly associated with reduced RCC risk [adjusted odds ratio (OR) = 0.67, 95% confidence intervals (CIs) = 0.47-0.95, GA+AA versus GG], particularly among subgroups of normal-weight individuals (OR = 0.51, 95%CI = 0.29-0.88), never-smokers (OR = 0.53, 95%CI = 0.33-0.85) and non-drinkers (OR = 0.57, 95%CI = 0.370.87). Furthermore, the rs7105934 GA genotype was associated with lower levels of CCND1 mRNA compared with GG genotype, although this association was only marginally significant (P = 0.055). No significant association between rs7579899 or rs7105934 and RCC risk was observed. Our results suggest that rs7105934 on 11q13.3 may confer susceptibility to RCC in our population. Large population-based prospective and functional studies are required to validate the associations between these loci and RCC risk.     

Familial 5q11.2→q13.3 segmental duplication cosegregating with multiple anomalies,including schizophrenia

We report on 2 relatives with a segmental duplication of 5q11.2→13.3. The phenotype is surprisingly limited for the degree of chromosome imbalance, the propositus presenting with schizophrenia. Using RFLP markers, we have shown that the gene for HEXB lies within the duplicated region. We suggest this region as a candidate region for the location of a single major gene which predisposes to schizophrenia and which may be assessed by linkage analysis.     

Cloning and characterization of the inversion breakpoint at chromosome 2q35 in a patient with Waardenburg syndrome type I.

We described cloning and characterization of an inversion breakpoint of chromosome 2 inv(2)(q35q37.3) observed in a patient with Waardenburg syndrome type I (WSI). Genomic cosmid clones containing the HuP2 gene, which was considered as a candidate for WSI, were isolated from a library constructed from the patient DNA. One of the clones contained the inversion breakpoint and revealed signals at both 2q35 and 2q37 by fluorescent in situ hybridization (FISH), indicating disruption of the HuP2 gene by the inversion. Our result further supports that the HuP2 gene is a candidate for Waardenburg syndrome type I and is located at q35.     

Molecular cloning of a translocation breakpoint hotspot in 22q11

It has been well documented that 22q11 contains one of the most rearrangement-prone sites in the human genome, where the breakpoints of a number of constitutional translocations cluster. This breakage-sensitive region is located within one of the remaining unclonable gaps from the human genome project, suggestive of a specific sequence recalcitrant to cloning. In this study, we cloned a part of this gap and identified a novel 595-bp palindromic AT-rich repeat (PATRR). To date we have identified three translocation-associated PATRRs. They have common characteristics: (1) they are AT-rich nearly perfect palindromes, which are several hundred base pairs in length; (2) they possess non-AT-rich regions at both ends of the PATRR; (3) they display another nearby AT-rich region on one side of the PATRR. All of these features imply a potential for DNA secondary structure. Sequence analysis of unrelated individuals indicates no major size polymorphism, but shows minor nucleotide polymorphisms among individuals and cis-morphisms between the proximal and distal arms. Breakpoint analysis of various translocations indicates that double-strand-breakage (DSB) occurs at the center of the palindrome, often accompanied by a small symmetric deletion at the center. The breakpoints share only a small number of identical nucleotides between partner chromosomes. Taken together, these features imply that the DSBs are repaired through nonhomologous end joining or single-strand annealing rather than a homologous recombination pathway. All of these results support a previously proposed paradigm that unusual DNA secondary structure plays a role in the mechanism by which palindrome-mediated translocations occur.     

Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3

BackgroundThe 22q13.3 deletion syndrome (or Phelan-McDermid syndrome, MIM 606232) is characterized by developmental delay, absent or severely delayed speech, neonatal hypotonia, autistic behavior, normal to accelerated growth, and minor dysmorphic facial features. Among the three genes in the minimal critical region (from the centromere to the telomere: SHANK3, ACR and RABL2B), the defect in the SHANK3 gene is considered to be the cause of the neurobehavioral symptoms.ObjectiveWe describe the molecular characterization of a de novo interstitial del(22)(q13.3q13.3) disrupting the SHANK3 gene in a child with a phenotype compatible with the 22q13.3 deletion syndrome.MethodsClinical work-up included clinical histories, physical, neurological, and ophthalmological examinations, and imaging of the brain. Commercially available MLPA for subtelomeric analysis, FISH specific probes and quantitative real-time PCR were used to characterize the rearrangement.ResultsSubtelomere analysis by MLPA showed a discrepancy between P036B and P070 kits (MCR Holland^®): the P070 MLPA 22q probe (targeting the ARSA gene) showed a deletion but the P036B one (targeting the RABL2B gene) showed a normal result. FISH analysis using LSI TUPLE1/LSI ARSA (Vysis^®) probes confirmed deletion of ARSA, whereas FISH with N25/N85A3 (Cytocell^®) probes, targeting the SHANK3 locus was normal. Supplemented FISH analysis using BAC clones allowed us to specify the centromeric breakpoint region of the interstitial deletion between clones RP11-354I12 and RP11-232E17, at less than 2 Mb from the telomere. Quantitative real-time PCR of exon 5, 22 and 24 and intron 9 of SHANK3 showed that the telomeric breakpoint occurred between intron 9 and exon 22.ConclusionsThese data highlight the difficulty of performing an appropriate test aimed at looking for cryptic 22q13.3 deletion. Furthermore, the molecular characterization of this interstitial 22q13.3 deletion contributes to the clinical and genetic delineation of the 22q13.3 deletion syndrome.     

Translocation breakpoint in t(11;14) in B-cell leukemia is not at the rare fragile site at 11q13.3

The cloned breakpoint at 11q13.3 of the t(11;14)(q13.3;q32.3) in a B-cell lymphocytic leukemia (B-CLL) was used to analyze DNA from individuals with and without the rare folate-sensitive fragile site at 11q13.3. On Southern blots there were no discernible differences. Subclones of the ends of the leukemia breakpoint clone were prepared and used for in situ hybridization to chromosomes expressing fra(11)(q13.3). Both subclones hybridized distal to the fragile site. These experiments indicate that the breakpoints at 11q13.3 in B-CLL (and in a B-cell lymphoma) are not at the fragile site at 11q13.3.     

Partial monosomy 5p and partial trisomy 5q due to paternal pericentric inversion 5(p15.1q35.1)

A male infant with karyotype 46,XY,rec(5),dup q,inv(5)(p15.1 q35.1)pat is presented. The proband showed growth and developmental retardation, complex cardiovascular abnormalities, inguinal hernia and microcephaly in addition to facial appearance and cat-like cry characteristic of the cri-du-chat syndrome. Growth and developmental retardation, and microcephaly noted in this patient were markedly more serious than those observed in patients either with partial monosomy 5p or with partial trisomy 5q alone.     

Linkage analysis of genetic loci for kyphoscoliosis on chromosomes 5p13, 13q13.3, and 13q32

Kyphoscoliosis, a three-dimensional deformity of spinal growth, is characterized by a curvature in the coronal plane (scoliosis) in conjunction with thoracic kyphosis in excess of the normal range in the sagittal plane. We identified kyphoscoliosis within members of seven families (53 individuals) originally ascertained as part of a large collaborative study of familial idiopathic scoliosis. Model-independent linkage analysis of a genome-wide microsatellite screen identified areas suggestive of linkage on chromosomes 2q22, 5p13, 13q, and 17q11. Single-point and multipoint analyses of an additional 25 flanking microsatellite markers corroborated linkage to these regions, with areas on chromosomes 5p13, 13q13, and 13q32 being the most significant (P < 0.005). Analyses of single nucleotide polymorphism (SNP) markers in the candidate region on chromosome 5 narrowed the region to approximately 3.5 Mb (P < 0.05), with the most significant P values (P < 0.01) occurring in approximately a 1.3-Mb region. Candidate loci in this region include IRX1, IRX2, and IRX4 of the Iroquois Homeobox protein family. On chromosome 13, single-point and multipoint analyses resulted in multiple SNPs having P values < 0.05 within five candidate genes: Osteoblast-specific factor 2 or periostin, forkhead box O1A, A-kinase anchor protein 11, TBC1 domain family member 4, and glypican 5, thus supporting the potential relevance of this region in the pathogenesis of kyphoscoliosis.     

Association of breakpoint 14q23 with uterine leiomyoma

A chromosomal study of short-term cultured tumor cells from a benign uterine leiomyoma showed a clonal insertion, dir ins(14;6)(q23;p23p25) as a unique change. This finding supports the hypothesis of a specific association of the breakpoint 14q23 with uterine leiomyoma.     

De novo t(12;17)(p13.3;q21.3) translocation with a breakpoint near the 5' end of the HOXB gene cluster in a patient with developmental delay and skeletal malformations

A boy with severe mental retardation, funnel chest, bell-shaped thorax, and hexadactyly of both feet was found to have a balanced de novo t(12;17)(p13.3;q21.3) translocation. FISH with BAC clones and long-range PCR products assessed in the human genome sequence localized the breakpoint on chromosome 17q21.3 to a 21-kb segment that lies <30 kb upstream of the HOXB gene cluster and immediately adjacent to the 3' end of the TTLL6 gene. The breakpoint on chromosome 12 occurred within telomeric hexamer repeats and, therefore, is not likely to affect gene function directly. We propose that juxtaposition of the HOXB cluster to a repetitive DNA domain and/or separation from required cis-regulatory elements gave rise to a position effect.     

Characterization of the translocation breakpoint on chromosome 22q12.2 in a patient with neurofibromatosis type 2 (NF2)

We previously described a patient with neurofibromatosis type2 (NF2) who showed a constitutional balanced translocation,t(4; 22). To characterize the breakpoint on chromosome 22 inthis patient in relation to a candidate gene (NF2) responsiblefor NF2, we analyzed DNAs from this patient and her parentsusing parts of NF2 cDNA as probes. Southern analyses and DNAsequencing revealed that the chromosome 22 breakpoint in thispatient lies within the intron between exons 14 and 15 of NF2.The results lend support to the conclusion that NF2 is the generesponsible for the CNS form of neurofibromatosis.