Interstitial microduplication of Xp22.31: Causative of intellectual disability or benign copy number variant?

The use of comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays has dramatically altered the approach to identification of genetic alterations that can explain intellectual disability and /or congenital anomalies. However, the discovery of numerous copy number changes with benign or unknown clinical significance has made interpretation problematic. Submicroscopic duplication of Xp22.31 has been reported as either a possible cause of intellectual disability and/or developmental delay or a benign variant. Here we report 29 individuals with the microduplication found as part of microarray analysis of 7793 samples submitted to an international group of 13 clinical laboratories. The referral reasons varied and included developmental delay, intellectual disability, autism, dysmorphic features and/or multiple congenital anomalies. The size of the Xp22.31 duplication varied between 149 kb and 1.74 Mb and included the steroid sulfatase (STS) gene with the male to female ratio of 0.7. Duplication within this segment is seen at a frequency of 0.15% in a healthy control population, whereas a frequency of 0.37% was observed in our cohort of individuals with abnormal phenotypes. We present a detailed comparison of the breakpoints, inheritance, X-inactivation and clinical phenotype in our cohort and a review of the literature for a total of 41 patients. To date, this report is the largest compilation of clinical and array data regarding the microduplication of Xp22.31 and will serve to broaden the knowledge of regions involving copy number variation (CNV).

Extreme variant of enlarged heterochromatin region on chromosome 9Q in a normal child and multiple family members.

Heteromorphisms of chromosome 9 are among the most common variations in the human karyotype. The pericentromeric polymorphisms of chromosome 9 include variations in the size of q-arm heterochromatin, pericentric inversions, and rarely, additional C-band-negative, G-band-positive material. The finding of a polymorphic variant, either in prenatal screening or in chromosomal analysis for phenotypic abnormalities, may cause parental anxiety and initiate genetic counselling. We report a case of a 39-year-old primigravida with unremarkable pregnancy, who had amniocentesis due to advanced maternal age. Chromosomal analysis demonstrated a long arm (q) variant of chromosome 9 with an enlarged heteromorphic area, approximately three times longer than known reported variants. Prenatal analysis demonstated an identical variant in the probands phenotypically normal father, uncle, and paternal grandmother, confirming an apparently "normal" variant.

A case study of "disorganized development" and its possible relevance to genetic determinants of aging.

In 1932, Bidder postulated that senescence results from "continued action of a (genetic) regulator (of development) after growth ceases (maturation occurs)." A 16-year-old girl who physically appears to be an infant has not been diagnosed with any known genetic syndrome or chromosomal abnormality. The subject's anthropometric measurements are that of an 11-month-old. Coordinated development of structures for swallowing/breathing has not occurred resulting in dysfunctional digestive and respiratory systems. Brain structure, proprioception and neuroendocrine functions are infantile. Dental and bone ages are pre-teen, while telomere length and telomerase inactivity suggest a cellular age at least comparable to her chronological age. Sub-telomeric microdeletions known to be responsible for developmental delay and chromosomal imbalances are not present. Findings suggest that the subject suffers from "developmental disorganization" resulting from spontaneous mutation of Bidder's putative "regulator" of development, thereby providing an opportunity to locate and identify developmental gene(s) responsible for ensuring integrated and coordinated change in form and function from conception to adulthood. If their continued expression beyond maturation erodes internal order to promote senescence then further study of her DNA and testing of homologous genes in animal models may provide clues to genetic determinants of aging and human life span.

Composite adrenal anaplastic neuroblastoma and virilizing adrenocortical tumor with germline TP53 R248W mutation.

Composite tumors are extremely rare. Such tumors in adrenal glands are usually of neuroendocrine-neural type and occur mostly in adults. Their pathogenesis remains elusive. We report a patient with composite neuroblastoma (NB), adrenocortical tumor (ACT), and Li-Fraumeni syndrome (LFS) with germline TP53 R248W mutation. LFS predisposes to the development of leukemia, sarcomas, adrenocortical and breast carcinomas, brain tumors and, questionably, NB. A unique correlation between a single TP53 mutation (R337H) and ACT has been reported in southern Brazilian children. It remains unclear at this time whether a similar association of NB and R248W in patients with LFS exists.

A patient with an interstitial duplication of chromosome 5p11-p13.3 further confirming a critical region for 5p duplication syndrome.

Partial or complete trisomy 5p has been associated with characteristic facial features, developmental delay, seizures, congenital heart defects, and respiratory compromise. We present a child with developmental delay, seizures, and congenital cardiac anomalies found to have a previously unreported de novo interstitial duplication of chromosome 5p, 46,XX,dup(5) (p11p13.3). The breakpoints of the duplication were further confirmed by fluorescence in situ hybridization analysis using bacterial artificial chromosome probes specific for the affected region. Comparison with previously reported cases of patients with duplications of 5p suggests loci of interest for both congenital heart anomalies and seizures.

Specific extra chromosomes occur in a modal number dependent pattern in pediatric acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (>50 chromosomes) are considered to have a relatively good prognosis. The specific extra chromosomes are not random; extra copies of some chromosomes occur more frequently than those of others. We examined the extra chromosomes present in high hyperdiploid ALL to determine if there were a relation of the specific extra chromosomes and modal number (MN) and if the extra chromosomes present could differentiate high hyperdiploid from near-triploid and near-tetraploid cases. Karyotypes of 2,339 children with ALL and high hyperdiploidy at diagnosis showed a distinct nonrandom sequential pattern of gain for each chromosome as MN increased, with four groups of gain: chromosomes 21, X, 14, 6, 18, 4, 17, and 10 at MN 51-54; chromosomes 8, 5, 11, and 12 at MN 57-60; chromosomes 2, 3, 9,16, and 22 at MN 63-67; chromosomes 1, 7 13, 15, 19, and 20 at MN 68-79, and Y only at MN >or=80. Chromosomes gained at lower MN were retained as the MN increased. High hyperdiploid pediatric ALL results from a single abnormal mitotic division. Our results suggest that the abnormal mitosis involves specific chromosomes dependent on the number of chromosomes aberrantly distributed, raising provocative questions regarding the mitotic mechanism. The patterns of frequencies of tetrasomy of specific chromosomes differs from that of trisomies with the exception of chromosome 21, which is tetrasomic in a high frequency of cases at all MN. These results are consistent with different origins of high hyperdiploidy, near-trisomy, and near-tetrasomy.

Chromosome 3p25 deletion in mother and daughter with minimal phenotypic effect.

3p25 deletion syndrome is characterized by mental retardation, growth retardation, hypotonia, microcephaly, ptosis, and micrognathia. Of the 42 persons with this deletion syndrome cited in the literature, only 2 patients, a mother-daughter pair, have previously been reported without apparent clinical consequence. We present a second mother-daughter dyad with a terminal 3p25.3-3pter deletion, who present with only mild clinical effects. In addition to cytogenetic analysis, array CGH was performed to determine the breakpoints at the molecular level. Our data show that the 3p25 deletion syndrome may, therefore, reflect a much broader phenotypic spectrum than previously recognized.

Translocation breakpoint in two unrelated Tourette syndrome cases, within a region previously linked to the disorder.

Tourette syndrome (TS) is a complex neuropsychiatric disorder characterized by both motor and vocal tics. The etiology of TS is poorly understood; however, evidence of genetic transmission arises from family and twin studies. A complex mode of inheritance has been suggested, likely involving contributions of several genes with different effect size. We describe here two unrelated families wherein balanced t(6;8) chromosomal translocations occur in individuals diagnosed with TS. In one of these families, the transmission of the translocation is associated with learning and behavioral difficulties; in the other family, one parent is unaffected and the other cannot be traced, thus transmission cannot be demonstrated and it is possible that the translocation may have occurred de novo. The breakpoint on chromosome 8 occurs within the q13 band in both families, suggesting that a gene or genes in this region might contribute to the TS phenotype. Existing linkage and cytogenetic data, suggesting involvement of chromosome 8 in TS families and individuals, further support this hypothesis. We have identified two YAC clones mapping distal and proximal to the chromosome 8 translocation site, as determined by fluorescent in situ hybridization (FISH). PCR amplification of genetic markers in this region, using isolated chromosomes from one of the patients, followed by BAC screening with the closest flanking genetic markers, has identified a 200-kb BAC, which, by FISH, we have demonstrated encompasses the chromosome 8 breakpoint in both families. The fact that the chromosomal breaks in the TS cases from both families occur within such a small region of chromosome 8 further supports the hypothesis that disruption of a gene or genes in this part of chromosome 8 contributes to the clinical phenotype.

Hepatosplenic gamma/delta T-cell lymphoma with isochromosome 7q, translocation t(7;21), and tetrasomy 8 in a 9-year-old girl.

The authors report a child younger than age 15 years with a rare hepatosplenic gamma/delta T-cell lymphoma, which is highly aggressive and primarily seen in young men. A 9-year-old girl presented with thrombocytopenia and hepatosplenomegaly. Bone marrow analysis revealed a metastatic pleomorphic lymphoma of peripheral T-cell phenotype, with rearrangement of the T-cell receptor gamma/delta and expression of CD3 and CD16/56. Instead of the previously reported primary, nonrandom, chromosomal abnormalities, isochromosome 7q and trisomy 8, this patient had four copies each of chromosome 7q, including isochromosome 7[i(7)(q10)] and der(21)t(7;21), as well as chromosome 8. This entity needs to be considered in women and children with lymphoma. Conventional therapy appears to be inadequate for cure.