Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements.

Interpretation of variants of uncertain significance, especially chromosomal rearrangements in non-coding regions of the human genome, remains one of the biggest challenges in modern molecular diagnosis. To improve our understanding and interpretation of such variants, we used high-resolution three-dimensional chromosomal structural data and transcriptional regulatory information to predict position effects and their association with pathogenic phenotypes in 17 subjects with apparently balanced chromosomal abnormalities. We found that the rearrangements predict disruption of long-range chromatin interactions between several enhancers and genes whose annotated clinical features are strongly associated with the subjects' phenotypes. We confirm gene-expression changes for a couple of candidate genes to exemplify the utility of our analysis of position effect. These results highlight the important interplay between chromosomal structure and disease and demonstrate the need to utilize chromatin conformational data for the prediction of position effects in the clinical interpretation of non-coding chromosomal rearrangements.

Vitamin B12 Deficiency in Infancy: The Case for Screening.

The classic principles put forth by Wilson and Jungner are often applied to determine the suitability of a condition for universal newborn screening. The three cases described here portray the harmful effects of vitamin B12 deficiency in infancy. The challenges and opportunities of early recognition and treatment are highlighted. Screening newborns would allow early detection and prevention of severe neurological damage in vitamin B12 -deficient infants and enable diagnosis of unrecognized maternal pernicious anemia in asymptomatic mothers. However, lack of standardized methodology and screening cutoffs present challenges to the use of current tandem mass spectrometry technologies for screening.

Suitability of rapid aneuploidy detection for prenatal diagnosis.

OBJECTIVE: To determine the suitability of replacing full karyotype analysis with molecular genetic rapid aneuploidy detection (RAD) methods, in particular quantitative fluorescence polymerase chain reaction (QF-PCR), for prenatal diagnosis in amniotic fluid samples obtained by amniocentesis. METHODS: We reviewed all fetal karyotypes done at our centre between August 29, 2000, and February 28, 2006. Outcome measures included (1) the proportion of prenatal samples with abnormal karyotypes that would not have been detected by RAD, as a whole and for each indication, and (2) pregnancy outcome for each chromosome abnormality that was predicted to be clinically significant or of uncertain significance and would not have been detected by RAD. RESULTS: Of the 6411 karyotypes reported in the study period, 70 (1.09%) were abnormal karyotypes which would not have been detected by RAD alone. These included 32 cases (0.50%) predicted to confer no increased risk to the fetus, 17 (0.27%) predicted to have a low risk of fetal abnormality, and 21 (0.33%) with an uncertain or high risk of fetal abnormality. If full karyotype was added for nuchal translucency greater than 3.5 mm, structural fetal abnormality on ultrasound, or parental balanced chromosome rearrangement, only five uncertain or high risk cases (0.08%) would not have been detected by RAD alone. CONCLUSION: These results suggest that if the policy of offering full karyotype analysis to all women were to be changed to a policy of offering RAD alone to women without other risk factors such as fetal abnormalities on ultrasound, increased nuchal translucency, or history of chromosome abnormality, this would mean that a chromosome abnormality with a substantial risk of clinically significant fetal abnormality would be missed in fewer than 1/1000 amniocenteses. Our results are similar to others previously reported.