Chromosome 22q11.21 contains a cluster of low-copy repeats (LCRs), referred to as LCR22A-H, that mediate meiotic non-allelic homologous recombination, resulting in either deletion or duplication of ...various intervals in the region. The deletion of the DiGeorge/velocardiofacial syndrome interval LCR22A-D is the most common recurrent microdeletion in humans, with an estimated incidence of ∼1:4,000 births. Deletion of other intervals in 22q11.21 have also been described, but the literature is often confusing, as the terms 'proximal', 'nested', 'distal', and 'atypical' have all been used to describe various of the other intervals. Individuals with deletions tend to have features with widely variable expressivity, even among families. This review concisely delineates each interval and classifies the reported literature accordingly.
Microarray testing is the recommended first‐tier diagnostic test for women who undergo invasive prenatal diagnostic procedures. It is well‐established that microarray analysis provides information ...regarding copy number for changes (or copy number variants, CNVs) that may be below the resolution level of standard chromosome analysis, and that such CNVs are not related to maternal age. What may not be appreciated by ordering providers, however, are the technical differences among laboratories with respect to the established laboratory cutoff values for reporting, the definition of targeted versus nontargeted regions, and how these differences may affect the interpretation and reporting of findings which, in turn, affects counseling and possible follow‐up testing of family members. Here, we provide a detailed explanation of these technical factors and clarify how they practically impact diagnostic results.
The proximal long arm of chromosome 15 has segmental duplications located at breakpoints BP1–BP5 that mediate the generation of NAHR-related microdeletions and microduplications. The classical ...Prader-Willi/Angelman syndrome deletion is flanked by either of the proximal BP1 or BP2 breakpoints and the distal BP3 breakpoint. The larger Type I deletions are flanked by BP1 and BP3 in both Prader-Willi and Angelman syndrome subjects. Those with this deletion are reported to have a more severe phenotype than individuals with either Type II deletions (BP2–BP3) or uniparental disomy 15. The BP1–BP2 region spans approximately 500 kb and contains four evolutionarily conserved genes that are not imprinted. Reports of mutations or disturbed expression of these genes appear to impact behavioral and neurological function in affected individuals. Recently, reports of deletions and duplications flanked by BP1 and BP2 suggest an association with speech and motor delays, behavioral problems, seizures, and autism. We present a large cohort of subjects with copy number alteration of BP1 to BP2 with common phenotypic features. These include autism, developmental delay, motor and language delays, and behavioral problems, which were present in both cytogenetic groups. Parental studies demonstrated phenotypically normal carriers in several instances, and mildly affected carriers in others, complicating phenotypic association and/or causality. Possible explanations for these results include reduced penetrance, altered gene dosage on a particular genetic background, or a susceptibility region as reported for other areas of the genome implicated in autism and behavior disturbances.
Disclaimer: These American College of Medical Genetics and Genomics standards and guidelines are developed primarily as an educational resource for clinical laboratory geneticists to help them ...provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient’s record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these standards and guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.
Cytogenetic analyses of hematological neoplasms are performed to detect and characterize clonal chromosomal abnormalities that have important diagnostic, prognostic, and therapeutic implications. At the time of diagnosis, cytogenetic abnormalities assist in the diagnosis of such disorders and can provide important prognostic information. At the time of relapse, cytogenetic analysis can be used to confirm recurrence of the original neoplasm, detect clonal disease evolution, or uncover a new unrelated neoplastic process. This section deals specifically with the standards and guidelines applicable to chromosome studies of neoplastic blood and bone marrow–acquired chromosomal abnormalities.
This updated Section E6.1–6.4 has been incorporated into and supersedes the previous Section E6 in Section E: Clinical Cytogenetics of the 2009 Edition (Revised 01/2010), American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories.
Interstitial deletions of the distal short arm of chromosome 2 including MYCN have only been reported for a small number of individuals. Germline deletions and mutations of MYCN cause Feingold ...syndrome 1 (FS1), a rare disorder characterized by microcephaly, digit anomalies, gastrointestinal atresias, short stature, dysmorphic features, and intellectual disability. We present a series of six individuals referred for SNP microarray with overlapping deletions of 2p ranging from 3.4 to 16.8 Mb in size, with a common overlapping region of 1.53 Mb spanning (14,614,477–16,148,021) hg19 and including five genes: NBAS, DDX1, MYCNUT, MYCNOS, and MYCN. Clinical information was available for five individuals. Clinical features included core features of FS1 such as microcephaly, digit anomalies, and gastrointestinal atresias as well as structural cardiac defects, hearing loss, and renal anomalies, which are features less consistently associated with FS1. Other features observed in several individuals, that have not specifically been associated with FS1 were motor delay, structural brain abnormalities, genital abnormalities, and radioulnar synostosis. These results indicate that while individuals with deletions of 2p spanning several megabases and including MYCN can present with features not typically associated with FS1, the common core features are usually present.
•Cost effective multidisciplinary testing protocol described for pediatric T-ALL leveraging the initial BCR/ABL1 FISH testing.•Novel mechanisms of genomic rearrangement described for some of the ...T-ALL clones indicated.•Two new gene fusions found in pediatric T-ALL: SPTAN1/ABL1 and ABL1/TNRC6B.•A high overall percentage of 9q34 rearrangements that do not involve BCR/ABL1 gene fusion.
T-cell acute lymphoblastic leukemia (T-ALL) is not as frequently reported as the B-cell counterpart (B-ALL), only occurring in about 15% of pediatric cases with a typically heterogeneous etiology. Approximately 8% of childhood T-ALL cases have rearrangements involving the ABL1 tyrosine kinase gene at 9q34.12; although a t(9;22), resulting in a fusion of ABL1 with the BCR gene at 22q11.23 is a common occurrence in B-ALL, it is not a typical finding in T-ALL. A subset of 10 of 40 documented cases of T-ALL analyzed over a 5-year period is presented, each having gene rearrangements within band 9q34 that resulted in fusions other than BCR/ABL1. These cases included fusions involving ABL1, SET (9q34.11), NUP214 (9q34.13), SPTAN1 (9p34.11), and TNRC6B (22q13.1). Among the 10 cases are: six SET/NUP214 fusions, two ABL1/NUP214 fusions (one of which was associated with episomal amplification) and novel SPTAN1/ABL1 and TNRC6B/ABL1 fusions. The evaluations of these clones were each significantly aided by FISH analysis, which directed subsequent microarray and anchored multiplex PCR testing for fusion confirmations.
The five segmental duplications (LCR22-D to -H) at the distal region of chromosome 22 band q11.2 in the region immediately distal to the DiGeorge/velocardiofacial syndrome deleted region have been ...implicated in the recurrent distal 22q11.2 microdeletions. To date, the distal 22q11.2 microdeletions have been grouped together as a single clinical entity despite the fact that these deletions are variable in size and position depending on the mediating LCR22s.
Here, we report 13 new unrelated patients with variable size deletions in the distal 22q11.2 region as shown by cytogenomic array analyses. We compare our patients' clinical features with those of previously reported cases to better dissect the phenotypic correlations based on the deletion size and position.
Six patients had the 1.1-Mb deletion flanked by LCR22-D and -E, and presented clinically with a phenotype consistent with previously reported cases with distal 22q11.2 microdeletions. Three patients had the 1.8-Mb deletion flanked by LCR22-D and -F, and presented with a similar phenotype. Four patients had the 700-kb deletion flanked by LCR22-E and -F, and presented with a milder phenotype that lacked growth restriction and cardiovascular defects.
We suggest that the recurrent distal 22q11.2 microdeletions do not represent a single clinical entity, and propose categorizing these deletions into three types according to their genomic position. All three deletion types are thought to be pathogenic and are most often de novo. They all share some presenting features but also have their unique features and risks.
Constitutional chromoanagenesis events, which include chromoanasynthesis and chromothripsis and result in highly complex rearrangements, have been reported for only a few individuals. While rare, ...these phenomena have likely been underestimated in a constitutional setting as technologies that can accurately detect such complexity are relatively new to the mature field of clinical cytogenetics. G-banding is not likely to accurately identify chromoanasynthesis or chromothripsis, since the banding patterns of chromosomes are likely to be misidentified or oversimplified due to a much lower resolution. We describe a patient who was initially referred for cytogenetic testing as a child for speech delay. As a young adult, he was referred again for recurrent strokes. Chromosome analysis was performed, and the rearrangement resembled a simple duplication of 13q32q34. However, SNP microarray analysis showed a complex pattern of copy number gains and a loss consistent with chromoanasynthesis involving distal 13q (13q32.1q34). This report emphasizes the value of performing microarray analysis for individuals with abnormal or complex chromosome rearrangements.
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