Copy Number Variants – Benign or Pathogenic – a complex issue


Molecular cytogenetics offers the opportunity to recognize the smallest changes in the human karyotype. These methods show that the karyotype is not as stable as previously thought. Almost every person has small deletions or duplications, involving different areas of the genome. These small anomalies collectively are called copy number variants (CNV). These CNVs may involve one or several genes or may contain only gene-free areas of DNA. CNV may be sporadic or may be inherited. Currently all CNVs are divided into 3 groups:

  1. Benign CNV;
  2. CNVs of unknown (or uncertain) significance (VOUS);
  3. Pathogenic CNV.

Benign CNVs are mostly small (less than 0.2 Mb) deletions or small (less than 0.5 Mb) duplications, which do not include any genes or include genes, which do not cause any disorders. Most pathogenic CNVs are relatively large (more than 1 Mb) and include several genes. If any CNV is repeatedly found in association with a certain phenotype (for example, seizures or autism) such a CNV is considered as pathogenic. Deletions and duplications of chromosomes 15q13.3, 16p11.2, and 16p13.11 are examples of pathogenic CNV. VOUS are CNV, when it is not yet clear whether these variants are benign or may cause pathologic conditions. Further studies are necessary to reassign these CNV into “pathogenic” or “benign” classes.

In some families the same CNV which was found in a child with a clinical abnormality (for example, a heart defect or developmental delay) is found in one of his/her parents. Sometimes this parent is also affected (usually with milder clinical manifestations), but in most cases the carrier parent is absolutely healthy. It raises a question: how to explain that a child with a given CNV has some pathology, but his/her parent with the same CNV does not.

This explanation will be different for “benign” CNV and “pathogenic” CNVs. Benign CNVs are not related to any disorders. However, some authors just report all CNVs found in the specific group of patients (for example, patients with tetralogy of Fallot or cleft palate) but do not classify these CNVs into the sub-groups. The same situation may occur when a family considers a CNV found in a child as a cause of his/her disorder. Actually, however, if this CNV is benign it has no connection with child’s abnormality. It is evident that the same CNV may be found in a healthy parent. When a CNV is found in the examined child, all families have to ask whether this CNV is benign or pathogenic. If a CNV is benign we have to look for other explanations of the child’s disorder.

Explanations of the occurrence of a pathogenic CNV in a healthy parent are not so easy. To be honest, the nature of this phenomenon is not always clear. In most families, however, it is caused by participation of other genetic factors. The easiest example: assume that a healthy mother has a microdeletion of chromosome 16p13.11 involving the NDE1 gene, known to cause a severe autosomal-recessively inherited brain disorder. The non-deleted copy of this gene in this woman is normal. She transmits this deletion to her son. But if the healthy father of this child has a mutation in the same gene he can transmit the mutated copy to his son. In this case the child having a maternal CNV and a paternal mutated gene will develop an autosomal-recessive brain disorder. Several dozens of similar situations have been reported so far in the literature. But this explanation covers only a small fraction of cases where a healthy parent has the same CNV as his/her affected child. Another explanation presumes the influence of other genetic factors somehow controlling the expression of the pathogenic CNV. For example, small deletions 1q21.1 may produce a very serious condition – TAR syndrome (thrombocytopenia – absent radius) if the patient also inherits a small specific non-coding area of DNA. Sometimes regulatory genes may directly affect expression of the “critical” genes. And we cannot exclude the phenomenon of incomplete penetrance known in numerous dominant disorders, when a person having a mutant gene has no clinical manifestations. It is not clear yet whether some environmental factors may affect expression of CNVs.

CNV is a relatively new topic in human cytogenetics, and there are many white spots regarding the role of these microdeletions and microduplications in humans.

Is it reasonable to test small brothers and sisters of the child with pathogenic CNV if this CNV is inherited from the healthy parent? The results of the test will not change health of the child but (if the test is positive) may add a psychological burden. When the child reaches child-bearing age this testing may become more reasonable, especially if we know not only the possible clinical consequences of the given CNV, but also know the proportion of the affected persons among all carriers of the given CNV.

Dr. Iosif Lurie, Medical Geneticist, CDO Medical Consultant

Early Developmental Stage Correction of Chromosomal Abnormalities

A few weeks ago an article appeared online on with the title: Genetic Testing Sometimes Finds Chromosomal Abnormalities In Embryos, But They May Turn Normal Before Birth. This article as written appears to give a false impression that chromosome abnormalities diagnosed prenatally may correct themselves before birth.

Dr. Iosif Lurie, medical geneticist and CDO Medical Advisor offers his comments.

Recent data (especially after invention of molecular methods in cytogenetics) shows that at the early stages of development a cell may attempt to correct some cytogenetic anomalies. Trisomic cells may “evict” the additional chromosome, cells with a structural anomaly in one chromosome may use either the same “expulsion” tactics or another rescue mechanism involving many chromosomes (chromothripsis). However, these mechanisms may be successful only at the earliest stages (maybe in the first 1-2 weeks after fertilization), and definitely before any prenatal diagnosis. A fetus at 9-10 weeks already has the same chromosomal complement as he/she will have after birth.

Moreover, sometimes a cell having, for example, two identical maternal chromosomes and one paternal expels the paternal one. A chromosomally normal embryo (child) will result but with uniparental disomy. And if this chromosome has a recessive gene this gene will be homozygous in the child. I think that rare cases of UPD5, for example, are results of such rescues at the early stages of development.

After an unfavorable prenatal diagnosis should parents decide to terminate a pregnancy, most centers will confirm the prenatal diagnosis by pathologic and/or cytogenetic examination of the fetus. Should numerous cases of a chromosomally normal fetus being mistakenly aborted after an erroneous diagnosis of chromosomal pathology we would correspondingly expect to see an increase in “wrongful death” litigation. And we have not seen this.

This article gives a false impression that in many cases chromosomal abnormalities revealed by prenatal diagnosis may be restored by themselves. This underscores the importance of always checking with your personal healthcare provider about any information you locate online or elsewhere, it may not always be complete or accurate.

Dr. Iosif Lurie, Medical Geneticist
Linda Sorg, CDO President