Are Rare Chromosome Disorders Really All That Rare


Chromosome disorders: 2014 outlook

The whole concept of chromosomal disorders has drastically changed in the last several years. Traditionally, the examination of chromosomes under the microscope was the main (or even the only) way of diagnosing chromosomal pathology. However, even in optimal variants visual examination allows recognition of deletions or duplications not less than 5 Mb. Actually, the vast majority of patients recognized as having chromosomal anomalies had an excess of deficit of very large segments of DNA (at least 10-15 Mb). Of course, such large segments contain dozen of genes – including genes involved in mental development and numerous morphogenetic processes. Virtually all persons with unbalanced chromosomal abnormalities recognized by a “standard” cytogenetics had delayed psycho-motor development, facial dysmorphism and (in many cases) defects of the brain, eyes, heart and other organs. As a result, chromosomal disorders were considered conditions involving (as mandatory traits) dysmorphic features and delay in psycho-motor development.

Methods of molecular cytogenetics which have become a common practice over the last few years allow recognition of even the smallest imbalances. As a result it has been found that a large number of patients previously reported as having a normal karyotype, actually have small deletions or duplications. Contemporary data shows that ~25% of persons with facial dysmorphism and a various degree of psycho-motor delay have deletions or duplications of chromosomal material. Only one third of these abnormalities could have been diagnosed by “standard” cytogenetic examination.

It has been shown that several syndromes of “unknown” etiology actually are caused by small chromosomal imbalances (Williams syndrome is caused by 1.5-2 Mb deletion of 7q11.23, TAR syndrome is caused by proximal del 1q21.1). Many other syndromes can be considered as etiologically heterogeneous: in some cases these conditions are caused by a mutation of one gene, in other cases by microdeletions involving the causative genes. It may be true for Sotos syndrome, where many patients have del 5q35, for Rokitansky-Küster syndrome in patients with del 17q12, etc. Numerous new syndromes caused by chromosomal microdeletions or microduplications have been delineated over the last 4-5 years (del 1p34, del 2p15p16, del 17q21.31, etc.). These new syndromes involve all chromosomes and almost all segments of DNA. In all these conditions there are no doubts about the pathological role of the given deletion or duplication.

Molecular cytogenetics has shown that above evidently pathological microdeletions and microduplications there are 3 other classes of microanomalies: a) “presumably pathogenic” copy number variants (CNV); b) benign CNV, and c) variants of unknown significance (VOUS).

Examination of a large group of persons has shown that several forms of microdeletions and microduplications (del/dup 15q11, del/dup 15q13, del/dup 16p11, del 16p13) are relatively common and may be found even in healthy persons. However among patients with clinical abnormalities which do not seem to be characteristic for traditional “chromosomal disorders” (e.g., in patients with autism or epilepsy) these CNV have been discovered much more commonly (sometimes 10 times more commonly) than in general population. There is doubt that these variants strongly predispose to some forms of pathology although the mechanisms of the realization of these effects are not fully explained.

Special examinations has shown that up to 8% of patients with epilepsy, 6% persons with autism and 2-3% of persons with schizophrenia may have copy number variants as causative factors of afore-mentioned conditions. Epilepsy, autism and schizophrenia are very common disorders. Even if only 2-3% of the patients with these conditions are caused by chromosomal rearrangements it will considerably increase the general pool of persons with rare chromosomal disorders.

An increased frequency of copy number variants was found among persons with different forms of heart defects (tetralogy of Fallot, stenosis of pulmonary artery), among patients with cryptogenic cerebral palsy (cerebral palsy without evident acquired cause) and even among obese persons. All these facts lead to significant expansion of the general pool of “rare chromosomal anomalies”. Of course, these calculations include only definitely pathogenic or presumably pathogenic CNV. And neither developmental delay nor dysmorphism seem to be mandatory for disorders caused by excess or deficiency of chromosomal material.

If any given variant occurs in affected and healthy persons with the same frequency this variant should be considered as benign.

The largest problem is variants of unknown significance (VOUS) when (at least currently) it is not possible to determine significance of the found variant. Several factors should be considered upon analysis of each such variant.

  •   Character of the lost (or added) genes. If the list of abnormal genes includes genes known to be related to human disorders, the variant is likely pathologic. If the given variant does not involve any genes, it almost certainly has to be considered as benign.
  •   Type of variant – a deletion of the same size is ~ twice more likely to be pathologic than a duplication of the same size.
  •   Size of deletion (or duplication) – basically the larger size presumes involvement of a larger number of genes.
  •   Inheritance of the variant: the variants inherited from healthy parents are most likely benign variants, whereas sporadic deletions (or duplications) are more likely to be pathologic.

    Although the list of VOUS is shrinking (some variants became considered as benign and vice versa), the large number of VOUS remains a significant obstacle in interpretation of data obtained by molecular cytogenetics.


Dr. Iosif Lurie, Medical Geneticist, CDO Consulting Medical Advisor