Genome SNP Microarray Research Articles

A case report of familial 4q13.3 microdeletion in three individuals with syndromic intellectual disability

BackgroundInterstitial 4q deletions are rare chromosomal alterations. Most of the previously reported deletions involving the 4q13.3 region are large chromosomal alterations with a common loss of band 4q21 resulting in marked growth restriction, severe intellectual disability, and absent or severely delayed speech. A microdeletion of 4q13.3 hasn’t been previously reported. We discuss the involvement of genes and the observed phenotype, comparing it with that of previously reported patients.Case presentationWe report on a 4q13.3 microdeletion detected in three affected individuals of a Lithuanian family. The clinical features of two affected children and their affected mother are very similar and include short stature, congenital heart defect, skeletal anomalies, minor facial anomalies, delayed puberty, and intellectual disability. Whole genome SNP microarray analysis of one child revealed an interstitial 4q13.3 microdeletion, 1.56 Mb in size. FISH analysis confirmed the deletion in the proband and identified the same deletion in her affected sib and mother, while it was not detected in a healthy sib. Deletion includes ADAMTS3, ANKRD17, COX18, GC, and NPFFR2 protein-coding genes.ConclusionsOur findings suggest that 4q13.3 microdeletion is a cause of a recognizable phenotype of three affected individuals. The detected microdeletion is the smallest interstitial deletion in 4q13. We highlight ADAMTS3, ANKRD17 and RNU4ATAC9P as candidate genes for intellectual disability, growth retardation and congenital heart defect.

Spinal dysraphism, club feet, and dextrocardia with situs inversus totalis in a neonate: a rare association and review

AbstractObjectivesThe spinal dysraphism and situs inversus are a rare association. Since 1909, reports on the coincidence of malformations of the spine and gastrointestinal tract have been published. So far there is no plausible explanation for the association.Case presentationWe report a term female infant with spinal dysraphism with club feet associated with dextrocardia and situs inversus totalis. Whole genome SNP microarray analysis was normal. However, there are extended contiguous regions of allele homozygosity [>8 Mb[megabase]) observed in chromosome 6 and 14.ConclusionsWe report a rare association of spinal dysraphism and situs inversus totalis in a neonate. We review the literature. There have recently been theorized by some to in fact represent nothing more than the presence of two or more polytopic field defects, with all the anomalies present sharing a common molecular basis.

Stable transmission of complex chromosomal rearrangements involving chromosome 1q derived from constitutional chromoanagenesis

BackgroundChromoanagenesis events encompassing chromoanasynthesis, chromoplexy, and chromothripsis are described in cancers and can result in highly complex chromosomal rearrangements derived from ‘all-at-once’ catastrophic cellular events. The complexity of these rearrangements and the original descriptions in cancer cells initially led to the assumption that it was an acquired anomaly. While rare, these phenomena involving chromosome 1 have been reported a few individuals in a constitutional setting.Case presentationHere, we describe a newborn baby who was initially referred for cytogenetic testing for multiple congenital anomalies including cystic encephalomalacia, patent ductus arteriosus, inguinal hernia, and bilateral undescended testicles. Chromosome analysis was performed and revealed a derivative chromosome 1 with an 1q24-q31 segment inserted into 1q42.13 resulting in gain of 1q24-q31. Whole genome SNP microarray analysis showed a complex pattern of copy number variants with four gains and one loss involving 1q24-q31. Mate pair next-generation sequencing analysis revealed 18 chromosome breakpoints, six gains along an 1q24-q31 segment, one deletion of 1q31.3 segment and one deletion of 1q42.13 segment, which is strongly evocative of a chromoanasynthesis event for developing this complex rearrangement. Parental chromosome analyses were performed and showed the same derivative chromosome 1 in the mother.ConclusionsTo our knowledge, our case is the first case with familial constitutional chromoanagenesis involving chromosome 1q24-q42. This report emphasizes the value of performing microarray and mate pair next-generation sequencing analysis for individuals with germline abnormal or complex chromosome rearrangements.

Multiple Congenital Anomalies in a Patient with Interstitial 6q26 Deletion

We report a preterm male neonate presenting with a lumbosacral meningomyelocele, type II Arnold Chiari malformation, hypoplasia of the aortic arch, bicuspid aortic valve, ventricular septal defect, secundum atrial septal defect, multicystic dysplastic kidney, and hydronephrosis. Analysis with whole genome SNP microarray revealed an interstitial deletion of about 237 kb in chromosome 6q26. Long contiguous stretches of homozygosity (>3 Mb) were seen in 18 chromosomes with a total genomic size of 219 Mb. The phenotype seen in our patient has not been reported in association with the genes in the homozygous regions. However, our patient shares many phenotypic features with other reported cases that have shown a deletion in the same region of chromosome 6.

A Novel Homozygous Deletion within the FRY Gene Associated with Nonsyndromic Developmental Delay

The role of autosomal recessive (AR) variants in clinically heterogeneous conditions such as intellectual disability and developmental delay (ID/DD) has been difficult to uncover. Implication of causative pathogenic AR variants often requires investigation within large and consanguineous families, and/or identifying rare biallelic variants in affected individuals. Furthermore, detection of homozygous gene-level copy number variants during first-line genomic microarray testing in the pediatric population is a rare finding. We describe a 6.7-year-old male patient with ID/DD and a novel homozygous deletion involving the FRY gene identified by genomic SNP microarray. This deletion was observed within a large region of homozygosity on the long arm of chromosome 13 and in a background of increased low-level (2.6%) autosomal homozygosity, consistent with a reported common ancestry in the family. FRY encodes a protein that regulates cell cytoskeletal dynamics, functions in chromosomal alignment in mitosis in vitro, and has been shown to function in the nervous system in vivo. Homozygous mutation of FRY has been previously reported in 2 consanguineous families from studies of autosomal recessive ID in Middle Eastern and Northern African populations. This report provides additional supportive evidence that deleterious biallelic mutation of FRY is associated with ID/DD and illustrates the utility of genomic SNP microarray detection of low-level homozygosity.

Pediatric acute myeloid leukemia with t(7;21)(p22;q22)

The t(7;21)(p22;q22) resulting in RUNX1-USP42 fusion, is a rare but recurrent cytogenetic abnormality associated with acute myeloid leukemia (AML) and myelodysplastic syndromes. The prognostic significance of this translocation has not been well established due to the limited number of patients. Herein, we report three pediatric AML patients with t(7;21)(p22;q22). All three patients presented with pancytopenia or leukopenia at diagnosis, accompanied by abnormal immunophenotypic expression of CD7 and CD56 on leukemic blasts. One patient had t(7;21)(p22;q22) as the sole abnormality, whereas the other two patients had additional numerical and structural aberrations including loss of 5q material. Fluorescence in situ hybridization analysis on interphase cells or sequential examination of metaphases showed the RUNX1 rearrangement and confirmed translocation 7;21. Genomic SNP microarray analysis, performed on DNA extracted from the bone marrow from the patient with isolated t(7;21)(p22;q22), showed a 32.2 Mb copy neutral loss of heterozygosity (cnLOH) within the short arm of chromosome 11. After 2-4 cycles of chemotherapy, all three patients underwent allogeneic hematopoietic stem cell transplantation (HSCT). One patient died due to complications related to viral reactivation and graft-versus-host disease. The other two patients achieved complete remission after HSCT. Our data displayed the accompanying cytogenetic abnormalities including del(5q) and cnLOH of 11p, the frequent pathological features shared with other reported cases, and clinical outcome in pediatric AML patients with t(7;21)(p22;q22). The heterogeneity in AML harboring similar cytogenetic alterations may be attributed to additional uncovered genetic lesions.

47. Serendipitous identification of meiotic crossover events in struma ovarii tumors by whole genome SNP microarray analysis

Germ cell divisions, Meiosis I and II, specifically produce haploid gametes (2n→n) required for sexual reproduction. Reciprocal crossing over between homologues of a chromosome pair is a fundamental event ensuring genomic contribution from each parent in a gamete. Using the OncoScan SNP microarray, we have identified and quantified the number and location of crossovers distributed throughout the genome. This exposure of crossovers was noted serendipitously while studying the genetic constitution of tumors of ovarian origin (struma ovarii). In tumors displaying segmental whole genome homozygosity, the precise locations of transitions from homozygosity to heterozygosity could be visualized and represent the sites of crossovers. Our analysis and data from 7 struma ovarii specimens revealed that the number of total whole genome crossovers events ranged from 41 to 99 events. Also, the total number of crossovers (summed by chromosome across these 7 struma ovarii samples) in Group A chromosomes (1–3) ranged from 23 to 41 events, in Group B (4–5) from 24 to 34 events, in Group C (6–12, X) from 17 to 25 events, in Group D (13–15) from 12 to 20 events, in Group E (16–18) from 15 to 19 events, in Group F(19–20) from 14 to 16 events, and in Group G (21–22) from 7 to 10 events. Moreover, the data revealed a) the frequency of the crossover events was directly proportional to the length of the chromosome, b) an increased (p < 0.01) number of genome-wide crossovers in the “p” arm versus the “q” arm, c) the percent homozygosity between individual chromosomes ranged between 20 and 50%, and no correlation between the percent homozygosity per chromosome, between chromosome arms, or chromosome length.

47 - Utility of Whole Genome SNP Microarray and Targeted Somatic Mutations in Evaluation of FFPE (Formalin Fixed Paraffin Embedded) Surgical Oncology Specimens

47 - Utility of Whole Genome SNP Microarray and Targeted Somatic Mutations in Evaluation of FFPE (Formalin Fixed Paraffin Embedded) Surgical Oncology Specimens

38 - Utilization of a SNP Microarray for the Study of Multiple Myeloma Patients: Novel Findings and Better Stratification of Patients

Multiple myeloma (MM) is a plasma cell malignancy and serious disorder of the elderly accounting for ~10% of hematologic disorders. It has a variable clinical course and genetic anomalies have been demonstrated as important prognostic factors. However, only around 30% of MM patients have an abnormal karyotype and only 80% of MM patients have genetic alterations that are detected by FISH. In this study, a total of 413 samples from patients confirmed to have MM were studied after plasma cell enrichment using a whole genome SNP microarray analysis along with FISH for the three major translocations. The array detected abnormalities in 99.9% of the samples, and when FISH analysis was abnormal, detected additional findings in 99.8% of those samples. It also showed additional poor prognostic factors, not detectable by standard FISH, such as 12p deletions, a gain of MYC, chromothripsis, and hypodiploidy. Additionally, copy-neutral loss of heterozygosity was detected in a much greater frequency than expected (28.7%). Furthermore, the array revealed changes suggesting a poorer prognosis within patients that had factors thought to be associated with a better prognosis, such as hyperdiploidy or an 11;14 translocation. Additional disorders, such as myelodysplasia or CLL, were detected by the array that would have otherwise not been detected by myeloma FISH. This was particularly evident when the negative fraction of the enrichment analysis was also studied. Overall, these findings indicate that the array is clearly more effective in detecting abnormalities than FISH alone and has added information in providing better prognostic information.

5 - Utility of Whole Genome SNP Microarray and Targeted Somatic Mutations in Evaluation of Melanoma, Histologic Mimics of Melanoma, and Glioblastoma

5 - Utility of Whole Genome SNP Microarray and Targeted Somatic Mutations in Evaluation of Melanoma, Histologic Mimics of Melanoma, and Glioblastoma