Prenatal Counseling

Into the clinical realm

Specialized “targeted” arrays can be applied to clinical work in several ways, including:

And consider what is anticipated: highly dense arrays that are capable of assessing single nucleotide alterations, making it possible to detect single-gene mutations.

Because array-CGH technology utilizes DNA and does not require cell culture, the time to results is significantly shorter. Furthermore, many aspects of the assessment are automated, providing both high resolution and rapid processing and reporting.

Array CGH uncovers genomic problems in the young

Causes of mental retardation, developmental deficits, congenital anomalies, and more are localized

Miyake N, Shimaokawa O, Harada N, et al. BAC array CGH genomic aberrations in idiopathic mental retardation. Am J Med Genet. 2006;140A:205–211.

Ming J, Geiger E, James A, et al. Rapid detection of submicroscopic chromosomal rearrangements in children with multiple congenital anomalies using high density oligonucleotide arrays. Hum Mutat. 2006;27:467–473.

Early use of array CGH in the study of solid tumors was followed closely by its clinical application to children with mental retardation or developmental deficits, with or without birth defects. Historically, suspicion of a duplication or deletion syndrome despite a normal chromosome analysis in these children could prompt specific testing for that disorder. More often, however, it was impossible to delineate a specific syndrome, and disorder-by-disorder testing was not feasible. Today, estimates are that submicroscopic duplications and deletions on chromosomes, detected primarily by array CGH, occur in 1 of every 1, 000 births.

Initial work in the pediatric population by Vissers, in 2003, and Shaw-Smith, in 2004, showed that, with array CGH at a resolution of 1 Mb, 14% to 20% of children who were mentally retarded had duplications or deletions that could not be detected by routine karyotype analysis. Further detail on this approach, using an array with 1.4-Mb coverage, appears in the article by Miyake and co-workers. Among 30 children with idiopathic mental retardation and dysmorphic features, 17% (5 of 30) had submicroscopic deletions or duplications by array CGH. The imbalances ranged from 0.7 Mb to 1.0 Mb and spanned numerous and various chromosomes. The investigators emphasized the need to:

Numerous “copy number polymorphisms” have been uncovered—do they always matter?

Work with array CGH among the pediatric population was expanded by Ming and colleagues, who obtained greater resolution and coverage of the genome by utilizing a 2nd-generation array of oligonucleotides with >100,000 single-nucleotide polymorphisms. With this array, intermarker distance is estimated at 25 Kb—a resolution at which very small genomic imbalances can be identified. Of 10 children evaluated using this greater-density array, 2 (20%) had a previously unidentified genomic imbalance—both deletions.

Ming also put forward concerns that more non–disease-causing “copy number polymorphisms” (CNPs) will be uncovered as higher-density arrays increase the resolution of array CGH. These polymorphisms are encountered in healthy persons and are considered clinically insignificant. Consequently, when a copy number imbalance is detected by array, several actions are warranted: comparison with normal controls, evaluation of published CNP databases, and—most important—array CGH analysis of both parents’ DNA.

Such an approach adds to the labor-intensity of array CGH, but is necessary to ensure that imbalances that are clinically relevant and causative are distinguished from normal variants. With more than 250 discrete CNPs reported in normal controls, the use of denser arrays will uncover more CNPs than arrays targeted to significant fetal and pediatric disorders. Applying array CGH to clinical practice will entail (1) ongoing assessment of the technology and the results it provides and (2) perhaps, targeting of arrays to particular populations—the goal being to balance the yield of useful information against the increase in reported CNPs.

Where is the potential of array CGH in prenatal diagnosis?

Le Caignec C, Boceno M, Saugier-Veber P, et al. Detection of genomic imbalances by array based comparative genomic hybridization in fetuses with multiple malformations. J Med Genet. 2005;42:121–128.

Rickman L, Fiegler H, Shaw-Smith C, et al. Prenatal detection of unbalanced chromosomal rearrangements by array CGH. J Med Genet. 2006;43:353–361.

Sahoo T, Cheung S, Ward P, et al. Prenatal diagnosis of chromosomal abnormalities using array-based comparative genomic hybridization. Genet Med. 2006;8:719–727.

Prenatal diagnosis can be enhanced by array CGH

If ongoing research on array CGH can accomplish any of the following goals, it is likely that the technology will be propelled into clinical use as part of prenatal counseling within the next 5 years:

Le Caignec and colleagues’ work on applying array CGH to DNA specimens from fetuses that had multiple malformations—but in whom cytogenetic study was normal—have provided a foundation for subsequent prenatal studies. Using an array that targeted subtelomeres and specific DNA loci that are important in cytogenetic deletion–duplication syndromes, Le Caignec found that 5 of 49 (10.2%) fetuses studied had clinically significant genomic imbalances. These included: