Prenatal cytogenetic assessment and inv(2)(p11.2q13).

OBJECTIVES: To present a series of prenatally detected cases of recurrent pericentric inversions with euchromatic breakpoints and to review the literature to determine whether parental karyotyping is required for genetic counselling. METHODS: Cases of recurrent pericentric inversions with euchromatic breakpoints were collected from Canadian Cytogenetic Laboratories. Cases included inversions for chromosome 1(p13q21), chromosome 2(p11.2q13), chromosome 5(p13q13) and chromosome 10(p11.2q21.2). RESULTS: The incidence of de novo inv(2)(p11.2q13) was low, with one case among 91 inversions. There were no cases of de novo inv(10) (p11.2q21.2) among 17 reported and one case of de novo inv(5)(p13q13) among 21 reported. CONCLUSION: Our study, and data from the literature, suggests that most cases of inv(2)(p11.2q13) have been stably inherited, that de novo cases of inv(2) are rare and that both inherited and de novo forms are without phenotypic or developmental consequences. We suggest that parental karyotyping for cases of inv(2) is not useful in counselling as it may generate unnecessary parental anxiety over a chromosomal finding that is likely innocuous.

Complete DiGeorge anomaly in the absence of neonatal hypocalcemia and velofacial and cardiac defects.

We report an atypical case of complete DiGeorge (DG) anomaly that presented initially exclusively as severe combined immunodeficiency (SCID). The child had severe infections at diagnosis, in keeping with the SCID phenotype; however, normal lymphocyte counts and immunoglobulin levels were noted at admission, which delayed diagnosis. Importantly, the child presented without neonatal hypocalcemia or velofacial or cardiac abnormalities at the time of diagnosis, which masked underlying DG. This case outlines the difficulties in making the diagnosis of SCID in a timely manner and illustrates the variation in presentation of the 22q11.2 deletion syndrome. There should be a high index of suspicion for primary immunodeficiency among children with severe infections and, because management may vary, DG anomaly should be considered in the differential diagnosis of T- B+ natural killer+ SCID.

A fragile site at 10q23 (FRA10A) in a phenytoin-exposed fetus: a case report and review of the literature.

OBJECTIVE: To report fragility at 10q23.3 in a fetus exposed to phenytoin during pregnancy. Review of the literature. METHODS: Amniocytes were cultured in A10 (WISENT) culture medium. Molecular polymorphism studies of MTHFR gene using PCR were performed on fetal tissues. RESULTS: The fragile site was expressed in all 22 amniocyte colonies analyzed. Analysis of fetal blood showed 46,XX[98]/46,XX,fra(10)(q23.3)[3]/46,XX,del(10)(q23.3) [1]. Molecular studies of the MTHFR (methylenetetrahydrofolate reductase) gene identified a compound heterozygote genotype for two polymorphisms, 677C>T and 1298A>C. CONCLUSION: The fragility at 10q23.3 is unlikely to be due to culture condition-induced folic acid deficiency (medium contains folate). It is possible that this finding represents a previously undescribed folic acid-insensitive fragile site in the region of 10q23.3. Alternatively, the fetal cells may have had decreased folate metabolism, and the fragile site was the known folate-sensitive FRA10A. Since phenytoin has been shown to decrease MTHFR activity in mice, we postulate that the fragile site at 10q23.3 in this fetus may have arisen secondary to a combination of the polymorphisms in MTHFR and exposure to this drug, and is indeed FRA10A.

Lissencephaly with der(17)t(17;20)(p13.3;p12.2)mat.

The isolated lissencephaly sequence may be caused by point mutations of the LIS1 gene or by FISH-detectable microdeletions of the 17p13.3 region, which carries the LIS1 gene. These have various patterns of phenotypic presentations, including the Miller-Dieker syndrome (MDS). Approximately 20% of these deletions are associated with a derivative chromosome 17 inherited from a parent who has a balanced reciprocal translocation involving chromosome 17 and another chromosome. We report a case of lissencephaly associated with a maternally inherited unbalanced translocation involving chromosome arms 17p and 20p. This results in partial monosomy of 17p13.3-->pter and partial trisomy of 20p12.2-->pter. To our knowledge, this is the first report of a reciprocal translocation between 17p and 20p. Our patient has a combination of findings of the MDS and trisomy 20p, along with several unique anomalies not described in either of those two conditions. This report may contribute to the delineation of a phenotype resulting from partial monosomy 17p and partial trisomy of 20p.

Regulation of cisplatin resistance and homologous recombinational repair by the TFIIH subunit XPD.

We have recently completed screening of the National Cancer Institute human tumor cell line panel and demonstrated that among four nucleotide excision repair proteins (XPA, XPB, XPD, and ERCC1), only the TFIIH subunit XPD endogenous protein levels correlate with alkylating agent drug resistance. In the present study, we extended this work by investigating the biological consequences of XPD overexpression in the human glioma cell line SK-MG-4. Our results indicate that XPD overexpression in SK-MG-4 cells leads to cisplatin resistance without affecting the nucleotide excision repair activity or UV light sensitivity of the cell. In contrast, in SK-MG-4 cells treated with cisplatin, XPD overexpression leads to increased Rad51-related homologous recombinational repair, increased sister chromatid exchanges, and accelerated interstrand cross-link removal. Moreover, we present biochemical evidence of an XPD-Rad51 protein interaction, which is modulated by DNA damage. To our knowledge, this is the first description of functional cross-talk between XPD and Rad51, which leads to bifunctional alkylating agent drug resistance and accelerated removal of interstrand cross-links.