Morteza Hemmat

Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility

Copy neutral segments with allelic homozygosity, also known as regions of homozygosity (ROHs), are frequently identified in cases interrogated by oligonucleotide single-nucleotide polymorphism (oligo-SNP) microarrays. Presence of ROHs may be because of parental relatedness, chromosomal recombination or rearrangements and provides important clues regarding ancestral homozygosity, consanguinity or uniparental disomy. In this study of 14 574 consecutive cases, 832 (6%) were found to harbor one or more ROHs over 10 Mb, of which 651 cases (78%) had multiple ROHs, likely because of identity by descent (IBD), and 181 cases (22%) with ROHs involving a single chromosome. Parental relatedness was predicted to be first degree or closer in 5%, second in 9% and third in 19%. Of the 181 cases, 19 had ROHs for a whole chromosome revealing uniparental isodisomy (isoUPD). In all, 25 cases had significant ROHs involving a single chromosome; 5 cases were molecularly confirmed to have a mixed iso- and heteroUPD15 and 1 case each with segmental UPD9pat and segmental UPD22mat; 17 cases were suspected to have a mixed iso- and heteroUPD including 2 cases with small supernumerary marker and 2 cases with mosaic trisomy. For chromosome 15, 12 (92%) of 13 molecularly studied cases had either Prader–Willi or Angelman syndrome. Autosomal recessive disorders were confirmed in seven of nine cases from eight families because of the finding of suspected gene within a ROH. This study demonstrates that ROHs are much more frequent than previously recognized and often reflect parental relatedness, ascertain autosomal recessive diseases or unravel UPD in many cases.

Abnormalities in spontaneous abortions detected by G-banding and chromosomal microarray analysis (CMA) at a national reference laboratory

BackgroundCytogenetic evaluation of products of conception (POC) for chromosomal abnormalities is central to determining the cause of pregnancy loss. We compared the test success rates in various specimen types and the frequencies of chromosomal abnormalities detected by G-banding analysis with those found by Oligo-SNP chromosomal microarray analysis (CMA). We evaluated the benefit of CMA testing in cases of failed culture growth.MethodsConventional cytogenetic results of 5457 consecutive POC specimens were reviewed and categorized as placental villi, fetal parts, and unspecified POC tissue. The CMA was performed on 268 cases. Of those, 32 cases had concurrent G-banding results. The remaining 236 cases included 107 cases with culture failure and 129 cases evaluated by CMA alone.ResultsThe overall POC culture success rate was 75%, with the lowest for fetal parts (37.4%) and the highest for placental villi (81%). The abnormality rate was 58% for placental villi, but only 25% for fetal parts. Of the abnormalities detected, the most common were aneuploidies, including trisomy 16, triploidy, monosomy X, trisomy 22, trisomy 21 and trisomy 15, while the least encountered aneuploidies were trisomy 1, trisomy 19 and monosomies (except monosomy 21). Overall, POC specimens studied by CMA were successful in 89.6% of cases and yielded a 44.6% abnormality rate.ConclusionsPlacental villi yielded higher rates of culture success and a higher percentage of abnormal karyotypes than did other specimen types. The Oligo-SNP CMA method has demonstrated a viable alternative to the G-banding method in view of its advantages in detection of submicroscopic genomic aberrations, shorter turnaround time due to elimination of time required for culture and a higher test success rate.

Genotype-phenotype analysis of recombinant chromosome 4 syndrome: an array-CGH study and literature review

BackgroundRecombinant chromosome 4, a rare constitutional rearrangement arising from pericentric inversion, comprises a duplicated segment of 4p13~p15→4pter and a deleted segment of 4q35→4qter. To date, 10 cases of recombinant chromosome 4 have been reported.ResultWe describe the second case in which array-CGH was used to characterize recombinant chromosome 4 syndrome. The patient was a one-year old boy with consistent clinical features. Conventional cytogenetics and FISH documented a recombinant chromosome 4, derived from a paternal pericentric inversion, leading to partial trisomy 4p and partial monosomy of 4q. Array-CGH, performed to further characterize the rearranged chromosome 4 and delineate the breakpoints, documented a small (4.36 Mb) 4q35.1 terminal deletion and a large (23.81 Mb) 4p15.1 terminal duplication. Genotype-phenotype analysis of 10 previously reported cases and the present case indicated relatively consistent clinical features and breakpoints. This consistency was more evident in our case and another characterized by array-CGH, where both showed the common breakpoints of p15.1 and q35.1. A genotype-phenotype correlation study between rec(4), dup(4p), and del(4q) syndromes revealed that urogenital and cardiac defects are probably due to the deletion of 4q whereas the other clinical features are likely due to 4p duplication.ConclusionOur findings support that the clinical features of patients with rec(4) are relatively consistent and specific to the regions of duplication or deletion. Recombinant chromosome 4 syndrome thus appears to be a discrete entity that can be suspected on the basis of clinical features or specific deleted and duplicated chromosomal regions.

Neocentric X-chromosome in a girl with Turner-like syndrome

BackgroundNeocentromeres are rare human chromosomal aberrations in which a new centromere has formed in a previously non-centromeric location. We report the finding of a structurally abnormal X chromosome with a neocentromere in a 15-year-old girl with clinical features suggestive of Turner syndrome, including short stature and primary amenorrhea.ResultG-banded chromosome analysis revealed a mosaic female karyotype involving two abnormal cell lines. One cell line (84% of analyzed metaphases) had a structurally abnormal X chromosome (duplication of the long arm and deletion of the short arm) and a normal X chromosome. The other cell line (16% of cells) exhibited monosomy X. C-banding studies were negative for the abnormal X chromosome. FISH analysis revealed lack of hybridization of the abnormal X chromosome with both the X centromere-specific probe and the “all human centromeres” probe, a pattern consistent with lack of the X chromosome endogenous centromere. A FISH study using an XIST gene probe revealed the presence of two XIST genes, one on each long arm of the iso(Xq), required for inactivation of the abnormal X chromosome. R-banding also demonstrated inactivation of the abnormal X chromosome. An assay for centromeric protein C (CENP-C) was positive on both the normal and the abnormal X chromosomes. The position of CENP-C in the abnormal X chromosome defined a neocentromere, which explains its mitotic stability. The karyotype is thus designated as 46,X,neo(X)(qter- > q12::q12- > q21.2- > neo- > q21.2- > qter)[42]/45,X[8], which is consistent with stigmata of Turner syndrome. The mother of this patient has a normal karyotype; however, the father was not available for study.ConclusionTo our knowledge, this is the first case of mosaic Turner syndrome involving an analphoid iso(Xq) chromosome with a proven neocentromere among 90 previously described cases with a proven neocentromere.

Identification and clinical evaluation of segments of homozygosity, uniparental disomy and complex chromosomal abnormalities revealed by copy-number SNP arrays

Background Presence of such segments of homozygosity (SOH) may be due to parental relatedness, chromosomal recombination or rearrangements and provides important clues regarding ancestral homozygosity, parental consanguinity or uniparental disomy. We have determined the frequency and nature of copy neutral segments with allelic homozygosity identified in cases interrogated by oligonucleotide-SNP microarrays.

Isochromosome Yp and jumping translocation of Yq resulting in five cell lines in an infertile male: a case report and review of the literature

BackgroundJumping translocations are a rare type of mosaicism in which the same portion of one donor chromosome is translocated to several recipient chromosomes. Constitutional forms of jumping translocations are rare, and the 48 cases reported to date have been associated with both normal and abnormal phenotypes. Concurrence of isochromosome (i) of one arm and translocation of the other is also rare, with seven reported cases. We describe a unique case involving concurrence of i(Yp) and a jumping translocation of Yq to the telomere of chromosomes 12q and 17q, which resulted in five cell lines.Case presentationThe patient, an otherwise healthy 35-year-old man, was referred for cytogenetic studies because of absolute azoospermia. He had elevated levels of follicle stimulating hormone and luteinizing hormone, consistent with abnormal spermatogenesis, and decreased levels of free testosterone and inhibin B. G-banded chromosome analysis revealed a mosaic male karyotype involving five abnormal cell lines. One of the cell lines showed loss of chromosome Y and presence of i(Yp) as the sole abnormality. Three cell lines exhibited jumping translocation: two involved 17qter, and the other involved 12qter as the recipient and Yq as the common donor chromosome. One of the cell lines with der(17) additionally showed i(Yp). The other der(17) and der(12) cell lines had a missing Y chromosome. All five cell lines were confirmed by FISH. Subtelomric FISH study demonstrated no loss of chromosome material from the recipient chromosomes at the translocation junctions.ConclusionsWe postulate that a postzygotic pericentromeric break of the Y chromosome led to formation of isochromosome Yp, whereas Yq formed a jumping translocation through recombination between its internal telomere repeats and telomeric repeats of recipient chromosomes. This in turn led to either pairing or an exchange at the complimentary sequences. Such translocation junctions appear to be unstable and to result in a jumping translocation. Cryptic deletion or disruption of AZF (azoospermic factor) genes at Yq11 during translocation or defective pairing of X and Y chromosomes during meiosis, with abnormal sex vesicle formation and consequent spermatogenetic arrest, might be the main cause of the azoospermia in our patient.

Paternal mosaic inv(20) resulting in a recombinant chromosome 20 in two siblings

Recombinant chromosomes often derive from cross-over within the inversion loop during meiosis in known carriers of a pericentric inversion. The cross-over generally results in a single recombinant chromosome with partial duplication of one arm and partial deletion of the other. Proportionally longer inverted segments appear to be associated with a greater likelihood of cross-over; no recombinants have been reported to arise from pericentric inversions containing very short inverted segments. Partial trisomy 20p resulting from recombination of chromosome 20 is a very rare constitutional rearrangement. Previously described cases include three involving postnatal diagnosis and one involving prenatal diagnosis; in each, inheritance was via meiotic cross-over from a carrier of a pericentric inversion. We report a recombinant chromosome 20 resulting in partial 20p trisomy and partial 20q deletion in two siblings with mild congenital anomalies. The rearranged chromosome 20 was inherited from their father, who was mosaic for a pericentric inversion of chromosome 20.